Diastereoselective synthesis of 1,3,5- Trisubstituted 4-nitropyrrolidin-2- ones via a nitro-mannich/lactamization cascade

Article abstract of DOI:10.1021/ol202710g

A versatile one-pot nitro-Mannich/lactamization cascade for the direct synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones has been developed. The reaction is easy to perform and broad in scope, and high levels of diastereoselectivity can be achiev

Full text of DOI:10.1021/ol202710g

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6406–6409
Diastereoselective Synthesis of 1,3,5-
Trisubstituted 4-Nitropyrrolidin-2-ones via
a Nitro-Mannich/Lactamization Cascade
Sophie M.-C. Pelletier,† Peter C. Ray,‡ and Darren J. Dixon*,†
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U.K., and MSD Research Institute, Newhouse,
Motherwell, ML1 5SH, U.K.
Darren.Dixon@chem.ox.ac.uk
Received October 10, 2011
ABSTRACT
A versatile one-pot nitro-Mannich/lactamization cascade for the direct synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones has been
developed. The reaction is easy to perform and broad in scope, and high levels of diastereoselectivity can be achieved.
In recent times, the nitro-Mannich1 reaction has
emerged as a powerful synthetic tool for the construction
of important intermediates and building blocks. We re-
cently described2 an efficient nitro-Mannich/lactamization
cascade3 of methyl 3-nitropropanoate for the direct pre-
paration of pyrrolidin-2-ones4 (Scheme 1).
† University of Oxford.
‡ MSD Research Institute.
€
€
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2669. (b) Jakubec, P.; Helliwell, M.; Dixon, D. J. Org. Lett. 2008, 10, 4267.
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Scheme 1. Previous Work: One-Pot Synthesis of Pyrrolidinones
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r
10.1021/ol202710g
Published on Web 11/23/2011
2011 American Chemical Society

In order to extend this chemistry to enable the synthesis
of biologically active compounds5,6 and natural products7
(Figure 1), we required a method of introducing an
alkyl substituent alpha to the lactam carbonyl. A range of
conditions to directly alkylate the previously synthesized
pyrrolidin-2-ones were attempted but failed to yield any of
the desired products.
Table 1. Preliminary Conditions Screen in the Nitro-Mannich/
Lactamization Cascade
1H NMR
entry
solvent
yield (%)a
dr
1
2
3
4
5
6
MeOH
EtOAc
Et2O
29
62
84
60
92
93
ꢀ
3:1
3.5:1
3.5:1
4.5:1
4.5:1
THF
Hexane
Toluene
a 1H NMR yield measured against an internal standard.
Figure 1. Pyrrolidin-2-one natural products and biologically
active compounds.
in the formation of the fully substituted pyrrolidin-2-one
products remained to be investigated. First, a range of
alkyl substituted methyl 3-nitropropanoate starting mate-
rials were synthesized using a modification of literature
procedures (Scheme 2).8 The desired monoalkylated nitro-
esters 1bꢀe were isolated in moderate to good yields (38%
to73%), and in some cases, gem-alkylated nitroesters1fꢀg
were obtained as a minor side product of the reaction
(10ꢀ20% yield).
Accordingly, and in order to circumvent this issue,
we decided to investigate an alternative route in which
the methyl 3-nitropropanoate was C-alkylated prior to the
nitro-Mannich/lactamization cascade. In relation to our
previously published work, this development would raise
new issues of reactivity, reaction scope, and diastereoselec-
tion in the products and as such was a worthy pursuit.
Herein we wish to report our findings leading to a diaste-
reoselective synthesis of 1,3,5-trisubstituted 4-nitropyrro-
lidin-2-ones via a nitro-Mannich/lactamization cascade.
Following modified literature procedures,8 methyl
2-benzyl-3-nitropropanoate 1b was synthesized in one
scaleable step from the parent methyl 3-nitropropanoate
1a. With 1b in hand, a range of preliminary experiments
to identify conditions for a nitro-Mannich lactamization
cascade were performed using isobutyraldehyde (1.5 equiv),
butylamine (1.5 equiv), and benzoic acid (1.5 equiv) in a
range of solvents at 70 °C for a fixed time of 12 h. Although
little product was observed in methanol, pleasingly with
ethyl acetate, diethyl ether, and tetrahydrofuran as sol-
vents, the reactions were efficient and the diastereoselec-
tivities were moderate. Further screening revealed hexane
and toluene to be optimal with respect to both reaction
yield and diastereoselectivity (Table 1). Additional studies
revealed that variations to the dilution, the temperature,
the nature of the acid, and the stoichiometry of the reagents
had no significant influence on the reaction dr which re-
mained at ∼4.5:1.
Scheme 2. Synthesis of R-Substituted Methyl 3-Nitropropanoates
Initially with alkyl-substituted nitropropanoate methyl
esters 1bꢀd, we probed the scope of the nitro-Mannich/
lactamization reaction using 1.5 equiv respectively of
amine, aldehyde, and benzoic acid in toluene at 70 °C.
The results are presented in Scheme 3. Initially, the reac-
tion was performed using isobutyraldehyde and butyla-
mine. Pleasingly, monosubstituted alkylnitroesters 1bꢀ1d
all provided the desired products 2aꢀ2c. Reaction yields
averaged 73%, and moderate to good diastereoselectivities
(rangingfrom 3.5:1 to5.5:1 dr) were obtained. Substituting
butylamine for 2-(2-methoxyphenyl)ethanamine gave similar
results with isobutyraldehyde (2dꢀ2f). In each case, the 2-
methylsubstituted nitroester starting material 1d gave a lower
diastereoselectivity than the analogous benzyl substituted or
ethyl substituted starting materials, 1b and 1c respectively.
With the sterically hindered gem-dialkylated starting mate-
rial (1f and 1g) no reactivity under these conditions was
With optimal reaction conditions established, the scope
of the reaction and the degree of stereocontrol possible
(6) Enz, A.; Feuerbach, D.; Frederiksen, M. U.; Gentsch, C.; Hurth,
€
K.; Muller, W.; Nozulak, J.; Roy, B. L. Bioorg. Med. Chem. Lett. 2009, 19,
1287.
ꢀ
(7) Guntern, A.; Ioset, J.-R.; Queiroz, E. F.; Sandor, P.; Foggin,
C. M.; Hostettmann, K. J. Nat. Prod. 2003, 66, 1550.
(8) (a) O’Neil, I. A.; Bhamra, I.; Gibbsons, P. D. Chem. Commun.
2006, 4545. (b) Seebach, D.; Henning, R.; Mukhopadhyay, T. Chem.
Ber. 1982, 115, 1705.
Org. Lett., Vol. 13, No. 24, 2011
6407

1
the H NMR coupling constants, the stereochemistry of
observed. Interestingly, when p-methoxybenzaldehyde was
employed in the cascade, a significant increase in diaste-
reocontrol was observed. With ethyl and benzyl substi-
tuted nitroesters the diastereoselectivity was greater than
10:1. This high level of diastereocontrol was maintained
through ortho (2j), meta (2k), and para (2g) substitution
around the ring and for electron-rich (2g), electron-poor
(2l), and halide substituted (2m) rings.
the major diastereoisomer of pyrrolidinones 2bꢀk and
2mꢀo was assigned by analogy. Similarly, the trans/cis
relative stereochemistry of the minor diastereoisomers of
the reaction was assigned by analogy to that of 2n which
was unambiguously determined by single crystal X-ray
analysis;9 see Supporting Information for details.
Analysis of the data from Scheme 3 suggested that the
degree of diastereocontrol varied as a function of the steric
demand of the reagents. Accordingly sterically demanding
methyl 2-isopropyl-3-nitropropanoate 1e was investigated
(Scheme 4), and indeed good to excellent diastereocontrol
ranging from 7.5:1 for 2t to 30:1 for 2p was observed.
Using the hindered amine, isopropylamine, also gave rise
to improved dr (5:1 for 2u vs 3.5:1 for 2o), but the reaction
is significantly slower and when reacted with 3-isopropyl-
nitroester 1e, no formation of product was observed.
Scheme 3. Scope of Nitro-Mannich/Lactamization Cascade
Scheme 4. Influence of Steric Hindrance on the Diastereocontrol
In order to begin to rationalize these data, the major and
the minor diastereoisomer of 2c, once separated, were
subjected to simulated reaction conditions. After 48 h at
70 °C, no epimerization was observed. Furthermore, sub-
jection of (S)-1d to the cascade reaction with p-methoxy-
benzaldehyde and butylamine afforded (þ)-2i in >99%
ee: racemization was not occurring at any point in the
reaction pathway between 1d and 2i (Scheme 5).
The trans/transrelativestereochemistryof themajordia-
stereomer was unambiguously determined by single crystal
X-ray analysis of compounds 2a and 2l. By comparison of
(9) Data for 2a and 2l were collected at 100 K using a Bruker Apex II
diffractometer and solved and refined using SHELXTL [G. M. Sheldrick,
G. M. Acta Crystallogr. 2008, A64, 112–122]. Data for 2n were collected
at 150 K[Cosier, J.; Glazer, A. M. J. Appl. Crystallogr. 1986, 19, 105ꢀ107]
using a Nonius KCCD Diffractometer[Otwinowski, Z.; Minor, W.
Processing of X-ray Diffraction Data Collected in Oscillation Mode,
Methods in Enzymology; Carter, C. W., Sweet, R. M., Eds.; Academic
Press: 1997; p 276], solved with SIR92 [ Altomare, A.; Cascarano, G.;
Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M.
J. Appl. Crystallogr. 1994, 27, 435] and refined with CRYSTALS
[Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin,
D. J. J. Appl. Crystallogr. 2003, 36, 1487. Cooper, R. I.; Thompson,
A. L.; Watkin, D. J. J. Appl. Crystallogr. 2010, 43, 1100–1107]. Crystal-
lographic data have been deposited with the Cambridge Crystallo-
graphic Data Centre (CCDC 853455 - 853457) and can be obtained
via www. ccdc.cam.ac.uk/data_request/cif.
Scheme 5. Cascade Reaction with Enantiopure Substrate
6408
Org. Lett., Vol. 13, No. 24, 2011

reaction speed varies strongly with the ester substituent:
the reaction with 1h is approximately twice as slow as the
reaction with 1a and approximately three times slower
than the reaction with 1i. Hence, the rate increases with
decreasing size or increasing reactivity of the ester moiety.
By assuming that exchanging ethyl for methyl or phenyl
does not significantly affect the pKa of the carbon bearing
the nitro group, these results suggest that lactamization is
rate-determining. It is therefore reasonable that the origin
of diastereocontrol lies in the favorable pseudoequatorial
positioning of the substituents during the lactamization
step and not during the nitro-Mannich reaction, which we
suspect is reversible.
Scheme 6. Investigation of the Rate-Determining Step
In summary, an efficient diastereoselective nitro-Mannich/
lactamization reaction cascade of methyl 2-alkyl 3-nitro-
propanoate with imines generated in situ has been de-
veloped. This versatile extension of our previous work
now allows direct, diastereoselective preparation of 1,3,
5-trisubstituted 4-nitropyrrolidin-2-one derivatives. The
diastereocontrol is likely to originate during the rate-
determining lactamization step of this reaction cascade.
Acknowledgment. We thank the EPSRC (for a student-
ship to S.M.P. and for a Leadership Fellowship to D.J.D.)
and MSD (for a studentship to S.M.P.) for support. We
thank Alison Hawkins of the Department of Chemistry,
University of Oxford, for X-ray structure determination
and the Oxford Chemical Crystallography service for use
of the instrumentation. We also thank Georgina Rosair
of the Heriot Watt University for X-ray structure deter-
mination.
Further studies were undertaken, using a cyclic imine 3
as a model substrate, to establish which one of the nitro-
Mannich or the lactamization reactions was the rate-
determining step. Three nitroesters 1a, 1h, and 1i bearing
different ester groups (ethyl 1h, methyl 1a,10 and phenyl 1i)
were synthesized and reacted with 3,4-dihydroisoquinoline
3 and benzoic acid in deuterated toluene in an NMR tube
at 35 °C. The conversion to 4 was measured by 1H NMR
spectroscopy at 10 min intervals over 8 h, and the results
are displayed in Scheme 6. As shown in the graph, the
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for products 1aꢀf
and 2aꢀv. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) Prepared according to literature. (a) Griesser, H.; Ohrlein, R.;
Schwab, W.; Ehrler, R.; Jager, V. Org. Synth. 2004, Coll. Vol. 10, 577.
(b) Silva, P. C.; Costa, J. S.; Pereira, V. L. P. Synth. Commun. 2001, 31, 595.
Org. Lett., Vol. 13, No. 24, 2011
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