Efficient synthesis of N-benzyl-3-aminopyrrolidine-2,5-dione and N-benzyl-3-aminopyrrolidin-2-one

Article abstract of DOI:10.1016/j.tetlet.2004.03.052

Reaction of N-tert-butyloxycarbonylasparagine (Boc-Asn) with 2equiv of benzyl bromide in presence of cesium carbonate led to N-benzyl-3-Boc-amino- pyrrolidin-2,5-dione 1a (N-benzyl-3-Boc-aminosuccinimide). Borane dimethylsulfide reduced 3-Boc-aminopyrrolidine-2,5-dione 1a into 3-Boc-aminopyrrolidin-2-one 2a. The same procedure could also be used to prepare derivatives 1 and 2 substituted on the aromatic ring.

Full text of DOI:10.1016/j.tetlet.2004.03.052

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3603–3605
Efficient synthesis of N-benzyl-3-aminopyrrolidine-2,5-dione and
N-benzyl-3-aminopyrrolidin-2-one
a
Yen Vo-Hoang, Cecile Gasse, Michel Vidal, Christiane Garbay and Herve Galons
a
b
b
a,
*
ꢀ
ꢀ
aLaboratoire de Chimie Organique, Facultꢀe de Pharmacie, 4, avenue de l’Observatoire 75270 Paris Cedex 06, France
bLaboratoire de Pharmacochimie Molꢀeculaire et Cellulaire, INSERM U266, FRE2463 CNRS, U.F.R. biomꢀedicale des Saints Pꢁeres,
45, rue des Saints Pꢁeres, 75006 Paris, France
Received 2 February 2004; revised 5 March 2004; accepted 10 March 2004
Abstract—Reaction of N-tert-butyloxycarbonylasparagine (Boc-Asn) with 2 equiv of benzyl bromide in presence of cesium car-
bonate led to N-benzyl-3-Boc-amino-pyrrolidin-2,5-dione 1a (N-benzyl-3-Boc-aminosuccinimide). Borane dimethylsulfide reduced
3-Boc-aminopyrrolidine-2,5-dione 1a into 3-Boc-aminopyrrolidin-2-one 2a. The same procedure could also be used to prepare
derivatives 1 and 2 substituted on the aromatic ring.
ꢀ 2004 Published by Elsevier Ltd.
Succinimides are an important class of heterocyclic
compounds with numerous pharmacological applica-
tions in different fields such as inhibition of human
leukocyte elastase, cathepsin G, and proteinase 3.1
Furthermore, aminosuccinimides are useful synthetic
intermediates. They can be reduced with lithium alu-
minum hydride or borane dimethylsulfide2 or by cata-
lytic hydrosilylation3 to aminopyrrolidines, which have
been incorporated into numerous biologically active
compounds.4 Sodium borohydride reduced 3-amino-
succinimide to 3-amino-5-hydroxypyrrolidine-2-one.5
N-Benzyl-3-benzyloxycarbonyl-aminosuccinimide was
prepared from N-benzyloxycarbonyl-asparagine (Z-
Asn) in a three step procedure.6
most cases these methods are not appropriate on a lar-
ger scale. We wish to present a fast and cheap access to
these compounds. The approach relies on a one step
efficient synthesis of N-benzyl-3-Boc-aminopyrrolidin-
2,5-dione 1a, which only differs from the previously
described product by the protecting group,6 from Boc-
Asn and further its reduction to N-benzyl-3-amino-
pyrrolidin-2-one 2a. We have previously described
several syntheses of cyclic imides.11 These procedures are
based on reaction of primary amines with diacids in
presence of N-ethyl-N0-(3-dimethylaminopropyl)carbo-
diimide hydrochloride (EDCCl) and of N-hydroxy-
benzotriazole (HOBt). EDCCl is a rather expensive
coupling agent.
The 3-aminopyrrolidin-2-one motive is present in com-
pounds of biological interest such as antithrombotics7
and farnesyltransferase inhibitors.8 N-Benzyl-3-Boc-
aminopyrrolidin-2-one derivatives are obtained by
cyclization of 2-Boc-amino-4-amino-butanoic acid fol-
lowed by N-alkylation of the lactam.9 Another classical
approach relies on the cyclization of S-dimethylsulfo-
nium derivative of methionine amides.10
As Boc-Asn benzyl ester is routinely prepared by
alkylation of Boc-Asn cesium salt with benzyl bro-
mide,12 we observed the formation of noticeable
amounts (5–10%) of 1a as side product. The conditions
were optimized in order to drive the reaction toward this
compound 1a. When the reaction was conducted with
1.5 equiv of Cs2CO3 and 2 equiv of benzyl bromide
compound 1a was the only formed product (Scheme
1).13 This cyclization performed at room temperature
worked also with substituted benzyl bromides (Table 1)
and with Z-Asn. Alternative basic conditions were tried
without success.14
All syntheses of these two series of compounds imply
multistep procedures and/or expensive reagents and in
Keywords: Cyclic-imide; Aminosuccinimide; Aminopyrrolidinedione;
Aminopyrrolidinone.
With regard to the mechanism of formation of 1a, al-
though N-alkylation of the nitrogen imide by electro-
philes is well documented,6 we observed under the same
* Corresponding author. Tel.: +33-01-53-73-96-84; fax: +33-1-43-29-
05-92; e-mail: herve.galons@univ-paris5.fr
0040-4039/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.052

3604
Y. Vo-Hoang et al. / Tetrahedron Letters 45 (2004) 3603–3605
O
O
R
O
R
NH2
OH
1. Cs2CO3, MeOH
2. Cs2CO3, DMF
(CH3)2S.BH3
N
N
1a-c
BocNH
BocNH
THF
H2N
O
O
R
Boc-Asn
1a-f
2a-c
Br
Scheme 4.
Scheme 1.
Table 2. Aminopyrrolidinone derivatives 2a–c produced via Scheme 4
Table 1. Aminosuccinimide derivatives 1a–f produced via Scheme 1
Entry
Derivative
R
Yield (%)
Entry
Derivative
R
Yield (%)
1
2
3
2a
2b
2c
H
40
54
58
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
70
71
38
55
67
13
3-Chloro
4-Fluoro
3-Chloro
4-Fluoro
4-Cyano
4-Methoxycarbonyl
4-Nitro
explained by the presence of the Boc-amino group
(Table 2).
reaction conditions, that cyclization of 3 took place with
better outputs than alkylation of 4 (Scheme 2). This is an
argument in favor of the amide N-alkylation of Boc-Asn
benzyl ester prior to cyclization.
As expected, formation of aminopyrrolidinone 2 from
pyrrolidinedione 1 is limited to derivatives insensitive to
the reducing agent. Thus, reduction of 1d led to a
complex mixture.
In order to establish its enantiomeric purity, 1a was
coupled with N-Boc-phenylalanine (Boc-Phe) and the
purity of the dipeptide 6 was determined by H NMR
and HPLC (Scheme 3).15 The formation of a single
diastereoisomer was observed (d.r.>98:2).
The procedure presented in this paper offers a short and
efficient route to several chiral heterocycles useful for
drug synthesis. For example, the presented approach
provides a shorter route to 2c as part of farnesyltrans-
ferase inhibitors.8a Purification by recrystallization from
isopropanol of the aminosuccinimide 1 makes this
approach suitable for a large scale synthesis.
1
In contrast to a previous report,2 the reduction of 1a–c
with borane hydride–dimethylsulfide complex selectively
afforded the 3-aminopyrrolidin-2-one 2a–c (Scheme 4).16
The less hindered carbonyl group is the only one to be
reduced in these conditions. Such a selectivity may be
Acknowledgements
We acknowledge Dr. Noad Gresh for his help during the
preparation of the manuscript and Sophie Mairesse-
Lebrun for performing the microanalyses.
NHCH2C6H5
O
Cs2CO3
DMF
1a (76%)
1a (22%)
OCH2C6H5
BocNH
BocNH
O
O
3
References and notes
O
1. (a) Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R.
Chem. Rev. 1970, 70, 439; (b) Groutas, W. C.; Brubaker,
M. J.; Chong, L. S.; Venkataraman, R.; Huang, H.; Epp,
J. B.; Kuang, R.; Hoidal, J. R. Bioorg. Med. Chem. 1995,
3, 375–381.
C6H5CH2Br
NH
Cs2CO3, DMF
4
2. Ballini, R.; Bosica, G.; Cioci, G.; Fiorini, D.; Petrini, M.
Tetrahedron 2003, 59, 3603–3608.
Scheme 2.
O
N
O
O
C6H5
C6H5
_
+
N
CF3COOH
BocHN
H3N
CF3COO
1a
N
H
Boc-Phe-OH
DCC, HOBt
O
O
C6H5
5
6
Scheme 3.

Y. Vo-Hoang et al. / Tetrahedron Letters 45 (2004) 3603–3605
3605
3. Kuwano, R.; Takahashi, M.; Ito, Y. Tetrahedron Lett.
1998, 39, 1017–1020.
(270 MHz, CDCl3) d (ppm): 28.5 (3C, CH3), 36.3 (CH2),
43.7 (CH), 48.3 (NCH2), 81.1 (C quat.), 128.1–129.3 (C Ar),
155.5, 174.1, 175.9 (C@O). Compound 1b: colorless crys-
tals: mp 122–123 ꢁC. 1H NMR (270 MHz, CDCl3) d (ppm):
1.50 (s, 9H), 2.94 (dd, 1H, J1 ¼ 17:8 Hz, J2 ¼ 4:7 Hz), 3.12
(dd, 1H, J1 ¼ 17:8 Hz, J2 ¼ 9:1 Hz), 4.20 (m, 1H), 4.65 (d,
1H, J ¼ 14:4 Hz), 4.70 (d, 1H, J ¼ 14:4 Hz), 5.30 (s, 1H),
7.25 (m, 3H), 7.40 (m, 1H). 13C NMR (270 MHz, CDCl3) d
(ppm): 27.9 (3C, CH3), 35.4 (CH2), 41.6 (CH), 49.8 (NCH2),
80.7 (C quat.), 128.2–129.8 (4C Ar), 134.1, 136.8 (quat. Ar),
154.7, 173.6, 175.3 (C@O). Compound 1c: colorless crys-
tals: mp 130 ꢁC. 1H NMR (270 MHz, CDCl3) d (ppm): 1.42
(s, 9H), 2.95 (dd, 1H, J1 ¼ 17:5 Hz, J2 ¼ 4:7 Hz), 3.14 (dd,
1H, J1 ¼ 17:5 Hz, J2 ¼ 9:1 Hz), 4.12 (m, 1H), 4.71 (s, 2H),
5.14 (s, 1H), 7.33 (d, 2H, J ¼ 8:0 Hz), 8.11 (d, 2H,
J ¼ 8:0 Hz). Compound 1d: colorless crystals: mp 188–
192 ꢁC. 1H NMR (270 MHz, CDCl3) d (ppm): 1.50 (s, 9H),
2.93 (dd, 1H, J1 ¼ 17:8 Hz, J2 ¼ 4:7 Hz), 3.15 (dd, 1H,
J1 ¼ 17:8 Hz, J2 ¼ 9:2 Hz), 4.15 (dd, 1H, J1 ¼ 14:9 Hz,
J2 ¼ 6:1 Hz), 4.70 (d, 1H, J ¼ 15:7 Hz), 4.77 (d, 1H,
J ¼ 15:7 Hz), 5.25 (s, 1H), 7.53 (d, 2H, J ¼ 8:0 Hz), 7.62
(d, 2H, J ¼ 8:0 Hz). Compound 1e: colorless crystals: mp
157–159 ꢁC. 1H NMR (270 MHz, CDCl3) d (ppm): 1.48 (s,
9H), 2.95 (dd, 1H, J1 ¼ 17:8 Hz, J2 ¼ 4:3 Hz), 3.11 (dd, 1H,
J1 ¼ 17:8 Hz, J2 ¼ 9:1 Hz), 4.14 (m, 1H), 4.71 (d, 1H,
J ¼ 14:5 Hz), 4.77 (d, 1H, J ¼ 14:5 Hz), 5.12 (br s, 1H), 7.20
(d, 2H, J ¼ 7:9 Hz), 7.95 (d, 2H, J ¼ 7:9 Hz). Compound
1f: colorless crystals: mp 180–183 ꢁC. 1H NMR (270 MHz,
CDCl3) d (ppm): 1.33 (s, 9H), 2.95 (dd, 1H, J1 ¼ 17:5 Hz,
J2 ¼ 4:5 Hz), 3.14 (dd, 1H, J1 ¼ 17:5 Hz), 4.16 (m, 1H), 4.62
(s, 2H), 5.11 (s, 1H), 6.93 (d, 2H, J ¼ 8:0 Hz), 7.32 (d, 2H,
J ¼ 8:0 Hz). To avoid the preparation of cesium carbonate
salt in hydromethanolic solution, we developed an alterna-
tive procedure: cesium carbonate (0.853 g, 2.63 mmol) was
added to Boc-Asn (0.205 g, 0.88 mmol) in 5 mL of DMF.
The mixture was stirred for 2 days at room temperature to
complete the salt formation. Then benzyl bromide (42 lL,
2.2 mmol) was added. After stirring for 6 h at room
temperature, the same treatment was applied. 1-Benzyl-3-
Bocaminosuccinimide 1a, was isolated in a similar yield.
14. Other unsuccessful experimented basic conditions: triethyl-
amine, N,N-dimethyl-4-aminopyridine, calcium carbonate
in DMF or CH3CN.
4. (a) Einsiedel, J.; Thomas, C.; Hubner, H.; Gmeiner, P.
Bioorg. Med. Chem. Lett. 2000, 10, 2041–2044; (b) Rosen, T.;
Chu, D. T.; Lico, I. M.; Fernandes, P. B.; Shen, L.; Borodkin,
S.; Pernet, A. G. J. Med. Chem. 1988, 31, 1586–1590; (c)
Klinkhammer, U.; Spurr, P.; Wang, S. U.S. Patent 5,977,381,
1999; (d) Moon, S. H.; Lee, S. Synth. Commun. 1998, 28,
3919–3926.
ꢁ
5. (a) Briere, J.-F.; Charpentier, P.; Dupas, G.; Guequiner,
G.; Bourguignon, J. Tetrahedron 1997, 53, 2075–2086; (b)
Allin, S. M.; Thomas, C. I.; Allard, J. E.; Duncton, M.;
Elsegood, M. R. J.; Edgar, M. Tetrahedron Lett. 2003, 44,
2335–2338; (c) Marson, C. M.; Pink, J. H.; Hall, D.;
Hursthouse, M. B.; Malik, A.; Smith, C. J. Org. Chem.
2003, 68, 792–798.
6. Maddaluno, J.; Corruble, A.; Leroux, V.; Ple, G.; Duh-
amel, P. Tetrahedron: Asymmetry 1992, 3, 1239–1242.
7. Choi-Sledeski, Y. M.; McGarry, D. G.; Green, D. M.;
Mason, H. J.; Becker, M. R.; Davis, R. S.; Ewing, W. R.;
Dankulich, W. P.; Manetta, V. E.; Morris, R. L.; Spada,
A. P.; Cheney, D. L.; Brown, K. D.; Colussi, D. J.; Chu,
V.; Heran, C. L.; Morgan, S. R.; Bentley, R. G.; Leadley,
R. J.; Maignan, S.; Guilloteau, J. P.; Dunwiddie, C. T.;
Pauls, H. W. J. Med. Chem. 1999, 42, 3572–3587.
8. (a) Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beese, L. S.;
Beshore, D. C.; Bhimnathwala, H.; Bogusky, M. J.; Buser,
C. A.; Culberson, J. C.; Davide, J.; Ellis-Hutchings, M.;
Fernandes, C.; Gibbs, J. B.; Graham, S. L.; Hamilton, K.
A.; Hartman, G. D.; Heimbrook, D. C.; Homnick, C. F.;
Huber, H. E.; Huff, J. R.; Kassahun, K.; Koblan, K. S.;
Kohl, N. E.; Lobell, R. B.; Lynch, J. J., Jr.; Robinson, R.;
Rodrigues, A. D.; Taylor, J. S.; Walsh, E. S.; Williams, T.
M.; Zartman, C. B. J. Med. Chem. 2002, 45, 2388–2409;
(b) Lee, H.; Lee, J.; Shin, Y.; Jung, W.; Kim, J.-H.; Park,
K.; Ro, S.; Chung, H.-H.; Koh, J. S. Bioorg. Med. Chem.
Lett. 2001, 11, 2963–2965.
9. Becker, M. R.; Ewing, W. R.; Davis, R. S.; Pauls, H. W.;
Ly, C.; Li, A.; Mason, H. J.; Choi-Sledeski, Y. M.; Spada,
A. P.; Chu, V. Bioorg. Med. Chem. Lett. 1999, 9, 2753–
2758.
10. (a) Bell, I. M.; Beshore, D. C.; Gallicchio, S. N.; Williams,
T. M. Tetrahedron Lett. 2000, 41, 1141–1145; (b) Frei-
dinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem.
1982, 47, 104–109.
11. Flaih, N.; Gadjou, C.; Lafont, O.; Galons, H. Synlett
2000, 896–898, and references quoted herein.
12. Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.;
Kulesha, I. D.; Tzougraki, C.; Meienhofer, J. J. Org.
Chem. 1977, 42, 1286–1290.
15. After elimination of the Boc group in 1a, the acylation of
1-benzyl-3-aminosuccinimide with BocPhe was achieved
with dicyclohexylcarbodiimide (DCC) and hydroxybenzo-
triazole (HOBt) as coupling reagents in AcOEt. HPLC
was performed on a Chiracel OJ (25 cm · 4.6 mm) column
using a photodiode array detector (Waters 994) and a
polarimetric detector (Jasco OR 990). MeOH (100%) was
13. To 300 mL of a 1:2 hydromethanolic solution of Boc-Asn
(13.92 g, 60 mmol), was added cesium carbonate (34.2 g,
105 mmol) and the mixture was evaporated to dryness.
Anhydrous dimethylformamide (DMF 150 mL) was added
and the solid was brought in suspension by stirring. DMF
was removed under vacuum. Anhydrous DMF (150 mL)
was added once more, the suspension was cooled at 15 ꢁC
and benzyl bromide (14.27 mL, 120 mmol) was added
dropwise. The mixture was further stirred for 6 h at room
temperature after completion of the addition. After evap-
oration of DMF under vacuum, the residue was taken up in
ethyl acetate (100 mL) and washed in water (2 · 75 mL). The
organic layer was dried and evaporated. The product was
purified by crystallization from isopropanol (12 g, 70%).
Compound 1a: colorless crystals: mp 144 ꢁC. 1H NMR
(270 MHz, CDCl3) d (ppm): 1.36 (s, 9H), 2.88 (dd, 1H,
J1 ¼ 17:0 Hz, J2 ¼ 4:5 Hz), 3.94 (dd, 1H, J1 ¼ 17:0 Hz,
J2 ¼ 8:2 Hz), 4.25 (m, 1H), 4.62 (d, 1H, J ¼ 14:5 Hz), 4.69
(d, 1H, J ¼ 14:5 Hz), 5.12 (s, 1H), 7.28 (m, 5H). 13C NMR
used as mobile phase and the flow rate 1 mL minꢀ1
.
16. To a cold (0 ꢁC) solution of 1a (5.7 g, 18.75 mmol) in
70 mL THF was added 28 mL borane dimethylsulfide 2 M
in THF (56 mmol). After 1 h stirring at room temperature
the mixture is refluxed for 6 h. After cooling to 0 ꢁC, NaF
(9.58 g, 228 mmol) in water (75 mL) and concentrated HCl
was carefully added. The mixture was refluxed for 2 h.
After cooling, the solution was neutralized with 4 N
NaOH. The mixture was then extracted with CH2Cl2
(3 · 75 mL). The crude 3-aminopyrrolidinone was purified
by column chromatography (CH2Cl2/MeOH 100:5 +NEt3
0.1%). Thick oil, 1H NMR (270 MHz, CDCl3) d (ppm):
1.62 (m, 1H), 2.33 (m, 1H), 3.11 (dd, 2H, J1 ¼ 9 Hz,
J2 ¼ 4:5 Hz), 3.55 (dd, 1H, J1 ¼ 9:0 Hz, J2 ¼ 9:4 Hz), 4.37
(s, 2H), 7.15–7.37 (m, 5H). The trifluoroacetate of 2a was
prepared: mp 95–97 ꢁC. 1H NMR (270 MHz, CDCl3) d
(ppm): 2.12 (m, 1H), 2.40 (m, 1H), 3.25 (m, 2H), 4.05 (t,
1H, J ¼ 9 Hz), 4.31 (d, 1H J ¼ 15 Hz), 4.38 (d, 1H
J ¼ 15 Hz), 7.20–7.35 (m, 5H), 8.4 (br s, 3H).