Efficient synthesis of 1-heterocyclic-3-aminopyrrolidinones

Article abstract of DOI:10.1016/S0040-4039(99)02282-0

A novel two-step synthesis of optically active 3-aminopyrrolidinones is described. The route allows access to pyrrolidinones with heterocyclic functionality that is incompatible with known methodology, and affords the final products in good to excellent yield and high enantiomeric purity. The Mitsunobu cyclodehydration is shown to be an efficient method for the formation of a variety of γ-lactams. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02282-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1141–1145
Efficient synthesis of 1-heterocyclic-3-aminopyrrolidinones
Ian M. Bell,∗ Douglas C. Beshore, Steven N. Gallicchio and Theresa M. Williams
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 4, West Point, PA 19486, USA
Received 29 September 1999; accepted 29 November 1999
Abstract
A novel two-step synthesis of optically active 3-aminopyrrolidinones is described. The route allows access to
pyrrolidinones with heterocyclic functionality that is incompatible with known methodology, and affords the final
products in good to excellent yield and high enantiomeric purity. The Mitsunobu cyclodehydration is shown to be
an efficient method for the formation of a variety of γ-lactams. © 2000 Published by Elsevier Science Ltd. All
rights reserved.
Keywords: 3-aminopyrrolidinones; nitrogen heterocycles; Mitsunobu reaction; cyclization.
The 3-aminopyrrolidinone moiety has found widespread use in biologically-active molecules.1,2 The
most common synthetic routes to these compounds are variants of the original conditions described by
Freidinger et al.,1,3 that rely on activation of a methionine amide by treatment with excess iodomethane,
followed by cyclization using sodium hydride as base (Scheme 1).
Scheme 1.
We were interested in the synthesis of enantiomerically pure 3-aminopyrrolidinones substituted with
various heterocycles at the 1-position. Many of the targets contained heterocyclic functionality that was
not compatible with iodomethane treatment, so we explored the alternative route shown in Scheme 2.
Specifically, we planned to open a suitably protected homoserine lactone with the dimethylaluminum
amide derivative of interest. We envisioned that a Mitsunobu cyclodehydration4 of the homoserine amide
would then lead to the desired γ-lactam. A similar Mitsunobu strategy has been demonstrated in the
synthesis of N-arylpiperazinones.5
To our knowledge, while Mitsunobu conditions have been employed in the cyclization of β-
hydroxyamides to give β-lactams,6 the only examples utilizing γ-hydroxyamides involved the cyclization
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02282-0
tetl 16210

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Scheme 2.
of α,α-spiro-substituted compounds or other constrained systems that were presumably predisposed to
ring closure.7 Other related examples use chemical modification at the amide nitrogen, for example
in homoseryl O-alkyl hydroxamates, to increase the acidity of the amide N–H and hence promote
cyclization.8 We expected that the enhanced acidity of the amide functionality in an N-(heteroaryl)amide
should also facilitate the cyclodehydration, but a range of structures, including N-(alkyl)amides, were
investigated to assess the scope of this reaction. Another important goal of this study was to provide the
1-heterocyclic-3-aminopyrrolidinones in optically pure form, since the only published examples were
synthesized as racemates.9
A series of heterocyclic amines were converted to the corresponding dimethylaluminum amides (1)
(Table 1) by reaction with trimethylaluminum in CH2Cl2,10 and the aluminum amides were then treated
with (S)-BOC-homoserine lactone. The results of this study are presented in Table 1. The desired γ-
hydroxyamides (2) were obtained in good to excellent yields, although a wide range of reactivity was
noted. For example the (R)-tetrahydrofuran-3-yl aluminum amide (1k) reacted essentially quantitatively
with the lactone at ambient temperature in 90 min, whereas the reaction between the pyridin-4-yl
aluminum amide (1c) and the lactone provided only about 50% product after 48 h at 40°C. While the
tetrahydrofuranyl example displays the typical reactivity profile expected for an aliphatic aluminum
amide, the electron-deficient 4-pyridyl system appears to have significantly reduced nucleophilicity.
Consistent with this observation are the data for the 3-pyridyl (1b) and 2-pyridyl (1a) examples, in which
the yields obtained (3-pyridyl>2-pyridyl>4-pyridyl) apparently reflect the electronic-withdrawing facility
of these heterocyclic systems. The data for the 5-isoquinolinyl (1f) and 5-quinolinyl (1g) examples
illustrate that steric considerations are also important as the reactions with these relatively hindered
aluminum amides required heating. In most cases some unreacted lactone was recovered. Attempts to
increase consumption of the lactone by use of greater than 1.2 equiv. of aluminum amide were moderately
successful, but led to decreases in the enantiomeric purity of the product.
Cyclodehydration of the homoserine amides shown proceeded in excellent yield using conditions
adapted from those described by Weissman et al.5 The preformed Mitsunobu complex of di-tert-butyl
azodicarboxylate and tri-n-butylphosphine was added to a solution of the alcohol in THF at 0°C, and the
mixture was allowed to warm slowly to ambient temperature. In all cases, the reaction was complete after
stirring for 18 h. Table 1 details the yield of each γ-lactam obtained and also the enantiomeric purity of
the final product, which was determined by conversion of the deprotected 3-aminopyrrolidinone to both
Mosher amide diastereomers and analysis by 1H NMR spectroscopy. In general, the optical purity of the
final products was excellent, although the examples that required heating in the first step tended to show
some epimerization (3c, 3e, and 3g, for example).
While we had expected that γ-hydroxyamides with relatively acidic amide functionality, such as 2a,
would undergo efficient ring closure, we were gratified with the scope of the reaction and the uniformally
high yields obtained. The amide groups in compounds 2k–2m presumably have significantly higher pKa
values than 2a, but the cyclizations of these substrates were still highly efficient. The lowest yield (70%)
was obtained for the cyclization of the 5-quinolinyl substrate (2g). In this case, the balance of the material
was converted to the imidate ester resulting from O-alkylation of the amide.11 A small amount of O-

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Table 1
Synthesis of 3-(tert-butoxycarbonylamino)pyrrolidinones
alkylation was also apparent in the case of the 5-isoquinolinyl substrate (2f), but this side reaction was
not observed for any of the other examples.
In conclusion, a novel two-step synthesis of optically active 3-aminopyrrolidinones has been deve-
loped. This route should be a useful complement to the known methodology, especially for structures
which contain functionality with undesirable reactivity towards iodomethane. The variety of substituents
tolerated on the amide nitrogen highlights the versatility of the Mitsunobu ring closure in the formation
of γ-lactams.
1. Representative experimental procedures
(S)-2-(tert-Butoxycarbonylamino)-4-hydroxy-N-pyridin-2-ylbutyramide (2a). To a stirred solution of
2-aminopyridine (126 mg, 1.34 mmol) in dry CH2Cl2 (3 mL) at ambient temperature, under argon, was
added trimethylaluminum (0.67 mL of a 2.0 N solution in hexane, 1.34 mmol) dropwise. The resulting

1144
mixture was stirred for 15 min, then (S)-N-(tert-butoxycarbonyl)homoserine lactone12 (224 mg, 1.11
mmol) in CH2Cl2 (3 mL) was added slowly and stirring was continued at ambient temperature for 18
h. The reaction was quenched carefully with 10% aqueous citric acid (1 mL) and, after effervescence
had stopped, the mixture was partitioned between saturated aqueous potassium sodium tartrate (10 mL)
and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica, eluting with a gradient of EtOAc–20 to 10% hexane
to yield the amide as an oil (221 mg, 67%). 1H NMR (CDCl3) δ 9.69 (1H, br s), 8.31 (1H, dd, J=4.8, 0.9
Hz), 8.20 (1H, d, J=8.1 Hz), 7.70 (1H, ddd, J=8.4, 7.3, 1.8 Hz), 7.04 (1H, ddd, J=7.3, 4.9, 0.9 Hz), 6.05
(1H, br d, J=5.1 Hz), 4.62 (1H, m), 3.93 (1H, m), 3.79 (2H, m), 2.14 (1H, m), 1.96 (1H, m), 1.48 (9H, s).
MS (EI) m/z=295 (M+=C14H21N3O4). HPLC purity=91.7% (215 nm).
(S)-3-(tert-Butoxycarbonylamino)-2-oxo-1-(2-pyridyl)pyrrolidine (3a). Tri-n-butylphosphine (0.208
mL, 0.83 mmol) was added to a solution of di-tert-butyl azodicarboxylate (191 mg, 0.83 mmol) in dry
THF (2 mL) at ambient temperature. The resulting mixture was stirred for 5 min, then added dropwise
to a solution of (S)-2-(tert-butoxycarbonylamino)-4-hydroxy-N-pyridin-2-ylbutyramide (190 mg, 0.64
mmol) in THF (1 mL) at 0°C, under argon. The reaction mixture was allowed to warm slowly to
ambient temperature and stirred for 18 h, then partitioned between saturated aqueous NaHCO3 (5 mL)
and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (10 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica, eluting with a gradient of hexane–20 to 40% EtOAc
1
to yield the lactam as a white solid (169 mg, 95%). H NMR (CDCl3) δ 8.38 (1H, d, J=8.4 Hz), 8.37
(1H, ddd, J=4.8, 1.8, 0.7 Hz), 7.71 (1H, ddd, J=8.5, 7.3, 2.0 Hz), 7.06 (1H, ddd, J=7.2, 4.9, 0.9 Hz), 5.16
(1H, br s), 4.42 (1H, m), 4.27 (1H, dd, J=11.0, 9.2 Hz), 3.82 (1H, td, J=11.1, 6.4 Hz), 2.75 (1H, m), 1.91
(1H, m), 1.44 (9H, s). MS (EI) m/z=277 (M+=C14H19N3O3). HRMS (EI) calculated for C14H19N3O3
m/z=277.1426; found m/z=277.1425. HPLC purity=100.0% (215 nm). Mosher amide analysis of this
product by 1H NMR indicated less than 0.5% of the undesired isomer.13
Acknowledgements
The authors thank Neville Anthony, Chris Dinsmore, and George Hartman for critical reading of the
manuscript, Joan Murphy and Steve Pitzenberger for NMR spectroscopy expertise, Art Coddington, Harri
Ramjit, and Charles W. Ross III for mass spectral analyses, Joanne Kinneary for literature searches, and
Joy Hartzell for manuscript preparation.
References
1. Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.; Saperstein, R. Science 1980, 210, 656.
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3. Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem. 1982, 47, 104.
4. (a) Kurihara, T.; Nakajima, Y.; Mitsunobu, O. Tetrahedron Lett. 1976, 2455. (b) Mitsunobu, O. Synthesis 1981, 1.
5. Weissman, S. A.; Lewis, S.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39, 7459.
6. Townsend, C. A.; Nguyen, L. T. J. Am. Chem. Soc. 1981, 103, 4582.
7. (a) Hinds, M. G.; Richards, N. G. J.; Robinson, J. A. J. Chem. Soc., Chem. Commun. 1988, 1447. (b) Genin, M. J.; Gleason,
W. B.; Johnson, R. L. J. Org. Chem. 1993, 58, 860. (c) Genin, M. J.; Ojala, W. H.; Gleason, W. B.; Johnson, R. L. J. Org.
Chem. 1993, 58, 2334. (d) Hadfield, P. S.; Galt, R. H. B.; Sawyer, Y.; Layland, N. J.; Page, M. I. J. Chem. Soc., Perkin Trans.
1 1997, 503. (e) Chu, W.; Perlman, J. H.; Gershengorn, M. C.; Moeller, K. D. Bioorg. Med. Chem. Lett. 1998, 8, 3093.

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8. (a) Miller, M. J. Acc. Chem. Res. 1986, 19, 49. (b) Crossley, M. J.; Crumbie, R. L.; Fung, Y. M.; Potter, J. J. Tetrahedron
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9. Cox, J. M.; Gillen, K. J.; Ellis, R. M.; Vohra, S. K.; Smith, S. C.; Matthews, I. R. US Patent 5,670,656 (1997).
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11. Structures of the N-alkylation and O-alkylation products confirmed by HRMS, 1H NMR, 13C NMR and NOE experiments.
12. Synthesized by EDC/HOBT-mediated cyclization of (S)-N-(tert-butoxycarbonyl)homoserine.
13. Representative determination of enantiomeric purity (for 3a): A solution of (S)-3-(tert-butoxycarbonylamino)-2-oxo-1-(2-
pyridyl)pyrrolidine (3a) (65 mg) in EtOAc (5 mL) at 0°C was saturated with HCl (g). The mixture was stood at 0°C for
15 min, then concentrated in vacuo to provide (S)-3-amino-2-oxo-1-(2-pyridyl)pyrrolidine dihydrochloride as a white solid
1
(59 mg, 100%). H NMR (CD3OD) δ 8.43 (1H, ddd, J=5.1, 1.9, 0.8 Hz), 8.29 (1H, dt, J=8.6, 0.9 Hz), 7.96 (1H, ddd,
J=8.5, 7.4, 1.8 Hz), 7.29 (1H, ddd, J=7.3, 5.1, 1.1 Hz), 4.37 (1H, dd, J=11.0, 8.8 Hz), 4.33 (1H, ddd, J=10.5, 9.2, 1.1 Hz),
3.82 (1H, td, J=10.5, 6.7 Hz), 2.70 (1H, m), 2.16 (1H, m). (S)-3-Amino-2-oxo-1-(2-pyridyl)pyrrolidine dihydrochloride (23
mg) was dissolved in CH2Cl2 (1 mL) and Et3N (45 µL), and (R)-α-methoxy-α-trifluoromethylphenylacetic acid chloride
(19 µL) was added. The mixture was stood at ambient temperature for 30 min, then partitioned between EtOAc (5 mL)
and sat. aq. NaHCO3 (3 mL). The organic layer was washed with sat. aq. NH4Cl (3 mL), then brine (3 mL), then dried
over Na2SO4 and concentrated to dryness in vacuo to give (S,S)-α-methoxy-N-[2-oxo-1-(2-pyridyl)pyrrolidin-3-yl]-α-
trifluoromethylphenylacetamide which was sufficiently pure for NMR spectroscopic analysis. 1H NMR (CDCl3) δ 8.38–8.34
(2H, m), 7.70 (1H, ddd, J=8.4, 7.3, 1.8 Hz), 7.59–7.56 (2H, m), 7.44–7.38 (3H, m), 7.32 (1H, br d, J=5.5 Hz), 7.07 (1H,
ddd, J=7.2, 4.9, 0.9 Hz), 4.68 (1H, ddd, J=11.4, 8.4, 6.0 Hz), 4.29 (1H, ddd, J=10.3, 9.1, 0.9 Hz), 3.87 (1H, td, J=11.0, 6.6
Hz), 3.40 (3H, q, J=1.3 Hz), 2.81 (1H, m), 1.94 (1H, m). The (S,R)-diastereomer was also synthesized (by the same method
but using the (S)-Mosher’s acid chloride) for comparison purposes.