Asymmetric synthesis of γ-nitroesters by an organocatalytic one-pot strategy

Article abstract of DOI:10.1021/ol3002514

An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of α,β- unsaturated aldehydes is presented. The procedure is based on merging the enantioselective organocatalytic nitroalkane addition with an N-bromosuccinimide-based oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.

Full text of DOI:10.1021/ol3002514

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1516–1519
Asymmetric Synthesis of γ-Nitroesters by
an Organocatalytic One-Pot Strategy
Kim L. Jensen,† Pernille H. Poulsen,† Bjarke S. Donslund,† Fabio Morana,†,‡ and
Karl Anker Jørgensen*,†
Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark,
and Department of Chemistry and Industrial Chemistry, University of Genova, Italy
kaj@chem.au.dk
Received January 31, 2012
ABSTRACT
An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of R,β-unsaturated aldehydes is
presented. The procedure is based on merging the enantioselective organocatalytic nitroalkane addition with an N-bromosuccinimide-based
oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-
aminoesters, 2-piperidones, and 2-pyrrolidones.
The catalytic Michael reaction is an important and well-
studied process for stereoselective carbonꢀcarbon bond
formations in organic synthesis.1 In recent years, the field
of asymmetric organocatalytic Michael reactions has
received widespread attention.2 Among the reactions
studied, the conjugate addition of nitroalkanes to R,β-
unsaturated systems is of great interest, because the
products obtained are direct precursors to important
structural moieties, such as γ-aminocarbonyls, amino-
alkanes, 2-pyrrolidones, and 2-piperidones.3 Several
methods have been developed for the conjugate addition
of nitroalkanes to enones4 and enals;5 however, notably,
no direct asymmetric addition to conjugate esters6 has
been reported to date, which is surprising given the broad
applicability of these compounds in the fields of organic,
pharmaceutical, and material chemistry (Figure 1).7
† Aarhus University.
‡ University of Genova.
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, U.K., 1992.
(2) For recent reviews on asymmetric organocatalytic Michael reac-
Figure 1. Application of γ-nitroesters in synthesis.
ꢀ
tions, see: (a) Almas-i, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Traditionally, esters are prepared from the free car-
boxylic acid, which most often needs activation prior to
Asymmetry 2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007,
1701.
(3) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem.
Rev. 2005, 105, 933.
ꢀ
(5) (a) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.;
Vera, S. Angew. Chem., Int. Ed. 2007, 46, 8431. (b) Gotoh, H.; Ishikawa,
H.; Hayashi, Y. Org. Lett. 2007, 9, 5307. (c) Zu, L.; Xie, H.; Li, H.;
Wang, J.; Wang, W. Adv. Synth. Catal. 2007, 349, 2660. (d) Wang, Y.; Li,
P.; Liang, X.; Zhang, T. Y.; Ye, J. Chem. Commun. 2008, 1232.
(6) For an intramolecular Michael addition to conjugated esters, see:
Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am.
Chem. Soc. 2009, 131, 16016.
(7) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Otera, J. Esterification: Methods, Reactions and Applications;
Wiley: New York, 2003.
(4) (a) Yamaguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama, M.
Tetrahedron Lett. 1994, 35, 8233. (b) Yamaguchi, M.; Igarashi, Y.;
Reddy, R. S.; Shiraishi, T.; Hirama, M. Tetrahedron 1997, 53, 11223. (c)
Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (d) Halland, N.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331. (e) Tsogoeva, S. B.;
Jagtap, S. B. Synlett 2004, 2624. (f) Prieto, A.; Halland, N.; Jørgensen,
K. A. Org. Lett. 2005, 7, 3897. (g) Mitchell, C. E. T.; Brenner, S. E.; Ley,
S. V. Chem. Commun. 2005, 5346. (h) Mitchell, C. E. T.; Brenner, S. E.;
Garcia-Fortanet, J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039. (i)
Hanessian, S.; Shao, Z.; Warrier, J. S. Org. Lett. 2006, 8, 4787.
r
10.1021/ol3002514
Published on Web 02/29/2012
2012 American Chemical Society

the esterification step. The direct formation of esters from
aldehydes, also known as one-pot oxidative esterification,
combines oxidation and CꢀO bondformation intoa single
step. This approach has become an economically attractive
alternative, because it utilizes readily available materials
and avoids isolation of the free carboxylic acid interme-
diates. These obvious advantages have inspired numerous
investigations of the direct conversion of aldehydes into
esters.8 We envisioned that a one-pot enantioselective
synthesis of γ-nitroesters9 could be accomplished by mer-
ging the organocatalytic Michael addition of nitroalkanes
to R,β-unsaturated aldehydes with a suitable oxidative
esterification process (Scheme 1).
2a (3 equiv) applying 10 mol % of (S)-2-(diphenyl-
(trimethylsilyloxy)methyl)pyrrolidine11 3 as the catalyst12
in MeOH at room temperature. Under these conditions,
full and clean conversion to the Michael adduct A was
observed. The anticipated oxidative esterification was then
attempted, and, gratifyingly, theaddition of1.5 equiv ofN-
bromosuccinimide 4 (NBS) gave full conversion to the
desired product 5a, by incorporation of the solvent,
MeOH. The product was obtained in 58% yield and
94% ee, along with a minor amount of the dimethyl acetal
6, which could be separated from the product by column
chromatography. It should be noted that no R-bromina-
tion of the aldehyde was observed.13 The appearance of 6
as a byproduct can be explained by the mechanistic
proposal presented in Scheme 2.
Scheme 1. Synthetic Outline for the Formation of γ-Nitroesters
Scheme 2. Mechanistic Proposal for the Oxidative Esterification
Process
Previous studies have demonstrated that bromine, io-
dine, or N-iodosuccinimide in alkaline alcoholic solutions
can function as mild oxidants for this transformation.10
However, a major complication of this reaction design is
the fact that the intermediate aldehyde products readily
undergo 1,2-intermolecular addition of nitromethane
via the Henry reaction under basic conditions. Therefore,
in order to achieve a successful oxidation, the use of a basic
oxidation medium should be avoided. Furthermore, the
oxidant should not react with the substrate in an enamine-
based reaction, thereby functionalizing the R-position.
Herein, we present a simple and straightforward asym-
metricsynthesisof γ-nitroesters from readily availableR,β-
unsaturated aldehydes, nitromethane, and MeOH
(Scheme 1). The reaction takes place under mild condi-
tions, and the products are formed in good yields and
enantioselectivities in a one-pot process.
The intermediate hemiacetal B is assumed to react with
NBS to form the corresponding hemiacetal hypobromite
species C. Subsequent elimination of HBr furnishes the
oxidized product 5 (Scheme 2).10 Notably, the acid formed
can function as a catalyst for the formation of the acetal
byproduct. In order to avoid the formation of 6, a screening
of weakly basic additives was attempted. These conditions
resulted in low conversions/yields and substantial amounts
of the Henry condensation product. Application of less than
1.5 equiv of NBS resulted in a reduced product to acetal
ratio, whereas increased amounts gave no improvement.
With the obtained conditions in hand, the scope of the
one-pot formation of γ-nitroesters 5 was examined for a
series of R,β-unsaturated aldehydes as demonstrated in
Scheme 3.
We started our studies by performing the initial Michael
reaction5 between cinnamaldehyde 1a and nitromethane
In general, all the reactions evaluated gave full conver-
sion to the desired products 5aꢀn with good yields ranging
(8) For a recent review on one-pot oxidative esterifications, see: (a)
Ekoue-Kovi, K.; Wolf, C. Chem.;Eur. J. 2008, 14, 6302. For carbene-
based oxidations, see e.g.: (b) Maki, B. E.; Scheidt, K. A. Org. Lett. 2008,
10, 4331. (c) Giun, J.; Sarkar, S. D.; Grimme, S.; Studer, A. Angew.
Chem., Int. Ed. 2008, 47, 8727. (d) Sarkar, S. D.; Grimme, S.; Studer, A.
J. Am. Chem. Soc. 2010, 132, 1190.
(9) For other procedures for the synthesis of optically active γ-
nitroesters, see e.g.: Baschieri, A.; Bernardi, L.; Ricci, A.; Suresh, S.;
Adamo, M. F. A. Angew. Chem., Int. Ed. 2009, 48, 9342.
(10) For an example with bromine as oxidant, see: (a) Williams,
D. R.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F. W. Tetrahedron
Lett. 1988, 29, 5087. For an example with N-iodosuccinimide
as oxidant, see: (b) McDonald, C.; Holcomb, H.; Kennedy, K.;
Kirkpatrick, E.; Leathers, T.; Vanemon, P. J. Org. Chem. 1989, 54, 1213.
(11) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. For
general and comprehensive reviews on applications of the diarylprolinol
silylether catalysts, see: (c) Palomo, C.; Mielgo, A. Chem.;Asian J.
2008, 3, 922. (d) Xu, L.-W.; Li, L.; Shi, Z.-H. Adv. Synth. Catal. 2010,
352, 243. (e) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.;
Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248.
(12) Other related catalysts were less effective.
(13) Bertelsen, S.;Halland,N.;Bachmann, S.;Marigo,M.;Braunton,A.;
Jørgensen, K. A. Chem. Commun. 2005, 4821.
Org. Lett., Vol. 14, No. 6, 2012
1517

good yields (59 and 56%) and 94% ee. Finally, the reaction
concept was extended toaliphaticaldehydesbyapplication
of non-2-enal 1n, which furnished the desired product 5n in
54% yield and 94% ee. It should be noted that substantial
amounts of the acetal 6 was formed in the reactions of
aldehydes 1b,c,e,f,k when 1.5 equiv of NBS was employed.
The problem was successfully addressed by employing 3.0
equiv of NBS.
Scheme 3. Scope of the One-Pot Process for the Formation of
γ-Nitroestersa
Scheme 4. Application of Nitropropane in the One-Pot Proce-
dure
The developed one-pot procedure also proved suitable
for other nitroalkanes as illustrated in Scheme 4.
Accordingly, the Michael addition of nitropropane 2b to
4-chlorocinnamaldehyde 1e proceeded smoothly, when
applying 20 mol % of catalyst 3. The subsequent oxidative
esterification with NBS afforded two diastereomeric pro-
ducts 5o and 5o0 in a combined yield of 94%. The isomers
were obtained in good enantioselectivities (85 and 92% ee)
and a diastereoselectivity of 55:45.
In order to demonstrate the synthetic value of the
formed γ-nitroesters 5, a series of transformations were
performed (Scheme 5). A reductive cyclization of the
para-chloro-substituted product 5e was easily achieved
by hydrogenation using NiCl2/NaBH4 affording the
2-pyrrolidone 7 in 88% yield. The lactam 7 can then be
hydrolyzed using 6 M HCl to afford the hydrochloride
salt of Baclofen,14 which is a therapeutically important
GABAB receptor agonist.15 The products also provide
access to 2-piperidones, which are key intermediates for
the preparation of pharmaceutically important drug can-
didates.16 The synthesis was accomplished by a one
carbon homologation via a nitro-Mannich reaction. In
practice, the reaction was carried out by treating product
ent-5d with benzylamine and formaldehyde in an i-PrOH/
H2O mixture. After 4 h the 2-piperidone product 8 was
obtained as a 3:1 diastereomeric mixture and the major
trans-diastereomer was isolated in 48% yield and 94% ee.
The obtained product could potentially be applied for
the synthesis of (3S,4R)-paroxetine, which is a selective
serotonin reuptake inhibitor used in the treatment of
depression.17
a For reaction conditions, see Supporting Information. b3.0 equiv of
NBS employed.
from 54 to 78% and high enantioselectivities (93 to 96% ee).
The scope of the 4-substituted cinnamaldehyde derivatives
was first examined, demonstrating that the electronic
nature of the substituent had little effect on the outcome
of the reaction. Electron-rich substituents, illustrated by a
methyl and tert-butyl group, gavethe products 5band 5c in
good yields (54 and 78%) with an enantioselectivity of
96% ee. Electron-poor substituents were also tolerated
affording the products 5dꢀi in good yields (59 to 67%) and
enantioselectivities (94 to 96% ee). To further test the
developed reaction concept, different substitution patterns
of the aldehyde were explored. Aldehydes with chloro- and
trifluoromethyl-substituents in the meta-position were
successfully applied, affording the products 5j and 5k in
good yields and enantioselectivities (70 and 69% with 94
and 93% ee, respectively). It was also demonstrated that
ortho-methyl and 2,4,5-trifluoro-substituted aldehydes
were tolerated, affording the γ-nitroesters 5l and 5m in
(14) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.
J. Am. Chem. Soc. 2005, 127, 119.
(15) For information on Baclofen, see: Felluga, F.; Gombac, V.;
Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2005, 16, 1341 and
references therein.
(16) Xu, F.; Corley, E.; Murry, J. A.; Tschaen, D. M. Org. Lett. 2007,
9, 2669 and references therein.
(17) Barnes, R. D.; Wood-Kaczmar, M. W.; Curzons, A. D.; Lynch,
I. R.; Richardson, J. E.; Buxton, P. C. U.S. Patent 24721723, 1986.
1518
Org. Lett., Vol. 14, No. 6, 2012

of γ-nitroesters in good yields and enantioselectivities. The
method is based on a one-pot asymmetric aminocatalyzed
addition of nitroalkanes to R,β-unsaturated aldehydes
followed by an oxidative esterification using NBS as the
oxidant. The system displays great tolerance toward a
number of aromatic as well as aliphatic aldehydes. The
synthetic usefulness of the products was demonstrated by
the synthesis of 2-pyrrolidones and 2-piperidones, which
can be utilized in the synthesis of pharmaceutically im-
portant compounds.
Scheme 5. Synthetic Transformations of the Formed γ-Nitroe-
sters
Acknowledgment. Thanks are expressed to Aarhus
University, Carlsberg Foundation and FNU for financial
support.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have designed a one-pot procedure,
classified as a Type A-2-1C2X reaction,18 for the synthesis
(18) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 8492.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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