Microwave-mediated solventless synthesis of new derivatives of marine alkaloid Leucettamine B

Article abstract of DOI:10.1016/S0040-4039(02)00575-0

New access to N-alkyl derivatives of the marine alkaloid Leucettamine B are described using two three-step convergent routes. For the formation of the 2-amino imidazolone ring, the key steps involve solvent-free condensations under microwaves and guanylation reactions with non-sterically hindered primary amines.

Full text of DOI:10.1016/S0040-4039(02)00575-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3581–3584
Microwave-mediated solventless synthesis of new derivatives of
marine alkaloid Leucettamine B
Jean-Rene´ Che´rouvrier, Franc¸ois Carreaux and Jean Pierre Bazureau*
Universite´ Rennes 1, Institut de Chimie, Synthe`se & Electrosynthe`se Organiques 3, UMR 6510, Baˆt. 10A, Campus de Beaulieu,
Avenue du Ge´ne´ral Leclerc, CS 74205, 35042 Rennes Cedex, France
Received 18 February 2002; accepted 19 March 2002
Abstract—New access to N-alkyl derivatives of the marine alkaloid Leucettamine B are described using two three-step convergent
routes. For the formation of the 2-amino imidazolone ring, the key steps involve solvent-free condensations under microwaves and
guanylation reactions with non-sterically hindered primary amines. © 2002 Elsevier Science Ltd. All rights reserved.
The 2-amino imidazolone core, a derivative of cyclic
guanidine, represent an interesting pharmacophore that
displays a wide range of pharmacological activities (for
example, they present hypoglycemic1 and hypotensive2
activities and they have been used also as inhibitors of
NF-kB activation3 and protein kinase C4). Over the
past decade, an increasingly important number of 2-
amino imidazolone derivatives have been isolated from
marine natural products,5 in particular those derived
from sponges. Among these are (Fig. 1) the Dis-
pacamide,6 isolated from Carriban Agelas sponges,
among which some members show a potent antihis-
tamine activity, or Leucettamine B from the sponge
Leucetta microraphis Haeckel (alcarea class) of the
Argulpelu Reef in Palau,7 which has been shown to
possess a role as mediator of inflammation.8 For these
alkaloids, their total synthesis9,10 has been also
reported.
During the course of our ongoing studies dealing with
the development of eco-friendly methodologies (sol-
vent-less reaction conditions11 with/or without room
temperature ionic liquid12) that could readily be
adapted for combinatorial and/or parallel synthesis
under microwave13 irradiations (mv), of relevant core
structures with potential therapeutic interest,14 we
focused our attention on the 2-amino imidazolone
nucleus of Leucettamine B. For the synthesis of 5-yl-
idene-3,5-dihydroimidazol-4-ones there are several
known methods15 which have one or more limitations
and their 2-alkylamino derivatives are not easily acces-
sible by general routes. Thus, we decided to develop an
economical and high yielding method suitable for pro-
ducing a wide variety of 2-amino imidazolone deriva-
tives. Here we wish to disclose two efficient and
convergent approaches to a stereocontrolled synthesis
of 2-alkylamino derivatives of Leucettamine B (Scheme
1).
The starting 3-substituted-2-thioxo-imidazolin-4-ones16
3a–c were easily prepared in large scale (up to 20 g)
with good yields (ꢀ96%) by addition of commercial
isothiocyanates 2a–c (R1=Me, Bu, Ph) to methyl glyci-
nate hydrochloride in basic medium (Table 1). With the
2-thiohydantoines 3 in hand, we have investigated two
convergent approaches for the synthesis of precursors
of Leucettamine B. In the first route (from 3 to 7a–c via
5), regioselective S-alkylation (with methyliodide 4a)
gave the 2-methylsulfanyl-3,5-dihydro-imidazol-4-ones
5a–c in the first step (Table 1). Then, condensation of
N-3,4-(methylenedioxy)benzylidenepropylamine 6 with
the 2-methylsulfanyl-3,5-dihydroimidazol-4-ones 5 con-
veniently provided stereochemically the (5Z) 5-benzo-
Figure 1.
Keywords: 2-amino imidazolone; Leucettamine B derivatives; solvent-
free; condensation; microwaves; guanylation.
* Corresponding author. Fax:
jean-pierre.bazureau@univ-rennes1.fr
+ (33) 02 23 23 63 74; e-mail:
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00575-0

3582
J.-R. Che´rou6rier et al. / Tetrahedron Letters 43 (2002) 3581–3584
H
N
MeS
R1
S
N
CO2Me
i
ii
N
N
2 : R1NCS
R1
4a : MeI
NH2, HCl
O
O
O
O
R3HN
R1
3(a-c) : R1 = Me, Bu, Ph
N
1
5
N
10
O
O
iv
iii
N
derivatives of Leucettamine B
O
Pr
6
O
O
- MeSH
vi
H
N
O
O
R2S
R1
S
N
v
N
N
R1
4b :
9 : R3NH2
7(a-c) : R2 = Me
7(d-f) : R2 = CH2CO2Et
O
8
O
ICH2CO2Et
Scheme 1. Reagents and reaction conditions: (i) Et3N 1 equiv., R1NCS 1 equiv., Et2O or AcOEt, reflux, 15 h. (ii) K2CO3 0.5 equiv.,
4a 1.5 equiv., MeCN, 40°C, 14 h. (iii) 6 1 equiv., mv (in the Synthewave® 402 reactor), 70°C, 1 h. (iv) 6 1 equiv., mv, 80°C, 1 h.
(v) K2CO3 0.5 equiv., 4b 1 equiv., MeCN, 80°C, 14 h. (vi) 9 7–10 equiv., 50°C, 2–7 days.
Table 1. Results of the preparation of 2-thiohydantoines 3, 8 and imidazolones 5
R1
Compound 3
Yield of 3 (%)a
Compound 5
Yield of 5 (%)a
Compound 8
Yield of 8 (%)a
Me
Bu
Ph
3a
3b
3c
95
96
97
5a
5b
5c
95
96
90
8a
8b
8c
77
75
87
a Yield obtained after purification by recrystallization.
[1,3]-dioxo-5-ylmethylene-2-methylsulfanyl-3,5-dihydro-
imidazol-4-ones 7a–c in yields ranging from 71 to 89%
(Table 2) with good purity by simple exposure of neat
reactants for 1 h to focused microwaves17 (in the Syn-
thewave® 402 reactor). The adequate reaction condi-
tions were found after several experiments (at various
powers, temperatures and irradiation times). It should
be noted that the 1H, 13C NMR data of 7a18 (R1,
R2=Me) were identical with those previously
reported.10a,11a Imine19 6 was quickly synthesized in
large scale from 2 equiv. of (volatile) propylamine and
1 equiv. of piperonal using solvent-free conditions
under focused microwave irradiations.
In the second route (from 3 to 7d–f via 8), the prepara-
tion of 2-thioxo-imidazolidin-4-ones 8a–c was easily
achieved under microwaves without solvent at 80°C
during 1 h from an equimolar mixture of 2-thiohydan-
toin 3 and imine 6. The desired 2-thioxo-imidazolidin-
4-ones 8a–c were obtained in good yields (Table 1) and
in all cases, the condensation reactions were stereospe-
cific. The (5Z)-stereochemistry of 8a–c was based on
the shielding effect of the carbonyl group on the olefinic
proton H-5 (8a–c: lH-5=6.51–6.65 ppm). In the second
step, addition of ethyl iodoacetate 4b to 8 gave regiose-
lective S-alkylation with retention of the (5Z)-stereo-
chemistry and produced in good yields the 5-benzo-
Table 2. Results of the preparation of 2-alkylsulfanyl-3,5-dihydro-imidazol-4-ones 7(a-f) and 2-alkylamino-3,5-dihydro-imida-
zol-4-ones 10a–f
Compound 7
R1
R2
Yield of 7 (%)a
Compound 10
R1
R3 Reaction time (days)b
Yield of 10 (%)c
7a
7b
7c
7d
7e
7f
Me Me
89
71
85
92
78
89
10a
10b
10c
10d
10e
10f
Me Pr
Me Bu
7
4
5
4
4
2
48
47
84
76
46
50
Bu
Ph
Me
Me
Bu
Bu
Ph
Ph
Pr
Bu
Pr
Me CH2CO2Et
Bu
Ph
CH2CO2Et
CH2CO2Et
Bu
a Isolated yields.
b Reaction time in days.
c Yield obtained after crystallization in ether.

J.-R. Che´rou6rier et al. / Tetrahedron Letters 43 (2002) 3581–3584
3583
References
[1,3]-dioxo-5-ylmethylene-2-ethyloxycarbonylmethylsul-
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During the study, we found that the guanylation (7“10
with 9) is the central step in the 2-amino imidazolone
synthesis for new derivatives of Leucettamine
B
(Scheme 1). There have been many reports20 around
guanylation conditions, reagents21 and precursors22 for
guanylation. Starting with 7a (R1, R2=Me) and iso-
propylamine in large excess (ꢀ5–7 equiv.) using sol-
ventless reaction conditions, we obtained after 7 days at
room temperature the 2-isopropylamino imidazolone 10
in poor yield (12%) together with by-products. It could
not be isolated by flash chromatography due to partial
decomposition by ring opening of the 2-isopropylamino
imidazolone 10. Similarly, when t-butylamine was
employed, no reaction occurred at 35°C and only the
formation of decomposition of products was observed
when the reaction conditions were forced (reflux, 7
days). These results indicate that this guanylation reac-
tion seems to be influenced by the steric effect of the
primary amines.23 Accordingly, when non-sterically
hindered primary amines 9 (9a: propylamine, 9b: n-
butylamine, 9: 7–10 equiv.) were allowed to react with
the 2-methylsulfanyl-3,4-dihydro-imidazol-4-ones 7a–c
at 50°C without solvent for a period of 2–7 days
1
(reaction progress was conveniently monitored by H
NMR spectroscopy), the guanylation reaction took
place and the desired 2-alkylamino imidazolinones 10
as new derivatives of Leucettamine B were isolated
(after elimination of excess of volatile amine 9 in vacuo)
by crystallization and repeated washing with ether in
yields ranging from 46 to 84% (Table 2). The structure
of the new 2-amino imidazolinones 10 were substanti-
11. (a) Che´rouvrier, J. R.; Boissel, J.; Carreaux, F.;
Bazureau, J. P. Green Chem. 2001, 3, 165; (b) Fraga-
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1
ated by the H, 13C NMR and HRMS analysis.24
13. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett.
2001, 42, 6097.
In summary, we report versatile and efficient routes to
new derivatives of the marine alkaloid Leucettamine B.
The precursors were synthesized by condensation
reactions of N-3,4-(methylenedioxy)benzylidenepropyl-
amine 6, respectively, with 2-thioxo-imidazolin-4-ones 3
14. (a) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225; (b) Meddad, N.; Rahmouni,
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Jacquault, P.; Mathe´, D. Synthesis 1998, 1213; (e) Cad-
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15. (a) Szyman˜ska, E.; Kiec-Kononowicz, K.; Bialecka, A.;
Kasprowiez, A. Farmaco 2002, 57, 39; (b) Fu, M.; Fer-
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1, 1351; (c) Ding, M. W.; Xu, Z. F.; Wu, T. J. Synth.
Commun. 1999, 29, 1171; (d) Ozaki, T.; Kikuchi, K.;
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and 2-methylsulfanyl-3,4-dihydro-imidazol-4-ones
5
using solvent-free reaction conditions assisted by
focused microwave technology. The final guanylation
step gave good results only with non-sterically hindered
primary amines 9. Work is now in progress to study the
protein kinase C inhibition activities25 of these new
2-alkylamino imidazolones26 10. The results of these
pharmacological activities will be reported in due
course.
Acknowledgements
16. Jakse, R.; Recnik, S.; Svete, J.; Golobic, A.; Golic, L.;
Stanovnik, B. Tetahedron 2001, 57, 8395.
We thank the ‘Conseil Re´gional de Bretagne’ (for
J.R.C.) for a research fellowship of the Green Chem-
istry program (contract No. 99CBQ4). The authors
thank Merck Eurolab Prolabo (Fr.) for providing the
Synthewave 402® apparatus and also Professor Jack
Hamelin for fruitful discussions.
17. (a) Commarmot, R.; Didenot, R.; Gardais, J. F. Fr
Demande, 25 560 529, 1985, Chem. Abstr. 1986, 105,
17442; (b) For description of commercial microwave
devices available with adequate mixing and control of
reaction parameters, see sites: http://www.cem.com and
http://www.personalchemistry.com.

3584
J.-R. Che´rou6rier et al. / Tetrahedron Letters 43 (2002) 3581–3584
18. (a) Typical procedure for the preparation of (5Z) 5-
benzo[1,3]dioxol-5-ylmethylene-3-methyl-2-methylsulfanyl-
of excess of propylamine in vacuo, compound 6 was used
without further purification.
3,5-dihydro-imidazol-4-one (7a): In
quartz tube (¥=1.5 cm) were placed successively the
3-methyl-2-methylsulfanyl-3,5-dihydro imidazol-4-one
a
cylindrical
20. (a) Burgess, K.; Chen, J. In Solid Phase Synthesis of
Guanidines; Burgess, K., Ed. Solid-Phase Organic Synthe-
sis; John Wiley: New York, 2000; pp. 1–23; (b) Gomez,
L.; Gellibert, F.; Wagner, A.; Mioskowski, C. Chem. Eur.
J. 2000, 6, 4016.
21. (a) Schneider, S. E.; Bishop, P. A.; Solazar, M. A.;
Bishop, O. A.; Anslvm, E. V. Tetrahedron 1998, 54,
15063; (b) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J.
Org. Chem. 1997, 62, 1540; (c) Atwal, K. S.; Admed, S.
Z.; O’Reilly, B. C. Tetrahedron Lett. 1989, 30, 7313.
22. Wilson, L. J.; Klofenstein, S. R.; Li, M. Tetrahedron Lett.
1999, 40, 3999.
5a (1.44 g., 10 mmol) and the N-3,4-(methylenedioxy)-
benzylidenepropylamine 619 (1.91 g, 10 mmol). Then, the
tube was introduced into a Synthewave® 402 Prolabo
microwave reactor [2.45 GHz, adjusted power within the
range 0–300 W and a wave guide (single mode T01) fitted
with a stirring device and an IR detector of temperature].
Microwave irradiation was carried out at 70°C during 60
min (the microwave oven is monitored by a computer
which allows the temperature of the reaction mixture to
be adjusted). The mixture was allowed to cool down.
After addition of 20 ml of a mixture of solvent (CH2Cl2/
hexane/Et2O: 1/1/1) in the reactor, the precipitate was
filtered off, washed twice with the same solvent (10 ml)
and dried in a dessicator over CaCl2. Recrystallization
from pentane gave pure compound 7a in 89% yield as
yellowish needles (mp=195–197°C). HRMS, m/z:
276.0576 (calcd for C13H12N2O3S: 276.0569). 1H NMR
(300 MHz, CDCl3, TMS as internal ref.) l 2.71 (s, 3H),
3.14 (s, 3H), 6.00 (s, 2H), 6.82 (d, 1H, J=8.1 Hz), 6.86 (s,
1H, ꢀCH), 7.37 (dd, 1H, J=8.1, 1.5 Hz), 8.04 (d, 1H,
J=1.5 Hz). 13C NMR (75 MHz, CDCl3, TMS as internal
ref.) l 12.92 (q, J=144 Hz), 26.48 (q, J=141 Hz), 101.41
(t, J=174 Hz), 108.44 (d, J=165 Hz, C-2%), 110.87 (dt,
J=167, 7.2 Hz, C-6%), 123.83 (ddd, J=156, 5.5, 4.3 Hz,
23. (a) Heras, M.; Ventura, M.; Linden, A.; Villalgardo, J.
M. Tetrahedron 2001, 57, 4371; (b) Li, M.; Wilson, L. J.
Tetrahedron Lett. 2001, 42, 1455.
24. Selected spectral data of (5Z) 5-benzo[1,3]dioxol-5-
yl-methylene-3-methyl-2-propylamino-3,5-dihydro-imida-
zol-4-one (10a) HRMS, m/z: 287.1279 (calcd for
1
C15H17N3O3: 287.0932). Mp=191–192°C from ether. H
NMR (300 MHz, CDCl3, TMS as internal ref.) l 1.02 (t,
3H, J=7.4 Hz); 1.74 (s, 2H, J=7.3 Hz); 3.11 (s, 3H); 3.54
(q, 2H, J=6.2 Hz); 4.95 (br s, 1H, NH); 5.98 (s, 2H); 6.62
(s, 1H); 6.81 (d, 1H, J=8.1 Hz); 7.34 (dd, 1H, J=8.1, 1.4
Hz); 7.99 (d, 1H, J=1.2 Hz). 13C NMR (75 MHz,
CDCl3, TMS as internal ref.) l 11.5 (qt, J=126, 4.0 Hz);
22.8 (tq, J=135, 3.7 Hz); 25.2 (q, J=140 Hz); 43.7 (tq,
J=142, 7 Hz); 101.10 (t, J=173 Hz); 108.40 (d, J=164
Hz, C-2%); 110.30 (dt, J=164, 7.1 Hz, C-6%); 116.80 (dt,
ꢀC6 H), 128.05 (dt, J=162, 6.2 Hz, C-5%), 129.07 (sm,
J=157, 3.5 Hz, ꢀC6 H); 126.10 (dt, J=162, 6.2 Hz, C-5%);
C-3%), 137.05 (s, C-5), 147.95 (sm, C-1%), 149.09 (sm, C-4%),
164.17 (sm, C-4), 169.95 (sm, C-2); (b) Part of this work
was presented at the ‘The First International Rhodia Con-
ference: Organic Chemistry, Novel methods for the future’,
Ecole Normale Supe´rieure de Lyon, 2–5 July 2001, Lyon,
France. Poster Abstracts: A-5, p 29.
130.20 (d, J=7.8 Hz, C-3%); 138.10 (s, C-5); 146.60 (s,
C-1%); 147.70 (sm, C-4%); 157.20 (sm, C-4); 170.40 (sm,
C-2).
25. Borgne, A.; Meijer, L. Med. Sci. 1999, 4, 496.
26. The new 2-alkylamino imidazolone derivatives of
Leucettamine B 10 will be evaluated in a drug discovery
program (protein kinase C inhibition activities) at the
‘Station Biologique de Roscoff, BP 74, 29682-Roscoff
Cedex, France’.
19. Solventless preparation of N-3,4-(methylenedioxy)-
benzylidenepropylamine 6 using focused microwave tech-
nology (Synthewave® 402 reactor, Prolabo17): After irra-
diation of the mixture at 60°C for 30 min and elimination
30 min., 60°C
O
O
O
O
N
O
1 eq.
H2N
µω
6 : (99%)
2 eq.