Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

Article abstract of DOI:10.3762/bjoc.13.3

The mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins was investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under drygrinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures.

Full text of DOI:10.3762/bjoc.13.3

Poly(ethylene glycol)s as grinding additives in the
mechanochemical preparation of highly functionalized
3,5-disubstituted hydantoins
Andrea Mascitti‡1,2, Massimiliano Lupacchini‡1,2, Ruben Guerra2, Ilya Taydakov3,4,
Lucia Tonucci5, Nicola d’Alessandro1, Frederic Lamaty2, Jean Martinez2
and Evelina Colacino*2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 19–25.
1Department of Engineering and Geology (INGEO), G.d’Annunzio
University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti Scalo,
Italy, 2Université de Montpellier, Institut des Biomolécules Max
Mousseron (IBMM), UMR 5247 CNRS - UM - ENSCM, Place E.
Bataillon, Campus Triolet, 34095 Montpellier CEDEX 5, France, 3P.N.
Lebedev Institute of Physics of RAS, Leninskiy pr-t, 53, 119991,
Moscow, Russia, 4Moscow Institute of Physics and Technology,
Institutskiy per., 9, 141700, Dolgoprudny, Russia and 5Department of
Philosophical, Educational and Economic Sciences, G. d’Annunzio
University of Chieti-Pescara, Via dei Vestini, 31, 66100 Chieti Scalo,
Italy
doi:10.3762/bjoc.13.3
Received: 01 October 2016
Accepted: 12 December 2016
Published: 04 January 2017
This article is part of the Thematic Series "Green chemistry".
Guest Editor: L. Vaccaro
© 2017 Mascitti et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Evelina Colacino* - evelina.colacino@umontpellier.fr
* Corresponding author ‡ Equal contributors
Keywords:
ball-milling; 1,1’-carbonyldiimidazole (CDI); hydantoins;
mechanochemistry; liquid-assisted grinding (LAG); poly(ethylene)
glycols (PEGs)
Abstract
The mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins was investigated in the presence of various
poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-
grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG
grinding agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures.
Introduction
Poly(ethylene) glycols (PEGs) are eco-friendly solvents [1,2], media [1] are safe reaction environments, efficiently heated by
finding applications in the biomedical field and for pharmaceu- microwaves [5], but their use in organic transformations acti-
tical formulations [3] and catalysis [4]. PEG-based reaction vated by other alternative energy inputs is still scarce. Only
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Beilstein J. Org. Chem. 2017, 13, 19–25.
three examples highlight their peculiar role for metal-catalysed Results and Discussion
processes in a ball mill (Mirozoki–Heck reaction) [6], by ultra- H-Leu-OMe was used as benchmark for the mechanochemical
sound (copper-catalysed cyanation reaction) [7], and for preparation of 3-ethyl-5-isobutylhydantoin (2a) (R1 =
co-crystal formation in the polymer-assisted grinding process CH2CH(CH3)2 and R2 = CH2CH3, Scheme 1) [9]. The reaction
(POLAG) [8]. However, to the best of our knowledge, the was screened in the presence of various PEG additives
systematic investigation of the influence of PEG polymers has (Table 1), by adding variable amounts of PEGs, with different
not been reported yet for organic syntheses promoted by me- molecular weights (600 < Mw < 5000 Dalton) or chain end
chanical energy.
groups (dihydroxy, mono- or dimethyl ether substituents) in the
second step (Table 1). The first set of experiments was aimed to
We firstly reported the positive influence of PEG solvents as determine if the addition of variable amounts of solid MeO-
grinding agents for the mechanochemical preparation of an PEG-2000-OMe (Table 1, entries 2–5) or HO-PEG-3400-OH
active pharmaceutical ingredient (API), the anticonvulsant drug (Table 1, entries 7–10) could impact both the reaction yield and
ethotoin 7 [9] (marketed as Peganone®, Scheme 1). We rate, compared to dry-grinding conditions previously reported
describe herein the impact of the addition of variable amounts [9] (Table 1, entry 1). Yields were generally improved in the
of PEG, PEG chain length and end terminal groups, for the presence of variable amounts of PEGs (Table 1, entries 2, 3 and
preparation of diverse 3,5-disubstituted hydantoins from 7, 8), starting to decrease when reaching a critical value at
α-amino methyl esters 1, via an in situ intramolecular cycliza- 675 mg (Table 1, entries 5 and 10). The substrate conversion
tion reaction of the ureido derivative B, which was obtained remained moderate, the cyclization reaction of the correspond-
from N-carbamoylimidazole activated amino ester derivative A ing ureido derivative B-Leu was slowed down and the methyl
by reaction with various amines [9-11] (Scheme 1). Hanusa’s ester moiety was partially hydrolysed. Indeed, the base activity
formalism was used to represent the reaction activated by was increased due to the presence of water in PEG as well as by
mechanochemical energy [12].
the PEG crown-ether-like effect [1], chelating the potassium
cations.
The yields, reaction rates and chemoselectivity obtained in the
presence of melted PEGs were compared with the results ob- It is worth noticing here that the crude mixture was cleaner in
tained in dry-grinding conditions. comparison with dry-grinding conditions. Indeed, the symmetri-
Scheme 1: PEG-assisted grinding strategy for the preparation of 3,5-disubstituted hydantoins.
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Beilstein J. Org. Chem. 2017, 13, 19–25.
Table 1: Screening of grinding additives using (L)-H-Leu-OMe.HCl as benchmark for the preparation of compound 2a.a
Entry
Grinding additive
Amount (mg)
Yield (%)b
1 [9]
2
–
–
61
MeO-PEG-2000-OMe
225
450
450c,d
675
450
225
450
450c,d
675
450
450
450
450
70
3 [9]
4c,d
5
70
71c,d
29e
68
6
MeO-PEG-2000-OH
HO-PEG-3400-OH
7
77
8
73
9c,d
10
11
12
13
14
73c,d
66e
57
HO-PEG-5000-OH
HO-PEG-1000-OH
HO-PEG-600-OH
Glycerol
66
56
58
aConditions: (step 1) (L)-H-Leu-OMe.HCl (1 mmol) and CDI (1.3 equiv.) at 450 rpm, in a planetary ball mill (PBM) using a 12 mL SS jar with 50 balls
(SS = stainless steel, 5 mm Ø) for 40 min; (step 2) EtNH2.HCl (1.6 equiv), K2CO3 (3.6 equiv) and the grinding additive RO-PEGn-OR (R = H, Me, n =
14, 23, 46, 77, 114) or glycerol (450 mg mmol−1) (see Supporting Information File 1 for experimental details); bIsolated yields; cThe reaction time in
the second step was 3 h; dPEG was precipitated in diethyl ether, then filtered and dried in the air before use [16]; e1H NMR yield.
cal urea of the starting amino ester – obtained from the corre- chain length. After selecting the optimal polymer amount
sponding N-carbamoyl imidazole amino ester A – was not ob- (450 mg mmol−1), the study was carried on by increasing
served, as shown by the LC–MS analyses of the crude mixture. (Table 1, entry 11) or reducing (Table 1, entries 12 and 13)
An approach complementing similar strategies was already de- the polymer chain length, changing the end terminal substitu-
scribed to avoid the formation of symmetrical ureas in solution ents (Table 1, entries 6 vs 3), and adding glycerol instead of
[13].
PEGs as additive (Table 1, entry 14). As a result, the effect of
using different end terminal groups was not markedly signifi-
The preparation of the hydantoin 2a was also investigated using cant, the yield was a function of the average molecular weight
batches of solid PEGs (Mw = 2000 and 3400) in which PEGs of the PEG used: HO-PEG-5000-OH (Table 1, entry 11) was
with lower molecular weight (Mw = 200–400) were eliminated probably too viscous to allow the diffusion of reactants. De-
before use by a precipitation/filtration procedure (Table 1, creased and comparable yields were also observed by reducing
entries 4 and 9), according to a well-established protocol [14- the PEG chain length (Table 1, entry 13) and by using glycerol.
16]. Even when the PEG polymers were supposed to be homo- It is also worth noting here that not only viscosity, but any mod-
geneously liquids (melting point around 55 °C) at the opera- ification of the physical state of the system impacted the
tional temperature, comparable yields could be obtained only by outcome of the reaction. Indeed, HO-PEG-600-OH (0.119 cSt)
extending the reaction time (3 h instead of 2 h), when ‘pre- led to comparable yields when replaced by a more viscous
treated’ PEGs were used instead of ‘unfiltered’ PEGs (Table 1, liquid like glycerol (1.12 cSt) (Table 1, entry 14), an eco-
entries 3 and 8).
friendly solvent still not investigated for liquid-assisted grinding
procedures. In fact such a compound is becoming a green
This observation suggested that changes in the ‘physical state of source of several building blocks since glycerol is actually pro-
the system could be induced by specific interactions with PEG duced in very large amount as byproduct from biodiesel synthe-
polymers and influenced both by the viscosity and the polymer sis [17].
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Beilstein J. Org. Chem. 2017, 13, 19–25.
With this background, 3-ethyl-5-benzylhydantoin (3a) [9] 4 (Table 3, entries 1, 4, and 7, respectively) and 5a (R2 = ethyl,
(R1 = CH2Ph and R2 = CH2CH3) was also prepared using solid Table 3, entry 8) or 2b and 6 (R2 = allyl , Table 3, entries 2 and
MeO-PEG-2000-OMe and HO-PEG-3400-OH as additives 12). However, the PEG influence on the reaction yield could not
(Table 2). Using (L)-H-Phe-OMe.HCl as substrate, as a general be excluded. The mechanochemical productivity was slightly
trend and in comparison with the dry-grinding procedure previ- improved when PEG polymers were used compared to dry-
ously reported [9] (Table 2, entry 1), yields were generally grinding conditions, as demonstrated for the synthesis of hydan-
lower with PEG additives, independently on their size and toins 2a–c (Table 3, entries 1–3), 5a (Table 3, entry 8) and 6
amounts (Table 2). This trend, apparently in contrast with the (Table 3, entry 12), with the exception of hydantoins 3a
results illustrated so far for 3-ethyl-5-isobutylhydantoin (2a) [9] (Table 3, entry 4) and 5b (Table 3, entry 9). Moreover, the prep-
suggested that the reactivity of the system might be also a func- aration of hydantoins 3b and 3c (Table 3, entries 5 and 6) in the
tion of the nature of the amino ester side chain, influencing the presence of PEG led to incomplete conversion of starting mate-
solubility of the reactants, reaction intermediates and final prod- rials, together with the formation of various unknown byprod-
ucts. However, no differences in yields were observed when ucts. A possible explanation can be related to the solubility of
(D)-H-Phe-OMe was used, instead of its enantiomer (Table 2, reactants, reaction intermediates and final products in PEG
entry 3).
polymers, although the existence of specific interactions with
PEG polymers cannot be excluded. Indeed, especially under
Therefore, the one-pot two-steps cyclization reaction was inves- mechanical stress, PEGs are known to induce changes in the
tigated with different amino ester/amine combinations (H-AA- physical state of the system [8].
OMe/R2-NH2) and comparative experiments using dry- or wet-
grinding with PEGs (Mw = 2000 and 3400, 450 mg mmol−1) These results confirmed the role played by polymers in
were also performed (Table 3).
mechanochemical transformations, also leading to cleaner reac-
tion profiles. However, the choice of the suitable polymer for a
Indeed, compounds with the same N-R2 substituent led to vari- specific transformation was not trivial: the ‘fine tuning’ of the
able yields for different amino esters (R1, Scheme 1 and physical state of the system was also related to specific physi-
Table 3), as shown for experiments performed in both dry- cal aspects also connected to the intrinsic properties of the
grinding conditions in the series 3b and 5b (R2 = 1-[4-(4- polymer. In addition, PEG polymers were demonstrated as a
methyl-1H-pyrazol-1-yl)phenyl]methyl, Table 3, entries 5 and valid eco-friendly and safe alternative to classic solvents used in
9), 3c and 5c (R2 = furan-1-ylmethyl, Table 3, entries 6 and 10), liquid-assisted-grinding procedures (LAG) [18-22] due to their
and wet-grinding experiments with PEGs, for the series 2a, 3a, low melting point (45–60 °C), enabling their use as melt during
Table 2: Optimization of liquid-assisted grinding conditions using (L)-H-Phe-OMe.HCl as benchmark for the preparation of compound 3a.a
Entry
Grinding additive
Amount (mg)
Yield (%)b [9]
1 [9]
2
–
–
84
MeO-PEG-2000-OMe
225
450
225
450
675
59
3c
4
70 (68)c
58
HO-PEG-3400-OH
5
60
6
62
aConditions: (step 1) (L)-H-Phe-OMe.HCl (1 mmol) and CDI (1.3 equiv) at 450 rpm, in a planetary ball-mill (PBM) using a 12 mL SS jar with 50 balls
(SS = stainless steel, 5 mm Ø) for 40 min; (step 2) EtNH2.HCl (1.6 equiv), K2CO3 (3.6 equiv) and RO-PEGn-OR (R = H, Me, n = 46, 77) (see Support-
ing Information File 1 for experimental details); bisolated yields; cD-H-Phe-OMe was used.
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Beilstein J. Org. Chem. 2017, 13, 19–25.
Table 3: Syntheses of 3,5-disubstituted hydantoins under dry-grinding (conditions A)a or PEG-assisted grinding (conditions B and C).b
Entry
H-AA-OMe
Yields (%)b vs conditionsa
Product
A
B
C
1
2
H-Leu-OMe
61 [9]
70
73
2a [9]
2b [9]
57 [9]
38 [9]
84 [9]
69
n.p.d
70
66c
48c
60
3
4
2c [9]
3a [9]
H-Phe-OMe
5
30
n.d.e
n.d.e
3b
6
70
n.d.e
n.d.e
3c
7
8
H-Ser(Ot-Bu)-OMe
H-Lys(Z)-OMe
51 [9]
31 [9]
70
70
4
47c
50c
5a [9]
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Beilstein J. Org. Chem. 2017, 13, 19–25.
Table 3: Syntheses of 3,5-disubstituted hydantoins under dry-grinding (conditions A)a or PEG-assisted grinding (conditions B and C).b (continued)
9
62
n.p.d
37c
5b
5c
10
37
n.p.d
n.p.d
11
12
47
n.p.d
n.p.d
5d
H-Aib-OMe
46 [9]
62
62
6 [9]
aConditions: (step 1) (L)-α-amino ester hydrochloride (1 equiv) and CDI (1.3 equiv) at 450 rpm, in a 12 mL inox jar with 50 balls (stainless steel, 5 mm
Ø) for 40 min; (step 2) R2NH2 (1.6 equiv) and K2CO3 (3.6 equiv) at 450 rpm for 2 hours. A: the reaction was performed with no additive (dry-grinding);
B: MeO-PEG-2000-OMe (450 mg mmol−1); C: HO-PEG-3400-OH (450 mg mmol−1) were added in the second step (wet-grinding conditions with a
PEG additive; bisolated yields; c1H NMR yield on the crude reaction mixture; dthe reaction was not performed (n.p.); ethe reaction yield was not deter-
mined (n.d.).
References
1. Chen, J.; Spear, S. K.; Huddleston, J. G.; Rogers, R. D. Green Chem.
grinding, low toxicity and low vapour pressure, reducing the
risk of explosions or overpressure that might be encountered on
2005, 7, 64–82. doi:10.1039/b413546f
large scale LAG-procedures.
2. Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.;
Abou-Shehada, S.; Dunn, P. J. Green Chem. 2016, 18, 288–296.
doi:10.1039/C5GC01008J
Supporting Information
3. Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U. S.
Angew. Chem., Int. Ed. 2010, 49, 6288–6308.
Supporting Information File 1
Experimental procedures, characterization of new
doi:10.1002/anie.200902672
4. Colacino, E.; Martinez, J.; Lamaty, F.; Patrikeeva, L. S.;
compounds and copies of 1H and 13C NMR spectra.
Khemchyan, L. L.; Ananikov, V. P.; Beletskaya, I. P.
[http://www.beilstein-journals.org/bjoc/content/
Coord. Chem. Rev. 2012, 256, 2893–2920.
supplementary/1860-5397-13-3-S1.pdf]
doi:10.1016/j.ccr.2012.05.027
5. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
doi:10.1002/anie.200400655
6. Declerck, V.; Colacino, E.; Bantreil, X.; Martinez, J.; Lamaty, F.
Chem. Commun. 2012, 48, 11778–11780. doi:10.1039/c2cc36286d
7. Giachi, G.; Frediani, M.; Oberhauser, W.; Lamaty, F.; Martinez, J.;
Colacino, E. ChemSusChem 2014, 7, 919–924.
doi:10.1002/cssc.201300997
Acknowledgements
The authors acknowledge the MIUR for the grants to A.M. and
M.L. (Fondo Sostegno Giovani – FSG – 2012 and 2013). I.T. is
grateful to Russian Scientific Foundation (grant 15-19-00205)
for partial financial support of this work.
24

Beilstein J. Org. Chem. 2017, 13, 19–25.
8. Hasa, D.; Schneider Rauber, G.; Voinovich, D.; Jones, W.
Angew. Chem., Int. Ed. 2015, 54, 7371–7375.
doi:10.1002/anie.201501638
9. Konnert, L.; Dimassi, M.; Gonnet, L.; Lamaty, F.; Martinez, J.;
Colacino, E. RSC Adv. 2016, 6, 36978–36986.
doi:10.1039/C6RA03222B
10.Konnert, L.; Gonnet, L.; Halasz, I.; Suppo, J.-S.;
Marcia de Figueiredo, R.; Campagne, J.-M.; Lamaty, F.; Martinez, J.;
Colacino, E. J. Org. Chem. 2016, 81, 9802–9809.
doi:10.1021/acs.joc.6b01832
11.Konnert, L.; Gonnet, L.; Halasz, I.; Suppo, J. S.;
Marcia de Figueiredo, R.; Campagne, J.-M.; Lamaty, F.; Martinez, J.;
Colacino, E. J. Org. Chem. 2016, 81, 12071.
doi:10.1021/acs.joc.6b02671
12.Rightmire, N. R.; Hanusa, T. P. Dalton Trans. 2016, 45, 2352–2362.
doi:10.1039/C5DT03866A
The formalism for mechanochemically activated reactions was recently
proposed by this group.
13.Duspara, P. A.; Islam, M. S.; Lough, A. J.; Batey, R. A. J. Org. Chem.
2012, 77, 10362–10368. doi:10.1021/jo302084a
14.Colacino, E.; Daïch, L.; Martinez, J.; Lamaty, F. Synlett 2007,
1279–1283. doi:10.1055/s-2007-980337
15.Colacino, E.; Villebrun, L.; Martinez, J.; Lamaty, F. Tetrahedron 2010,
66, 3730–3735. doi:10.1016/j.tet.2010.03.065
16.Bailey, F. E. J.; Koleske, J. V. Poly(Ethylene Oxide); Academic Press:
New York, 1976.
17.Canale, V.; Tonucci, L.; Bressan, M.; d'Alessandro, N.
Catal. Sci. Technol. 2014, 4, 3697–3704. doi:10.1039/C4CY00631C
18.Friščić, T. J. Mater. Chem. 2010, 20, 7599–7605.
doi:10.1039/c0jm00872a
19.Friščić, T. Chem. Soc. Rev. 2012, 41, 3493–3510.
doi:10.1039/c2cs15332g
20.Shimono, K.; Kadota, K.; Tozuka, Y.; Shimosaka, A.; Shirakawa, Y.;
Hidaka, J. Eur. J. Pharm. Sci. 2015, 76, 217–224.
doi:10.1016/j.ejps.2015.05.017
21.Juribašić, M.; Halasz, I.; Babić, D.; Cinčić, D.; Plavec, J.; Ćurić, M.
Organometallics 2014, 33, 1227–1234. doi:10.1021/om500008v
22.Chen, L.; Regan, M.; Mack, J. ACS Catal. 2016, 6, 868–872.
doi:10.1021/acscatal.5b02001
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