Oxidative cleavage of lactams in water using dioxiranes: An expedient and environmentally-safe route to ω-nitro acids

Article abstract of DOI:10.1016/j.tetlet.2012.11.074

By taking advantage of the appreciable stability of dioxiranes in water, a safe yet efficient route to ω-nitro acids by oxidation of lactams of various ring sizes under mild conditions has been reported. In essentially all the cases examined, reactions proceed selectively to afford products in remarkably high yields (up to 99%) and with high purity (94-99%). Also, an interesting example of higher reaction selectivity in water than in organic solvent (acetonitrile) is discussed.

Full text of DOI:10.1016/j.tetlet.2012.11.074

Tetrahedron Letters 54 (2013) 515–517
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative cleavage of lactams in water using dioxiranes: an expedient and
environmentally-safe route to
x-nitro acids
Cosimo Annese a, Lucia D’Accolti a, , Rosella Filardi a, Immacolata Tommasi a, Caterina Fusco b,
⇑
⇑
a Dipartimento di Chimica, Università di Bari ‘A. Moro’, v. Orabona 4, 70126 Bari, Italy
b CNR-ICCOM, Dipartimento di Chimica, Università di Bari, v. Orabona 4, 70126 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
By taking advantage of the appreciable stability of dioxiranes in water, a safe yet efficient route to
x-nitro
Received 15 October 2012
Revised 14 November 2012
Accepted 19 November 2012
Available online 29 November 2012
acids by oxidation of lactams of various ring sizes under mild conditions has been reported. In essentially
all the cases examined, reactions proceed selectively to afford products in remarkably high yields (up to
99%) and with high purity (94–99%). Also, an interesting example of higher reaction selectivity in water
than in organic solvent (acetonitrile) is discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
We are pleased to dedicate this work to
Professor Ruggero Curci (Brown University,
Providence, RI) on the occasion of his 75th
birthday.
Keywords:
Dioxiranes
Oxidation
Aqueous solvent
Lactams
x
-Nitro acids
In recent years, the search for a clean and a more sustainable
CH3CN) can be used when performing the oxidation reactions;
the others commonly employed in organic synthesis (e.g. ethers,
alcohols, alkanes) being easily oxidizable under the typical reaction
conditions. Nevertheless, dioxiranes appear sufficiently stable in
water to be amenable to convenient oxidations in aqueous media.
In spite of the beneficial aspects of this synthetic approach, the
chemistry of dioxiranes has not hitherto been thoroughly investi-
gated in water, even though these peroxides are notoriously gener-
ated in aqueous media.2,3
chemistry has urged chemists to develop synthetic procedures that
avoid the use of toxic solvents and hazardous chemicals. In this
direction, a number of classical synthetic procedures have simply
been turned into their clean version by adopting, for instance, sol-
vent-free conditions or even water as the reaction solvent.1
Over the past two decades, we and others have been actively
engaged in showing that the three-membered ring peroxides 1
(Fig. 1), that is, the dimethyldioxirane (DDO, 1a)2 and its trifluoro
analog 1b (TFDO),3 are powerful and versatile oxidants, rivaling
other popular oxidation methods in efficiency, selectivity, and sim-
plicity of experimental procedures. Dioxirane-mediated oxidations
range from epoxidation of olefins,4,5 oxidation of compounds con-
taining heteroatoms (e.g., sulfides ? sulfoxides ? sulfones; ami-
nes ? nitro compounds)6 to hydroxylation of the C–H bond.7
Noticeably, all these reactions occur under very mild conditions,
i.e. ambient or sub-ambient temperature and pH close to
neutrality.
With this in mind, we describe herein an efficient and environ-
mentally-benign synthesis of valuable
of representative lactams with dioxirane 1b in water. These com-
pounds, carrying two -functionalities, are of special interest
x-nitro acids by oxidation
a,x
in the synthesis of valuable targets.8,9 In general, organic nitro
compounds have recently received growing attention as building
blocks for the generation of carbon–carbon bond, since it was
shown that such reactions can be carried out as efficiently in water
solvent as in common organic solvents.9,10 This represents an
undeniable advantage from an industrial stand-point, since the
The remarkable versatility of dioxiranes suggests that a re-
stricted array of solvents (usually CH2Cl2, CHCl3, CCl4, acetone,
⇑
Corresponding authors. Tel.: +39 080 544 2070; fax: +39 080 553 9596.
E-mail addresses: lucia.daccolti@uniba.it (L. D’Accolti), fusco@ba.iccom.cnr.it
(C. Fusco).
Figure 1. Structure of commonly employed dioxiranes (1).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.074

516
C. Annese et al. / Tetrahedron Letters 54 (2013) 515–517
replacement of toxic solvents still remains a crucial challenge, in
terms of economical and environmental benefits.
Inspection of data in Table 1 suggests that the oxidation of lac-
tams 2a–f with TFDO (1b) to the corresponding -nitro acids 3a–f
x
To our knowledge, the only practical approach to
was described by Ballini et al.8 Such method appears quite general,
consisting in the ring cleavage of -nitrocycloalkanones in aqueous
x
-nitro acids
is a remarkably efficient process. Indeed, in practically all the cases
examined, the use of a moderate oxidant to substrate molar ratio
allows to drive the reaction to completion within a few hours.
Nonetheless, an outstandingly high selectivity is observed, so that
a
solution of 0.05 M sodium hydroxide, at 80 °C, in the presence of
catalytic amounts of cetyltrimethylammonium chloride (CTACl)
x-nitro acids could be obtained with excellent yields and high pur-
as a cationic surfactant. Accordingly, a variety of
nones (from 6-membered to 15-membered rings) can be converted
to the corresponding -nitro acids in good to excellent yields; the
only exception being represented by the fission of the -nitrocy-
a
-nitrocycloalka-
ity (94–99%, HPLC) even as crude products.
The only noticeable gap along the nicely smooth reaction trend
of Table 1 is represented by the oxidation of d-valerolactam (2c)
(entry 3), in which case the relatively small amount of nitro acid
2c obtained (42% isolated yield) is accompanied by 45% of glutaric
acid and 5% of glutarimide (Table 1, footnote c).
x
a
clooctanone, which leads to a mixture of unidentified products.8
It should be recalled that lactams are highly available starting
materials, many of which being useful building blocks for the
large-scale manufacture of commodities. Thus, concurrent with
Ballini’s approach mentioned above, we feel that the dioxirane-
mediated oxidation of lactams may represent a valuable route to
Due to the relatively high cost of 10-, and 11-membered lac-
tams as starting materials, we found it poorly convenient to pursue
the synthesis of the corresponding
scribed herein. On the other hand, we attempted the synthesis of
the valuable fatty
-nitro acid 3g12 by TFDO oxidation of the much
x-nitro acids by the method de-
x
-nitro acids. Table 1 collects the results of the dioxirane oxidation
x
of representative small- to large-ring lactams. Earlier attempts to
oxidize the 7-membered lactam 2d with DDO (1a) proved unsuc-
cessful. Therefore, oxidations were conveniently performed with
the more powerful dioxirane 1b.
accessible laurolactam 2g. Owing to the limited solubility of 2g in
water (ca. 0.012 mol/L at 25 °C), the oxidation of the latter was per-
formed in the presence of cetyltrimethylammonium hydrogensul-
fate (CTAHS) as a surfactant. Under the conditions specified in
Table 1 (entry 7), the reaction occurs selectively to give 12-nitrod-
odecanoic acid (3g) as the unique product in 95% isolated yield
(based on the amount of starting material reacted).13 In spite of
the eightfold larger molar amount of oxidant 1b employed, the
reaction conversion was somewhat low (46%), most likely due to
the competitive oxidation of the surfactant alkyl chains.
In an attempt to overcome this limitation, a suspension of fi-
nely-dispersed 2g in water was treated with 1b (4.5 equiv). Under
these conditions (entry 8, Table 1), a mixture of unidentified prod-
ucts was obtained, as revealed by the 1H- and 13C NMR analyses of
the crude reaction mixture. Yet, the NMR spectral profiles appear
even more complex when the oxidation of 2g with TFDO is run
in an acetonitrile solvent under similar conditions (entry 9, Ta-
ble 1). Thus, it seems likely that the presence of CTAHS would be
crucial in order to achieve selectivity. However, its role remains ob-
scure and needs further careful investigations. In any case, this rep-
resents a remarkable example of increased reaction selectivity in
the aqueous medium with respect to organic solvent.
Reactions were routinely carried out by addition (usually 3–
5 mL) of a cold solution (0.5–0.7 M) of the oxidant 1b in 1,1,1-tri-
fluroacetone (TFP) to a solution of the lactam substrate (30–
60 mg) in water (4–6 mL) kept at ca. 0 °C under vigorous stirring.
The reaction progress was monitored by periodical HPLC analyses
of the reaction mixture or by following the oxidant decay iodomet-
rically. Upon reaction completion, TFP (the product of 1b reduc-
tion) was recovered by distillation (80–85%) and reused for
regeneration of the oxidant 1b, thus closing what appears to be a
catalytic cycle with an ex-situ regeneration of the active species.
Products were obtained by extraction from the aqueous medium
or upon removal of the latter by distillation under reduced pres-
sure or by freeze-drying. In most of the cases, crude
x-nitro acids
displayed high purity (94–99%, HPLC) so that further purification
was not pursued. Characterization by means of 1H, 13C NMR, IR,
and GC–MS techniques provided spectra in full agreement with
the literature.8,11
To our knowledge, the oxidative cleavage of the amide bond
with 1b is unprecedented in dioxirane chemistry. Even in our re-
cent works on the oxyfunctionalization of peptides by dioxiranes,14
we never reported on sizeable amounts of products deriving from
the oxidative cleavage of the peptide bond. In this respect, one
might argue that, given the different chemical environment sur-
rounding the amidic bond, peptides and lactams should display a
diverse reactivity toward dioxirane oxidation. Consistent with this
view, reaction of 1,4-diketopiperazine (4) (formally both a cyclic
dipeptide and a lactam) with 1b (Scheme 1) provides no sizeable
oxidation products, suggesting that the cyclic arrangement of lac-
tams has little influence over the amide bond reactivity in the
transformations at hand. Rather, based on electronic effect argu-
ments, amidic bonds in peptides should experience an electron-
withdrawing effect exerted by the proximal amino acid residue
along the peptide chain; consequently, their oxidative cleavage
by the electrophilic dioxirane attack should be efficaciously
prevented.
Table 1
Oxidation of lactams to
x
-nitro acids by TFDO (1b)a
Entry
n
Substrate
Ox/Subb
Time (min)
Products
Yield (%)
1
2
3
4
5
6
7
8
9
2
3
4
5
6
7
10
10
10
2a
2b
2c
2d
2e
3.5
5.0
5.5
6.5
6.5
6.5
8.0
4.5
4.5
30
90
3a
3b
3c
3d
3e
3f
>99
>99
42c
>99
>99
>99
95e
—
120
120
120
120
90
2f
2gd
2gf
2gh
3g
g
90
90
—
—
g
—
a
Unless differently specified, all reactions were carried out in distilled water at
0 °C; solutions of 0.5–0.7 M TFDO (1b) in TFP were obtained by adopting proce-
dures, equipment, and precautions already reported in detail (Ref. 3).
b
Oxidant to substrate molar ratio.
Accompanied by 45% of glutaric and 5% of glutarimide.
Run in the presence of cetyltrimethylammonium hydrogensulfate (0.13 M).
Based on the amount of recovered substrate (54%) upon chromatographic
c
d
e
separation of the reaction mixture.
f
Run with substrate finely dispersed in water solvent.
Mixture of unidentified products.
Run in acetonitrile at 0 °C.
g
h
Scheme 1. Reaction of 1,4-diketopiperazine (4) with 1b, resulting in no products.

C. Annese et al. / Tetrahedron Letters 54 (2013) 515–517
517
Lindström, U. M., Ed.; Blackwell: Oxford, UK, 2007; (c)Aqueous-Phase
Organometallic Catalysis; Comils, B., Herrmann, W. A., Eds.; Wiley-VCH GmbH
& Co: Weinheim, 2004.
We mentioned previously that the oxidative cleavage of the
amidic bond by dioxiranes is unprecedented. However, it occurs
to us that primary amines provide nitro compounds through an
exhaustive, stepwise oxidation of the nitrogen functionality,
involving three molecules of dioxirane.6a,b Accordingly, one may
envisage that a similar reaction pathway is followed in the trans-
formations described herein, while an extra step (most likely
involving water) should account for the ring cleavage and the for-
mation of the carboxylic moiety.
2. Murray, R. W.; Singh, M. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Striven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; pp 429–
456.
3. (a) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J. Org. Chem. 1988, 53,
3890–3891; (b) D’Accolti, L.; Fusco, C.; Rella, M. R.; Curci, R. Synth. Commun.
2003, 33, 3009.
4. For reviews, see: (a) Shi, Y. In Modern Oxidation Methods; Bäckvall, J.-E., Ed.;
Wiley-VCH: Weinheim, 2008; pp 85–115; (b) Adam, W.; Saha-Möller, C. R.;
Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499–3548; (c) Adam, W.; Saha-Möller,
C. R.; Zhao, C.-G. Org. React. 2002, 61, 219–516.
5. (a) Annese, C.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Gandolfi, R.; Curci, R. J. Am.
Chem. Soc. 2008, 130, 1024–1197; (b) D’Accolti, L.; Fusco, C.; Annese, C.; Rella,
M. R.; Turteltaub, J. S.; Williard, P. G.; Curci, R. J. Org. Chem. 2004, 69, 8510–
8513; (c) D’Accolti, L.; Annese, C.; Fusco, C. Tetrahedron Lett. 2005, 46, 8459–
8462; (d) D’Accolti, L.; Annese, C.; De Riccardis, A.; De Giglio, E.; Cafagna, D.;
Fanelli, F.; Fusco, C. Eur. J. Org. Chem. 2012, 4616–4621; (e) D’Accolti, L.; Annese,
C.; Aresta, A.; Fusco, C. J. Heterocycl. Chem. 2012. http://dx.doi.org/10.1002/
jhet.1839.
In summary, with use of methyl(trifluoromethyl)dioxirane (1b),
representative small- to large-ring lactams can be cleanly con-
verted to the corresponding
x-nitro acids in water under mild con-
ditions. Besides the benefits of using water as the reaction solvent,
the method presents several advantages, the key ones being sum-
marized as follows:
6. (a) Murray, R. W.; Rajadhyaska, S. N.; Mohan, L. J. Org. Chem. 1989, 54, 5783–
5788; (b) Murray, R. W.; Jeyaraman, R.; Mohan, L. Tetrahedron Lett. 1986, 27,
2335–2336; (c) Murray, R. W.; Jeyaraman, R.; Pillay, M. K. J. Org. Chem. 1987, 52,
746–748.
7. For reviews, see: Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006, 39, 1–9.
8. Ballini, R.; Papa, F.; Abate, C. Eur. J. Org. Chem. 1999, 87–90.
9. Ballini, R.; Barboni, L.; Fringuelli, F.; Palmieri, A.; Pizzo, F.; Vaccaro, L. Green
Chem. 2007, 9, 823–838.
10. Ono, N. The Nitro Group in Organic Synthesis; John Wiley & Sons, Inc.: New York,
2001.
11. Addo, J. K.; Teesdale-Spittle, P.; Hoberg, J. O. Synthesis 2005, 12, 1923–1925.
12. Zanoni, G.; Valli, M.; Bendjeddou, L.; Porta, A.; Bruno, P.; Vidari, G. J. Org. Chem.
2010, 75, 8311–8314.
13. In a typical experiment, a 25-mL round-bottom flask was charged with 6 mL of
distilled water and 300 mg (0.79 mmol) of CTAHS. To this solution, 60 mg
(0.327 mmol) of 2g were added and the mixture was cooled to 0 °C. Under
vigorous stirring, 4.4 mL of a 0.60 M solution of 1b (2.616 mmol) in TFP were
rapidly added and the resulting mixture allowed to react until the oxidant was
consumed (1.5 h, iodometry). Then, the reaction flask was surmounted with a
distillation column equipped with an efficient condenser kept at ca. 0 °C and
the TFP was gently distilled off. The resulting residue was cooled to room
temperature, saturated with NaCl, then extracted with ethyl acetate
(3 Â 20 mL). The organic phase was dried over Na2SO4 and concentrated in
vacuo. Chromatographic separation (silica gel, ethyl acetate/hexane 2:3) of the
residue afforded 32.4 mg of unreacted 2g (0.178 mmol, conv. 46%) and 35.2 mg
(0.143 mmol, 95% yield based on the amount of substrate reacted; purity >98%,
HPLC).
ꢀ Many lactams are largely accessible starting materials.
ꢀ The high efficiency and selectivity of the oxidations described
provide highly pure products, which could be used directly in
subsequent reaction steps, avoiding costly and time-consuming
product purification procedures.
ꢀ The oxidant precursor, that is TFP, can be recovered and reused
for dioxirane regeneration, thus increasing the atom economy of
the process.
ꢀ In the case of the relatively hydrophobic laurolactam 2g, an
increased reaction selectivity in water/surfactant system than
in organic solvent (acetonitrile) is achieved. This seems promis-
ing on the road of selective oxidations of organic compounds in
aqueous media using dioxiranes.
Acknowledgments
Financial support by the Ministry of Education of Italy (MIUR,
Grant PRIN 2008) and by the Italian National Research Council
(CNR, Rome) is gratefully acknowledged.
14. (a) Annese, C.; D’Accolti, L.; De Zotti, M.; Fusco, C.; Toniolo, C.; Williard, P. G.;
Curci, R. J. Org. Chem. 2010, 75, 4812–4816; (b) Annese, C.; Fanizza, I.; Calvano,
C. D.; D’Accolti, L.; Fusco, C.; Curci, R.; Williard, P. G. Org. Lett. 2011, 13, 5096–
5099.
References and notes
1. (a) Li, C. J.; Chang, T. H. Comprehensive Organic Reactions in Aqueous Media; John
Wiley
& Sons, Inc.: Hoboken, NJ, 2007; (b)Organic Reactions in Water;