Direct N-acylation of lactams, oxazolidinones, and imidazolidinones with aldehydes by Shvo's catalyst

Article abstract of DOI:10.1021/ol302087z

Direct N-acylation of lactams, oxazolidinones, and imidazolidinones was achieved with aldehydes by Shvo's catalyst without using any other stoichiometric reagent. The N-acylations with α,β-unsaturated aldehydes were achieved with excellent yields.

Full text of DOI:10.1021/ol302087z

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Direct N‑Acylation of Lactams,
Oxazolidinones, and Imidazolidinones
with Aldehydes by Shvo’s Catalyst
Jian Zhang‡ and Soon Hyeok Hong*,†
Department of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 151-747, Korea, and Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
soonhong@snu.ac.kr
Received July 27, 2012
ABSTRACT
Direct N-acylation of lactams, oxazolidinones, and imidazolidinones was achieved with aldehydes by Shvo’s catalyst without using any other
stoichiometric reagent. The N-acylations with R,β-unsaturated aldehydes were achieved with excellent yields.
N-Acylated lactams, oxazolidinones, and imidazolidi-
nones are important organic molecules with a wide range
of biological activity. They are associated with certain
natural productsand drugs, suchasvariotin,1 aniracetam,2
piperlotine G,3 and imidapril.4 Functionalized chiral ox-
azolidinones are widely used as chiral auxiliaries and
ligands in asymmetric synthesis.5 A typical method for
the N-acylation of lactams, oxazolidinones, and imidazoli-
dinones is the usage of acyl chlorides or anhydrides in the
presence of a strong base such as nBuLi.6 Recent represen-
tative approaches are the N-acylation of oxazolidinones
with acid fluorides7 and mild bases, and the copper-
catalyzed coupling of aldehydes with free amides using
1.5 equiv of N-bromosuccinimide (NBS).8 These synthetic
methods are not environmentally friendly and atom eco-
nomical, as the reactions require more than stoichiometric
amounts of bases and generate halide and/or other wastes.
To develop a more versatile, operatively simple, and en-
vironmentally friendly synthetic route to the N-acylation
of cyclic amides from a readily available source, we envi-
sioned that the acylation could be carried out directly with
aldehydes generating hydrogen as the sole byproduct,
through generation of a hemiaminal intermediate and
dehydrogenation of the hemiaminal by a transition-metal
catalyst. Although there have been many reports on amide
‡ Nanyang Technological University.
† Seoul National University.
(1) (a) Takeuchi, S.; Yonehara, H.; Umezawa, H. J. Antibiot. 1959,
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Q. Y.; Katchman, A.; Lynch, G. Science 1991, 254, 288.
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N. X.; Thang, T. D.; Thanh, L. J. Agric. Food Chem. 2007, 55, 9436.
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r
10.1021/ol302087z
XXXX American Chemical Society

synthesis from amines and aldehydes,9 the acylation of
amides, which have a less nucleophilic N-atom, with
aldehydes has not been well studied.
Scheme 3. Selectivity Control by Sequential Hydrogenation or a
Hydrogen Acceptor
To achieve this goal, several transition-metal complexes
known to be active for alcohol dehydrogenation were
screened to afford N-benzoylpyrrolidone (3aa) from a
reaction of 2-pyrrolidinone (1a) and benzaldehyde (2a)
(Scheme 1). Among them, Ru-based Shvo’s catalyst (4a)
exhibited activity with a 21% yield of 3aa when 2.5 mol %
of 4a were used. Other Ru, Ir, or Rh complexes did not
exhibit any significant activity (please see the Supporting
Information, Table S1). Further optimization attempts to
improve the reaction by adding ligands and additives, such
as phosphines, bases, and Lewis acids, or by using a
different solvent were unsuccessful (Table S1). As we
observed benzyl benzoate and benzyl alcohol to be major
byproducts, we tried to increase the equivalence of alde-
hyde. The reaction was improved further to afford 52% of
3aa when the equivalence of 2a was increased to 5 equiv
(Scheme 1).
selectively, 1,4-benzoquinone was added as a hydrogen
acceptor. With 2 equiv of 1,4-benzoquinone, transfer
hydrogenation of the double bond did not occur and only
3ab-d was formed in 77% yield (condition C).
Due to the success in achieving a facile acylation of
2-pyrrolidinone directly with cinnamaldehyde, the scope
of the reaction was investigated (Table 1). Various func-
tionalgroupsincluding thiophene and furan weretolerated
in the reaction. Aliphatic aldehydes and aromatic alde-
hydes showed lower reactivity than R,β-unsaturated alde-
hydes. (2E,4E)-2,4-Hexadienal (2d) having a conjugated
diene groupwas a good acylating reagent, and there wasno
observation of a product with a reduced double bond, in
contrast to the cases using 2b (entries 5, 17, 20, and 23).
When R-methyl-trans-cinnamaldehyde (2e) was used, a
significantly lowered yield (20%) of 3ae was obtained
indicating the sensitivity to the steric hindrance of aldehydes.
In the case of 3ae formation, no double bond reduction was
observed. From the results in Table 1 (entries 1, 2, 4, 6, 10,
and 11), we speculate that the higher reactivity of cinnamal-
dehyde, compared to aromatic or aliphatic aldehydes, may
be due to less steric hindrance. Another reason could be the
bis-coordination of olefin and the carbonyl group as pro-
posed in the Yi’s report,10 which would facilitate the co-
ordination of ruthenium to the carbonyl group. In addition,
R,β-unsaturated aldehydes such as 2b and the acylation
products such as 2ab-d could work as hydrogen acceptors
to facilitate the reactions. A nootropic ampakine drug,
aniracetam (3ag),2 could be synthesized directly from 1a
and 2g with a moderate yield of 40% (entry 8).
Scheme 1. Direct N-Acylation of 2-Pyrrolidinone with
Benzaldehyde
Encouraged by the results, we searched for more acti-
vated aldehydes for the direct acylation of 1a. When
cinnamaldehyde (2b) was reacted with 1a, excellent yields
for the acylation products (93%, overall yields, Scheme 2)
were obtained with 1.5 equiv of 2b. As hydrogen transfer is
involved in the process, concurrent reduction of double
bond was observed with the acylation, generating two
products, 3ab-d and 3ab-s.
Scheme 2. Improved Reactivity of Cinnamaldehyde for
N-Acylation of 2-Pyrrolidinone
While 2-pyrrolidinone only showed moderate reactivity
to both alkyl aldehydes and aromatic aldehydes, 2-azeti-
dinone (1b), which has a more nucleophilic N-atom,
performed much better (entries 12À18). Good to excellent
yields were obtained with aliphatic, aromatic, and R-enals.
2-Azetidinone (β-lactam) derivatives have been widely
used as antibiotics.11 Here, a series of N-acylated β-lactam
Toselectively obtain either3ab-d or3ab-s asthe product,
we devised a few conditions (Scheme 3). First, atmospheric
pressure of hydrogen gas was applied to the reaction
mixture after the acylation reaction (condition A). Hydro-
genation catalyzed by a ruthenium species proceeded well
producing 3ab-s with a good yield of 81%. Even transfer
hydrogenation by adding isopropyl alcohol after the acy-
lation reaction was successful yielding 76% of 3ab-s
(condition B). These hydrogenations were carried out in
one pot without isolation of 3ab-d. Next, to obtain 3ab-d
(10) Kwon, K. H.; Lee, D. W.; Yi, C. S. Angew. Chem., Int. Ed. 2011,
50, 1692.
(11) (a) Fisher, J. F.; Meroueh, S. O.; Mobashery, S. Chem. Rev.
2005, 105, 395. (b) Elander, R. P. Appl. Microbiol. Biotechnol. 2003, 61,
385.
B
Org. Lett., Vol. XX, No. XX, XXXX

derivatives were successfully synthesized from aldehydes.
Even N-formylation of 1b was successful using paraform-
aldehyde (entry 18).
Acylation of six-membered 2-piperidone (1c) with 2b went
smoothly (entry 19). A reduced yield of 47% was observed
with 2d (entry 20). With a seven-membered lactam (1d), the
product yield dropped significantly demonstrating the reac-
tion efficiency was affected by the nucleophilicity of the
N-atom of lactams (entry 21). Dihydro-isoindol-1-one (1e)
also showed comparable reactivity with 1a (entries 22À25).
Table 1. Direct N-Acylation of Lactams with Aldehydesa
a Reaction conditions: Lactam (0.25 mmol, 1.0 equiv), aldehyde (3.0 equiv, unless otherwise noted), 4a (2.5 mol %), toluene (0.5 mL), 100 °C, 24 h.
b Yields are of the isolated product, and hydrogenation or hydrogen acceptor conditions applied after the reaction were noted in parentheses. c 5.0 equiv
of aldehyde were used. d 1.5 equiv of aldehyde were used. e Reaction was carried out in a sealed tube with 10 equiv of 2l at 120 °C for 24 h.
Org. Lett., Vol. XX, No. XX, XXXX
C

imidazolidin-2-one (3ha) was obtained if imidazolidin-2-
one (1h) reacted with 2a, while bis-substituted product
3hb-d was isolated if 2b was employed. We attributed this
to a solubility difference among the products as well as the
reactivity difference between 2a and 2b. Compound 3ha
was precipitated out of the toluene solution as the reaction
proceeded.
Table 2. Direct N-Acylation of Oxazolidinones and
Imidazolidinones with Aldehydesa
Based on the results and the reported studies on the
working mechanism of Shvo’s catalyst,12 a possible mech-
anism was proposed (Scheme 4). Nucleophilic attack of
lactam to the carbonyl functional group of aldehyde,
activated by 4b, could form a hemiaminal, which could
be further oxidized by a β-hydride elimination and proton
transfer to produce the acylation product and ruthenium
species 4c.12
Scheme 4. Proposed Mechanism
In summary, we have demonstrated that operatively
simple N-acylations of lactams, oxazolidinones, and imi-
dazolidinones could proceed directly with aldehydes by
Shvo’s catalyst without using any stoichiometric reagent.
The N-acylations with R,β-unsaturated aldehydes were
achieved with excellent yields. This current development
is a step forward to realizing the environmentally benign
and atom-economical N-acylation of amides directly
with aldehydes, which has wide applications in organic
synthesis.
a Reaction conditions: Heterocycle (0.25 mmol, 1.0 equiv), aldehyde
(3.0 equiv, unless otherwise noted), 4a (2.5 mol %), toluene (0.5 mL),
100 °C, 24 h. b Yields are of the isolated product, and hydrogenation or
hydrogen acceptor conditions applied after the reaction were noted in
parentheses. c 5.0 equiv of aldehyde were used. d 1.5 equiv of aldehyde
was used.
Next, we investigated the N-acylation of oxazolidinones
and imidazolidinones, which have a wide range of applica-
tions in biological and synthetic organic chemistry (Table 2).
Recently, Carreira and co-workers reported the N-acylation
of oxazolidinone derivatives using acid fluorides.7 Here,
N-acyl oxazolidinones were successfully synthesized di-
rectly from oxazolidinone and aldehydes with moderate
to good yields. Interestingly, monosubstituted N-benzoyl
Acknowledgment. This research was supported by the
Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by
the Ministry of Education, Science, and Technology
(2012R1A1A1004077).
Supporting Information Available. Details of experi-
mental procedures and characterization data. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
(12) (a) Casey, C. P.; Singer, S. W.; Powell, D. R.; Hayashi, R. K.;
Kavana, M. J. Am. Chem. Soc. 2001, 123, 1090. (b) Casey, C. P.;
Johnson, J. B.; Singer, S. W.; Cui, Q. J. Am. Chem. Soc. 2005, 127,
€
3100. (c) Johnson, J. B.; Backvall, J.-E. J. Org. Chem. 2003, 68, 7681. (d)
Conley, B. L.; Pennington-Boggio, M. K.; Boz, E.; Williams, T. J. Chem.
Rev. 2010, 110, 2294.
The authors declare no competing financial interest.
D
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