Novel spiroheterocycles by aziridination of α-methylene-γ- and -δ-lactams

Article abstract of DOI:10.1002/ejoc.200601034

New potentially bioactive α-spiroaziridino-γ- and -δ-lactams have been prepared by treatment of α-methylene-γ- and -δ-lactams with ethyl N-([(4-nitrophenyl)sulfonyl]oxy)-carbamate (NsONHCO₂Et) in the presence of CaO. These compounds, through reductive aziridine ring opening, can be intermediates for the synthesis of α- and β-aminolactams, which are useful as conformational constraints in peptides. The above procedure has been successfully extended to one α-methyleneoxindole to obtain a new spirooxindole derivative, a potential precursor of natural alkaloids. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200601034

FULL PAPER
DOI: 10.1002/ejoc.200601034
Novel Spiroheterocycles by Aziridination of α-Methylene-γ- and -δ-lactams
M. Antonietta Loreto,*[a,b] Antonella Migliorini,[a,b] P. Antonio Tardella,[a] and
Augusto Gambacorta[c]
Keywords: Aziridination / Lactams / Spiroheterocycles / Ring opening / Amino lactams
New potentially bioactive α-spiroaziridino-γ- and -δ-lactams
have been prepared by treatment of α-methylene-γ- and -δ-
which are useful as conformational constraints in peptides.
The above procedure has been successfully extended to one
α-methyleneoxindole to obtain a new spirooxindole deriva-
tive, a potential precursor of natural alkaloids.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
lactams
with
ethyl
N-{[(4-nitrophenyl)sulfonyl]oxy}-
carbamate (NsONHCO2Et) in the presence of CaO. These
compounds, through reductive aziridine ring opening, can be
intermediates for the synthesis of α- and β-aminolactams,
useful intermediates for the synthesis of valuable α- and β-
aminolactams, the latter resulting from the aziridine ring-
opening reaction of the former.
Introduction
Molecules with strained, three-membered heterocycles
have been arousing the interest of chemists for more than
100 years thanks to the varied reactivity of these rings.
Among them, aziridines are valuable intermediates in or-
ganic synthesis: the regio- and stereochemical control of the
ring-opening reactions can be a useful tool in the synthesis
of unnatural amino acids and other nitrogen-containing
compounds of biological importance.[1] In particular, spiro-
aziridines, where the aziridine ring is fused with a heterocy-
cle, are of synthetic interest because the presence of a spiro
carbon atom induces steric strain and allows for possible
rearrangements.[2] Among these molecules, we turned our
attention to spiroaziridino-γ- and -δ-lactams.
In general, the insertion of a spiranic moiety in a γ- or
δ-lactam results in interesting biological activities. For ex-
ample, marine amathaspiramides and pseudoindoxyl alka-
loids from plants are potent antiviral agents with potential
anticancer properties.[3] In addition, some -proline-derived
spirolactams have been studied for their use in constraining
peptides with -proline residues to mimic a β-turn, an im-
portant component of peptide secondary structures.[4] Nev-
ertheless, to the best of our knowledge, spiroaziridino lac-
tams are not reported in the literature, except for one paper
concerning the synthesis of unsaturated spiroaziridino-
δ-lactams.[2b] On these grounds, we felt that spiroaziridino-
γ- and -δ-lactams could be intriguing synthetic targets and
For some years our research program has been focused
on the synthesis of aziridines starting from electron-poor
olefins, such as α,β-unsaturated esters, phosphonates, and
amides.[5] In this field, we have recently succeeded
in the synthesis of N-(ethoxycarbonyl)spiroaziridino-γ-
lactones from simple α-ylidene-γ-butyrolactones with
NsONHCO2Et and CaO.[6] The subsequent regio- and
stereoselective aziridine ring opening provided simple ac-
cess to interesting homoserine lactone derivatives, which are
present in certain biologically active molecules.[7]
On the basis of the good results we obtained with α-
ylidene-γ-butyrolactones, we felt that the extension of our
synthetic procedure to other heterocyclic compounds like
α-methylene-γ- and -δ-lactams 1 (Scheme 1) could result in
the obtention of the spiroaziridinolactams 2 and, after azir-
idine ring opening, the corresponding amino derivatives 3
or 4.
Scheme 1.
[a] Dipartimento di Chimica, Università “La Sapienza”,
Piazzale Aldo Moro 5, Rome 00185, Italy
[b] Istituto C. N. R. di Chimica Biomolecolare, Dipartimento di
Chimica, Università “La Sapienza”,
Piazzale Aldo Moro 5, Rome 00185, Italy
[c] CISDiC, Dipartimento di Ingegneria Meccanica e Industriale,
Università “Roma Tre”,
Results and Discussion
Keeping in mind this program, our first objective was the
preparation of substrates 1 (Scheme 2). Compound 1a was
obtained according to a procedure reported in the litera-
ture.[8] The same procedure was extended to the synthesis
Via della Vasca Navale 79, Rome 00146, Italy
Fax: +39-06-490631
E-mail: mariaantonietta.loreto@uniroma1.it
Eur. J. Org. Chem. 2007, 2365–2371
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. A. Loreto, A. Migliorini, P. A. Tardella, A. Gambacorta
FULL PAPER
Scheme 2. Synthesis of substrates 1a–d.
of compounds 1b–c, although their preparation by a dif-
With the α-methylene-γ- and -δ-lactams 1a–d in hand,
ferent route has been already reported.[9] While for sub- we proceeded to the aziridination reaction, which was car-
strate 1a the procedure starts directly from the commer- ried out in CH2Cl2, according to the reported procedure,[6]
cially available ester 6a, in the case of substrates 1b–c, we by adding NsONHCO2Et and CaO portionwise, to reach
prepared the corresponding esters with the ethoxycarbonyl- the molar ratios shown in Table 1. After the addition of a
ation reaction reported by Rapoport for 1-methylpyrroli- few equivalents of reagents, we observed the complete dis-
din-2-one (5b).[10] The reduction of esters 6a–c with calcium appearance of the starting material and the formation of
tetrahydridoborate, afforded the known alcohols 7a[8] and the expected N-(ethoxycarbonyl)spiroaziridines (Scheme 3),
7b[11] and the novel alcohol 7c, which were obtained pure detected in the crude mixture by the characteristic NMR
and in good yields.
aziridine proton signals. Compounds 2a–d were purified by
α-Methylenelactams 1a–c were finally prepared by direct chromatography on silica gel and fully characterized.
dehydration of 7a–c with dicyclohexylcarbodiimide (DCC)
in the presence of catalytic amounts of cuprous iodide in
an aprotic solvent such as toluene.[8] Olefins 1a–c were puri-
fied by chromatography on silica gel and their structures
1
were confirmed by H and 13C NMR analysis.
In addition, we wanted to extend our aziridination pro-
cedure to the α-methylene-δ-lactam 1d, carrying a ethoxy-
carbonylmethyl group at the nitrogen atom as a suitable
Scheme 3. Synthesis of spiroaziridino-γ- and -δ-lactams.
anchor for an amino acid chain. Indeed, it is known that
The good results obtained in the synthesis of spiroazirid-
some lactam derivatives are useful conformational con- ino lactams 2a–d prompted us to start studying the amin-
straints in peptides and limit the number of available con- ation of more complex α-methylene-γ-lactams, charac-
formers. In particular, five- and six-membered lactams with terized by the oxindole moiety. To the best of our knowl-
amino acid chains at the lactam nitrogen atom are impor- edge, only one synthesis of spiroaziridinooxindole deriva-
tant scaffolds in conformationally restricted peptidomimet- tives is reported.[13]
ics.[12]
The oxindole ring system is found at the core of a
Substrate 1d was prepared starting from 1a according to number of natural alkaloids, which are interesting, chal-
a reported alkylation reaction at the nitrogen atom[8] lenging targets for chemical synthesis.[14] Most of these al-
(Scheme 2).
kaloids are characterized by a spirooxindole structure.[15]
Table 1. Synthesis of spiroaziridinolactams 2a–d: conditions and yields.
Entry
R
n
Molar ratio
1/NsONHCO2Et/CaO
2
1H NMR
Aziridine protons
Isolated yields [%]
a
b
c
H
Me
2
1
2
2
1:3:3
50
48
46
56
δ = 2.11 (d, J = 1.5 Hz, 1 H);
2.91 (d, J = 1.5 Hz, 1 H)
δ = 2.33 (d, J = 1.1 Hz, 1 H);
2.76 (d, J = 1.1 Hz, 1 H)
δ = 2.10 (d, J = 1.5 Hz, 1 H);
2.96 (d, J = 1.5 Hz, 1 H)
δ = 2.11 (d, J = 1.5 Hz, 1 H);
2.90 (d, J = 1.5 Hz, 1 H)
1:3:3
Me
1:3:3
d
CH2CO2Et
1:2.5:2.5
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Eur. J. Org. Chem. 2007, 2365–2371

Novel Spiroheterocycles by Aziridination of α-Methylene-γ- and -δ-lactams
FULL PAPER
Their appealing spiro architecture is often associated with peak with the same mass of 3b by GC-MS coupling. How-
biological activity, such as the antineoplastic activity dis- ever, only compound 3b was separated and purified by
covered for the spirotryprostatins.[16]
chromatography on silica gel. Spectroscopic data confirmed
As a model compound we took into consideration the structure. In contrast, carrying out the reaction on the
1-methyl-3-methylene-1,3-dihydro-2H-indol-2-one (10, spiroaziridinooxindole 11, we obtained the β-amino deriva-
Scheme 4). This compound was prepared by Peterson’s isa- tive 12 as the only product after 1 h (Scheme 5).
tin olefination, proposed by Rossiter for the preparation of
the α-methyleneoxindole itself.[17] It is reported that α-
methyleneoxindoles are very unstable compounds because
they can polymerize to afford dimers or higher-order poly-
mers.[18]
Scheme 5. Ring-opening reactions of aziridine 2b and 11.
The opposite regiochemistry observed in the aziridine
ring opening for compounds 2b and 11 could be explained
in terms of the relative stabilities of the respective interme-
diates involved. The ring-opening reaction can occur
through the competitive formation of an intermediate Pd
complex[20a] or a radical involving either the spiranic car-
bon atom or the aziridine methylene group. The former in-
termediate could be stabilized by the aromatic ring in 11, as
reported for benzylic and allylic aziridines and epoxides,[20]
while the corresponding intermediate for 2b could be disfa-
vored both by the absence of aromatic stabilization and the
presence of more steric hindrance.
Scheme 4. Synthesis and aziridination of 10.
Accordingly, compound 10 proved to be unstable and
not isolable. Thus, after extraction with dichloromethane
(solvent to be used in the subsequent reaction), the solution
containing 10 was only partially concentrated and rapidly
used for the aziridination reaction. After the addition of
only 1 equiv. of the NsONHCO2Et/CaO mixture, we ob-
tained a total conversion of 10 into the new spiroaziridi-
nooxindole 11 (Scheme 4), isolated in good yield (72%) by
chromatography and characterized.
Aziridine ring opening in spiroaziridinolactams 2a–d and
11 could be a suitable way to obtain the corresponding α-
or β-aminolactams, key components of many peptidomi-
metic structures.[12] In this context, in order to study the
regiochemistry of the aziridine ring-opening reaction, we
treated the spiroaziridines 2a–d and 11 with ammonium for-
mate and Pd/C under the conditions[19] previously used suc-
cessfully for the ring-opening reaction of spiroaziridino-γ-
lactones.
Compounds like 12 are very interesting targets, as some
of them are natural antibiotics produced by plants,[21] po-
tential antileukemics, and important intermediates in the
synthesis of other spirooxindole systems.[22]
Conclusion
With regard to the spiroaziridino-δ-lactams 2a, 2c, and
2d, we showed they were poorly reactive towards the re-
ductive ring opening. Despite long reaction times (8 d) we
observed only a partial disappearance of the starting mate-
rial and the formation of a mixture of products. These re-
sults indicate that this method is not suitable for converting
spiroaziridines from α-methylene-δ-lactams into α- or β-
aminolactams.
We present herein an easy procedure for the synthesis of
new spiroaziridinolactams starting from easily accessible α-
methylene-γ- and -δ-lactams, and we have confirmed the
possibility of using novel spiroaziridino-γ-lactams as pre-
cursors of α- and β-aminolactams. Considering the effi-
ciency of the aziridination protocol, when applied to the α-
methyleneoxindole 10 and the current interest in spirooxin-
doles in chemical synthesis, we are encouraged to carry on
our research work in this field.
Starting from the simple spiroaziridino-γ-lactam 2b, as
previously found for the corresponding spiroaziridino-γ-lac-
tones,[6] we obtained, after 4 h, the α-aminolactam deriva-
tive 3b (Scheme 5) as the main product, together with a very
small amount of a byproduct, which we suggest to be the
β-amino isomer 4b. In fact, we observed singlets attribut-
Experimental Section
General Experimental Methods: Solvents and common reagents
were purchased from commercial sources and used without further
1
able to additional N-CH3 and N-H groups in the H NMR
spectrum of the crude reaction mixture and found a minor purification. All reactions were monitored by GC-MS analysis with
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M. A. Loreto, A. Migliorini, P. A. Tardella, A. Gambacorta
FULL PAPER
an HP 5890 system equipped with a phenylmethylsilicon capillary
column (15 m, 0.25 mm i.d.), and by thin layer chromatography
(TLC) carried out on Merck F-254 silica glass plates and visualized
with UV light and I2. Chromatographic separations were per-
formed on Merck silica gel 60 (70–230 mesh). 1H and 13C NMR
spectra were recorded with a Varian Gemini 200 (200 MHz) spec-
trometer; chemical shifts are expressed in ppm (δ) and are refer-
enced to the carbon and residual proton signals of the NMR sol-
tracts were dried with Na2SO4, and the solvent was removed under
vacuum to give pure 7a as a white solid (700 mg, 5.43 mmol, 90%
yield). IR (CHCl ): ν = 3340, 1700 cm–1. 1H NMR (CDCl3,
˜
3
200 MHz, 25 °C): δ = 1.35–1.95 (m, 4 H, NCH2CH2CH2), 2.36–
2.59 (m, 1 H, CH), 3.16–3.41 (m, 2 H, NCH2), 3.61 (br., 1 H, OH),
3.60–3.84 (m, 2 H, CH2OH), 6.67 (br., 1 H, NH) ppm. 13C NMR
(CDCl3, 50 MHz, 25 °C):
δ
=
21.2 (NCH2CH2), 23.1
(NCH2CH2CH2), 41.7 (NCH2), 42.0 (CH), 63.5 (CH2OH), 175.3
vent (CHCl3: δ = 7.26 ppm for 1H NMR, δ = 77.0 ppm for 13C (NC=O) ppm. GC-MS: m/z (%) = 129 (12) [M]+, 99 (100).
NMR). IR spectra were obtained with a Perkin-Elmer 1600 (FT-
3-(Hydroxymethyl)-1-methylpyrrolidin-2-one (7b):[11] Compound 7b
was prepared from 6b (2 g, 11.70 mmol) according to the procedure
IR) spectrometer; data are presented in wavenumbers (cm–1).
HRMS data were recorded with a Micromass Q-TOF micro Mass
Spectrometer (Waters).
described for 7a. The product was obtained as a pure yellow liquid
(1.2 g, 9.36 mmol, 80% yield). IR (CHCl ): ν = 1705 cm–1. 1H
˜
3
Ethyl 1-Methyl-2-oxopyrrolidine-3-carboxylate (6b):[10] To a suspen-
sion of NaH (2.9 g, 120 mmol, 60% suspension in mineral oil) in
anhydrous toluene (160 mL), a solution of 5b (4 g, 40 mmol) and
diethyl carbonate (18.8 g, 160 mmol) in anhydrous toluene (40 mL)
was added dropwise under argon at room temperature. After 8 h
at reflux, the mixture was cooled to room temperature, and glacial
acetic acid (5 g, 83 mmol) was added. After 1 h of stirring, the re-
sulting slurry was filtered, the solid phase was washed with CH2Cl2,
and the organic phase was washed with a little water. The aqueous
phase was extracted with CH2Cl2 (3ϫ100 mL). The combined or-
ganic extracts were dried with anhydrous Na2SO4. After solvent
evaporation, the crude product was purified by chromatography on
silica gel (diethyl ether/methanol, 99:1) to obtain 6b as a yellow
NMR (CDCl3, 200 MHz, 25 °C):
δ = 1.65–1.90 (m, 1 H,
NCH2CHHCH), 2.05–2.25 (m, 1 H, NCH2CHHCH), 2.54–2.80
(m, 1 H, CH), 2.85 (s, 3 H, NCH3), 3.24–3.48 (m, 2 H, NCH2),
3.67 (dd, J = 11.0 Hz, J = 7.3 Hz, 1 H, CHHOH), 3.87 (dd, J =
11.0 Hz, J = 5.1 Hz, 1 H, CHHOH) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 21.2 (NCH2CH2), 29.5 (NCH3), 43.5 (CH),
48.0 (NCH2), 62.6 (CH2OH), 174.6 (NC=O) ppm. GC-MS: m/z
(%) = 129 (9.3) [M]+, 99 (100).
3-(Hydroxymethyl)-1-methylpiperidin-2-one (7c): Compound 7c was
prepared from 6c (360 mg, 2.16 mmol) according to the procedure
described for 7a. The product was obtained as a pure white solid
(278 mg, 1.94 mmol, 90% yield). IR (CHCl ): ν = 1710 cm–1. 1H
˜
3
NMR (CDCl3, 200 MHz, 25 °C):
δ = 1.35–1.60 (m, 1 H,
viscous oil (3.1 g, 18 mmol, 45% yield). IR (CHCl ): ν = 1740,
˜
3
CHHCH2CH), 1.70–2.00 (m, 3 H, CHHCH2CH), 2.33–2.59 (m, 1
H, CH), 2.94 (s, 3 H, NCH3), 3.19–3.34 (m, 2 H, NCH2), 3.46 (s,
1 H, OH), 3.55–3.80 (m, 2 H, CH2OH) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 22.1 (NCH2CH2), 26.0 (NCH2CH2CH2), 34.4
(CH), 42.9 (NCH3), 49.7 (NCH2), 64.7 (CH2OH), 173.1 (NC=O)
ppm. GC-MS: m/z (%) = 143 (39) [M]+, 113 (100). HRMS: calcd.
for C7H13NNaO2 166.0844; found 166.0840.
1680 cm–1. 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.25 (t, J =
7.1 Hz, 3 H, OCH2CH3), 2.13–2.56 (m, 2 H, CH2CH), 2.83 (s, 3
H, NCH3), 3.25–3.60 (m, 3 H, CH2CH2CH), 4.17 (q, J = 7.1 Hz,
2 H, OCH2CH3) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ =
14.1 (OCH2CH3), 21.0 (CH2CH), 32.3 (NCH3), 45.5 (NCH2), 49.3
(CH), 62.2 (OCH2CH3), 169.2 (CO2CH2CH3.), 171.1 (NC=O)
ppm. GC-MS: m/z (%) = 171 (63) [M]+, 98 (100).
Synthesis of α-Methylene-γ- and -δ-lactams 1a–d
Ethyl 1-Methyl-2-oxopiperidine-3-carboxylate (6c): To a suspension
of NaH (7.0 g, 160 mmol, 60% suspension in mineral oil) in anhy-
drous THF (70 mL), a solution of 5c (4.5 g, 40 mmol) and diethyl
carbonate (28.3 g, 360 mmol) in anhydrous THF (30 mL) was
added dropwise under argon at room temperature. After 7 h at re-
flux, the mixture was cooled to room temperature and stirred for
14 h. To the resulting mixture, water (150 mL) was added, and the
aqueous phase was extracted with diethyl ether (4ϫ200 mL). The
organic phase was dried with Na2SO4, and after solvent evapora-
tion, the crude product was purified by chromatography on silica
gel (diethyl ether/methanol, 99:1) to obtain 6c as a yellow viscous
3-Methylenepiperidin-2-one (1a):[8] Cuprous iodide (190 mg,
1.00 mmol) was added at 110 °C to a stirred solution of 7a (1.6 g,
12.00 mmol)
and
N,N-dicyclohexylcarbodiimide
(3.1 g,
15.00 mmol) in toluene (18 mL). The mixture was heated at reflux
for 70 min and cooled. Water (15 mL) was added, and the mixture
was stirred for 1 h. Diethyl ether (37 mL) was added, and the mix-
ture was filtered. The aqueous phase was separated and extracted
with CH2Cl2 (2ϫ40 mL). The combined organic phases were dried
with K2CO3, filtered, and concentrated to give pure 1a as a solid
(839 mg, 7.56 mmol, 63% yield). IR (CHCl ): ν = 3240, 1673,
˜
3
1628 cm–1. H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.75–1.95 (m,
1
oil (3.1 g, 16.80 mmol, 42% yield). IR (CHCl ): ν = 1730,
˜
3
1640 cm–1. 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.25 (t, J =
7.1 Hz, 3 H, OCH2CH3), 1.70–2.20 (m, 4 H, CH2CH2CH), 2.93 (s,
3 H, NCH3), 3.18–3.45 (m, 3 H, NCH2, CH), 4.09–4.28 (m, 2 H,
OCH2CH3) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.1
(OCH2CH3), 20.9 (CH2CH2CH2), 25.2 (CH2CH), 34.9 (NCH3),
49.1 (CH), 50.0 (NCH2), 61.2 (OCH2CH3), 165.8 (CO2CH2CH3),
171.1 (NC=O) ppm. GC-MS: m/z (%) = 185 (95) [M]+, 83 (100).
HRMS: calcd. for C9H15NNaO3 208.0950; found 208.0947.
2 H, NCH2CH2), 2.48–2.64 (m, 2 H, CH2CH2C), 3.30–3.46 (m, 2
H, NCH2), 5.26–5.37 (m, 1 H, C=CHH), 6.16–6.24 (m, 1 H,
C=CHH), 6.68 (br., 1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz,
25 °C): δ = 22.7 (NCH2CH2), 29.4 (CH2CH2C), 42.1 (NCH2),
121.3 (C=CH2), 137.3 (C=CH2), 166.0 (NC=O) ppm. GC-MS: m/z
(%) = 111 (100) [M]+.
1-Methyl-3-methylenepyrrolidin-2-one (1b):[9a] Compound 1b was
prepared from 7b (1 g, 7.75 mmol), according to the procedure de-
scribed for 1a. The product was obtained as a pure yellow liquid
3-(Hydroxymethyl)piperidin-2-one (7a):[8] A suspension of 6a (1 g,
6.00 mmol) and CaCl2 (700 mg, 6.00 mmol) in methanol (12 mL) (447 mg, 4.03 mmol, 52% yield). IR (CHCl ): ν = 1680, 1638 cm–1.
˜
3
was cooled to 0–5 °C and treated with sodium tetrahydridoborate
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 2.55–2.70 (m, 2 H,
(500 mg, 12 mmol), and cooling was continued for 2 h. After an
NCH2CH2), 2.78 (s, 3 H, NCH3), 3.20–3.35 (m, 2 H, NCH2), 5.09–
additional 14 h at room temperature, the solvent was removed un- 5.20 (m, 1 H, C=CHH), 5.68–5.78 (m, 1 H, C=CHH) ppm. 13C
der vacuum, and a solution of 3  citric acid was added dropwise
until the mixture was completely soluble (pH = 3.5–4). The aque-
NMR (CDCl3, 50 MHz, 25 °C): δ = 23.8 (NCH2CH2), 33.5
(NCH3), 49.2 (NCH2), 120.3 (C=CH2), 140.9 (C=CH2), 164.3
ous phase was extracted with CH2Cl2 (3ϫ40 mL), the organic ex- (NC=O) ppm. GC-MS: m/z (%) = 111 (100) [M]+.
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Novel Spiroheterocycles by Aziridination of α-Methylene-γ- and -δ-lactams
FULL PAPER
1-Methyl-3-methylenepiperidin-2-one (1c):[9b] Compound 1c was
prepared from 7c (270 mg, 1.89 mmol), according to the procedure
described for 1a. The product was obtained as a pure clear liquid
NCH2CH2, CHHNCO2), 2.76 (d, J = 1.1 Hz, 1 H, CHHNCO2),
2.93 (s, 3 H, NCH3), 3.35–3.64 (m, 2 H, NCH2CH2), 4.16 (q, J =
7.3 Hz, 2 H, OCH2CH3) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C):
δ = 14.2 (OCH2CH3), 23.8 (NCH2CH2), 30.6 (NCH3), 35.2
(140 mg, 1.12 mmol, 59% yield). IR (CHCl ): ν = 1680, 1630 cm–1.
˜
3
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.88 (p, J = 6.0 Hz, 2 H, (CH2NCO2), 45.2 (CH2CCH2), 45.7 (NCH2CH2), 62.4
NCH2CH2CH2), 2.49–2.62 (m, 2 H, CH2CH2C), 3.01 (s, 3 H, (OCH2CH3), 160.8 (NCO2), 168.9 (NCH3CO) ppm. GC-MS: m/z
NCH3), 3.37 (t, J = 5.9 Hz, 2 H, NCH2), 5.21–5.28 (m, 1 H,
(%) = 198 (Ͻ0.1) [M]+, 126 (100). HRMS: calcd. for C9H14N2NaO3
C=CHH), 6.14–6.21 (m, 1 H, C=CHH) ppm. 13C NMR (CDCl3, 221.0902; found 221.0899.
50 MHz, 25 °C): δ = 22.8 (NCH2CH2CH2), 29.8 (CH2CH2C), 34.8
Ethyl 5-Methyl-4-oxo-1,5-diazaspiro[2.5]octane-1-carboxylate (2c):
(NCH3), 50.1 (NCH2), 120.5 (C=CH2), 137.6 (C=CH2), 164.0
Compound 2c was prepared from 1c (140 mg, 1.20 mmol), accord-
ing to the procedure described for 2a. The crude product was puri-
fied by chromatography on silica gel (hexane/ethyl acetate, 1:1) to
obtain 2c as a pale yellow oil (117 mg, 0.55 mmol, 46% yield). IR
(NC=O) ppm. GC-MS: m/z (%) = 125 (100) [M]+.
Ethyl (3-Methylene-2-oxopiperidin-1-yl)acetate (1d):[8] To a suspen-
sion of NaH (218 mg, 4.54 mmol, 50% suspension in mineral oil)
in anhydrous THF (10 mL), a solution of 1a (504 mg, 4.54 mmol)
in toluene (1 mL) was added dropwise at 0 °C. After 3 h at room
temperature, the mixture was cooled again to 0 °C, and ethyl bro-
moacetate (0.5 mL, 4.54 mmol) was added. After stirring of the
mixture for 2 h, diethyl ether (10 mL) was added to the residue,
and the solids were filtered off and washed with diethyl ether. The
organic phase was concentrated to give a crude product, which was
purified by chromatography on silica gel (hexane/ethyl acetate, 1:1)
(CHCl ): ν = 1732, 1660 cm–1. 1H NMR (CDCl , 200 MHz, 25 °C):
˜
3
3
δ = 1.23 (t, J = 7.3 Hz, 3 H, OCH2CH3), 1.82–2.24 (m, 5 H,
CH2CH2C, CHHNCO2), 2.96 (d, J = 1.5 Hz, 1 H, CHHNCO2),
2.98 (s, 3 H, NCH3), 3.36–3.53 (m, 2 H, NCH2CH2), 4.00–4.27 (m,
2 H, OCH2CH3) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ =
14.3 (OCH2CH3), 21.4 (NCH2CH2), 30.1 (CH2NCO2), 35.3
(NCH3), 37.0 (CH2CH2C), 42.8 (CH2CCH2), 50.4 (NCH2CH2),
62.2 (OCH2CH3), 161.0 (NCO2), 165.5 (NCH3CO) ppm. GC-MS:
m/z (%) = 211 (17) [M – 1]+, 138 (100). HRMS: calcd. for
C10H16N2NaO3 235.1059; found 235.1057.
to give 1d as a yellowish viscous liquid (608 mg, 3.09 mmol, 68%
1
yield). IR (CHCl ): ν = 1730, 1680, 1635 cm–1. H NMR (CDCl ,
˜
3
3
200 MHz, 25 °C): δ = 1.18 (t, J = 7.3 Hz, 3 H, CO2CH2CH3), 1.79–
2.01 (m, 2 H, NCH2CH2CH2), 2.52–2.68 (m, 2 H, CH2CH2C),
3.39–3.50 (m, 2 H, NCH2), 4.10–4.26 (m, 4 H, NCH2CO2,
CO2CH2CH3), 5.27–5.33 (m, 1 H, C=CHH), 6.17–6.23 (m, 1 H,
C=CHH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.2
(CO2CH2CH3), 23.2 (NCH2CH2CH2), 30.1 (CH2CH2C), 49.3
(NCH2), 49.8 (NCH2CO2), 60.4 (CO2CH2CH3), 122.4 (C=CH2),
137.4 (C=CH2), 166.2 (CO2CH2CH3), 170.9 (NC=O) ppm. GC-
MS: m/z (%) = 197 (5) [M]+, 124 (100).
Ethyl
5-(2-Ethoxy-2-oxoethyl)-4-oxo-1,5-diazaspiro[2.5]octane-1-
carboxylate (2d): Compound 2d was prepared from 1d (290 mg,
1.47 mmol), according to the procedure described for 2a, reaching
a substrate/NsONHCO2Et/CaO molar ratio of 1:2.5:2.5. The crude
product was purified by chromatography on silica gel (hexane/ethyl
acetate, 3:7) to obtain the product 2d as a pale yellow oil (234 mg,
0.82 mmol, 56% yield). IR (CHCl ): ν = 1725, 1657 cm–1. 1H NMR
˜
3
(CDCl3, 200 MHz, 25 °C): δ = 1.10–1.31 (m, 6 H, NCO2CH2CH3,
CH2CO2CH2CH3), 1.84–2.23 (m, 5 H, CH2CH2C, CHHNCO2),
2.90 (d, J = 1.5 Hz, 1 H, CHHNCO2), 3.40–3.59 (m, 2 H,
NCH2CH2), 3.87 (d, J = 17.2 Hz, 1 H, NCHHCO2), 4.31 (d, J
= 17.2 Hz, 1 H, NCHHCO2), 3.99–4.23 (m, 4 H, NCO2CH2CH3,
CH2CO2CH2CH3) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ =
13.9 (NCO2CH2CH3), 14.1 (CH2CO2CH2CH3), 21.3 (NCH2CH2),
29.9 (CH2CH2C), 37.2 (CH2NCO2), 42.5 (CH2CCH2), 49.1
(NCH2CH2), 49.7 (NCH2CO), 61.1 (CH2CO2CH2CH3), 62.2
Synthesis of Spiroaziridinolactams 2a–d
Ethyl 4-Oxo-1,5-diazaspiro[2.5]octane-1-carboxylate (2a): To
a
stirred solution of the substrate 1a (96 mg, 0.87 mmol) in CH2Cl2
(0.5 mL), NsONHCO2Et (252 mg, 0.87 mmol) and CaO (49 mg,
0.87 mmol) were added portionwise every hour, reaching a sub-
strate/NsONHCO2Et/CaO molar ratio of 1:3:3. Because the reac-
tion was exothermic, the flask was cooled in a water bath during
the addition to avoid overheating. After 4 h, pentane was added.
The organic phase was filtered, and the solid residue was washed
again with pentane/CH2Cl2 (1:1) and then with CH2Cl2. The com-
bined organic phases were concentrated under vacuum and chro-
matographed on silica gel (hexane/ethyl acetate, 4:6) to obtain 2a
(NCO2CH2CH3),
160.8
(NCO2CH2CH3),
166.3
(CH2CO2CH2CH3), 168.5 (NCO) ppm. GC-MS: m/z (%) = 284 (1)
[M]+, 29 (100). HRMS: calcd. for C13H20N2NaO5 307.1270; found
307.1267.
3-Hydroxy-1-methyl-3-[(trimethylsilyl)methyl]-1,3-dihydroindol-2-
one (9): 1-Methylisatin (8, 1 g, 6.21 mmol) was suspended in dry
diethyl ether (24 mL) and the mixture cooled to –78 °C. [(Trimeth-
ylsilyl)methyl]magnesium chloride (12 mL of a 1  solution in di-
ethyl ether, 12.42 mmol) was added whilst stirring. The mixture was
stirred at –78 °C for 15 min and then warmed to room temperature
with stirring for a further 18 h. The reaction was quenched with
methanol, and then the mixture was concentrated in vacuo to give
a dark green solid, which was triturated first with hexane/ethyl ace-
tate (1:1) and then with ethyl acetate. After filtration, the combined
organic phases were concentrated in vacuo to give pure 9 as a solid
as a yellow oil (86 mg, 0.43 mmol, 50% yield). IR (CHCl ): ν =
˜
3
3240, 1733, 1680 cm–1. 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.24 (t, J = 7.3 Hz, 3 H, OCH2CH3), 1.74–2.22 (m, 5 H, CH2CH2C,
CHHNCO2), 2.91 (d, J = 1.5 Hz, 1 H, CHHNCO2), 3.26–3.56 (m,
2 H, NCH2CH2), 4.13 (q, J = 7.3 Hz, 2 H, OCH2CH3), 6.81 (br.,
1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.3
(OCH2CH3), 21.6 (NCH2CH2), 29.8 (CH2NCO2), 37.0
(CH2CH2C), 42.3 (CH2CCH2), 42.8 (NCH2CH2), 62.3
(OCH2CH3), 161.0 (NCO2), 167.6 (NHCO) ppm. GC-MS: m/z (%)
= 198 (7) [M]+, 125 (100). HRMS: calcd. for C9H14N2NaO3
221.0902; found 221.0900.
(1.5 g, 6.21 mmol, quantitative yield). IR (CHCl ): ν = 1700 cm–1.
˜
3
1H NMR (CDCl3, 200 MHz, 25 °C): δ = –0.30 [s, 9 H, Si(CH3)3],
1.55 (s, 2 H, SiCH2), 2.20 (br., 1 H, OH), 3.18 (s, 3 H, NCH3), 6.80–
7.40 (m, 4 H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ
= –2.5 [Si(CH3)3], 24.9 (SiCH2), 27.3 (NCH3), 74.4 (COH), 35.3
(NCH3), 107.1 (CHarom.), 121.9 (CHarom.), 122.9 (CHarom.), 128.3
(CHarom.), 130.1 (Carom.), 141.6 (Carom.), 177.3 (C=O) ppm. GC-
Ethyl 5-Methyl-4-oxo-1,5-diazaspiro[2.4]heptane-1-carboxylate (2b):
Compound 2b was prepared from 1b (300 mg, 2.70 mmol), accord-
ing to the procedure described for 2a. The crude product was puri-
fied by chromatography on silica gel (hexane/ethyl acetate, 4:6) to
obtain 2b as a pale yellow oil (257 mg, 1.30 mmol, 48% yield). IR
(CHCl ): ν = 1730, 1680 cm–1. 1H NMR (CDCl , 200 MHz, 25 °C): MS: m/z (%) = 249 (26) [M – 1]+, 75 (100). HRMS: calcd. for
˜
3
3
δ = 1.24 (t, J = 7.3 Hz, 3 H, OCH2CH3), 2.09–2.49 (m, 3 H,
C13H19NNaO2Si 272.1083; found 272.1079.
Eur. J. Org. Chem. 2007, 2365–2371
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2369

M. A. Loreto, A. Migliorini, P. A. Tardella, A. Gambacorta
FULL PAPER
1-Methyl-3-methylene-1,3-dihydro-2H-indol-2-one (10): 3-Hydroxy- 1:1) to give 12 as a yellow solid (22 mg, 0.09 mmol, 44% yield). IR
3-[(trimethylsilyl)methyl]-1-methyloxindole (9, 1.5 g, 6.21 mmol) in (CHCl ): ν = 1709, 1613 cm–1. 1H NMR (CDCl , 200 MHz, 25 °C):
˜
3
3
dry CH2Cl2 (120 mL) was cooled to –78 °C, and boron trifluoride– δ = 1.23 (t, J = 7.3 Hz, 3 H, OCH2CH3), 3.20 (s, 3 H, NCH3),
diethyl ether (7.5 mL, 30 mmol) was added. The mixture was 3.28–3.49 (m, 1 H, CHCHHNH), 3.52–3.66 (m, 1 H, COCHCH2),
stirred at –78 °C for 2 h, and then at 0 °C for a further 1 h. The 3.84–4.04 (m, 1 H, CHCHHNH), 4.10 (q, J = 7.3 Hz, 2 H,
mixture was poured into saturated aqueous NaHCO3 solution and OCH2CH3), 5.55 (br., 1 H, NH), 6.80–7.40 (m, 4 H, CHarom.) ppm.
extracted with CH2Cl2 (4ϫ300 mL). The combined organic layers 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.4 (OCH2CH3), 26.0
were washed again with NaHCO3, dried with Na2SO4, and the sol- (NCH3), 41.1 (NCH2CH), 45.5 (CHCH2N), 60.8 (OCH2CH3),
vent was partially evaporated to give a concentrated solution of 108.0 (CHarom.), 123.2 (CHarom.), 124.1 (CHarom.), 125.9 (Carom.),
pure product 10, which was immediately treated as described below. 128.4 (CHarom.), 144.3 (Carom.), 156.5 (NCO2), 176.6 (NCH3CO)
An analytical sample was concentrated to dryness for spectroscopic ppm. GC-MS: m/z (%) = 248 () [M]+, 159 (100). HRMS: calcd. for
1
characterization. H NMR (CDCl3, 200 MHz, 25 °C): δ = 3.24 (s, C13H16N2NaO3 271.1059; found 271.1055.
3 H, NCH3), 6.10 (s, 1 H, C=CHH), 6.40 (s, 1 H, C=CHH), 6.80–
7.47 (m, 4 H, CHarom) ppm. GC-MS: m/z (%) = 159 (98) [M]+, 130
(100).
Ethyl 1Ј-Methyl-2Ј-oxospiro[aziridine-2,3Ј-indoline]-1-carboxylate
Acknowledgments
(11): To a stirred solution of the substrate 10 (900 mg, 5.66 mmol)
in CH2Cl2 (2 mL), NsONHCO2Et (1.6 g, 5.66 mmol) and CaO
(317 mg, 5.66 mmol) were added portionwise. After 3 h, pentane
was added, and the mixture was stirred for a further 1 h. The or-
ganic phase was filtered, and the solid residue was washed first
We thank the Italian Ministero dell’Istruzione dell’Università e
della Ricerca (MIUR), and the University “La Sapienza” of Rome
(National Project “Stereoselezione in Sintesi Organica. Metodolo-
gie ed Applicazioni”) for financial support.
with pentane/CH2Cl2 (8:2) and then with pentane/CH2Cl2 (1:1).
The combined organic phases were concentrated under vacuum
and chromatographed on silica gel (hexane/ethyl acetate, 7:3) to
[1] a) K. B. Hansen, N. S. Finney, E. N. Jacobsen, Angew. Chem.
obtain 11 as a pale yellow solid (1 g, 4.07 mmol, 72% yield). IR
Int. Ed. Engl. 1995, 34, 676–678; b) P. Crotti, V. Di Bussolo, L.
(CHCl ): ν = 1732, 1621 cm–1. 1H NMR (CDCl , 200 MHz, 25 °C):
˜
3
3
Favero, M. Pineschi, Tetrahedron 1997, 53, 1417–1438.
[2] a) S. Rigolet, J. M. Mèlot, J. Vèbrel, A. Chiaroni, C. Riche, J.
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Fusi, F. Ponticelli, Tetrahedron Lett. 2002, 43, 9527–9530.
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δ = 1.25 (t, J = 7.3 Hz, 3 H, OCH2CH3), 2.84 (d, J = 1.5 Hz, 1 H,
NCHH), 3.12 (d, J = 1.5 Hz, 1 H, NCHH), 3.30 (s, 3 H, NCH3),
4.20 (q, J = 7.3 Hz, 2 H, OCH2CH3), 6.94–7.43 (m, 4 H, CHarom.
)
ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.6 (OCH2CH3),
27.1 (NCH3), 39.4 (NCH2C), 45.2 (NCCH2), 63.4 (OCH2CH3),
109.1 (CHarom.), 122.0 (CHarom.), 123.2 (CHarom.), 123.7 (Carom.),
130.1 (CHarom.), 144.7 (Carom.), 160.0 (NCO2), 170.4 (NCH3CO)
ppm. GC-MS: m/z (%) = 246 (100) [M]+. HRMS: calcd. for
C13H14N2NaO3 269.0902; found 269.0899.
[4] F. Kelleher, S. Kelly, Tetrahedron Lett. 2006, 47, 3005–3008.
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Borschberg, Helv. Chim. Acta 1996, 79, 151–168.
Aziridine Ring-Opening Reactions
Ethyl (1,3-Dimethyl-2-oxopyrrolidin-3-yl)carbamate (3b): To
a
stirred suspension of 2b (40 mg, 0.20 mmol) and 10% Pd/C (80 mg)
in dry methanol (1 mL), anhydrous ammonium formate (63 mg,
1 mmol) was added in a single portion, and the resulting mixture
was stirred at room temperature under argon for 4 h. The catalyst
was removed by filtration through a Celite pad and washed with
methanol. The filtrate was concentrated under reduced pressure,
and the residue was triturated with water and extracted with ethyl
acetate (5 mL). The combined organic phases were dried with
Na2SO4 and concentrated in vacuo. The crude product was purified
by chromatography on silica gel (hexane/ethyl acetate, 2:8) to ob-
tain 3b as a yellow oil (24 mg, 0.12 mmol, 60% yield). IR (CHCl3):
ν = 1735, 1675 cm–1. 1H NMR (CDCl , 200 MHz, 25 °C): δ = 1.23
˜
3
(t, J = 7.3 Hz, 3 H, OCH2CH3), 1.37 (s, 3 H, CH2CCH3), 2.09–
2.55 (m, 2 H, CH2CH2C), 2.89 (s, 3 H, NCH3), 3.20–3.44 (m, 2 H,
NCH2), 4.08 (q, J = 7.3 Hz, 2 H, OCH2CH3), 5.23 (br., 1 H, NH)
ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 13.3 (OCH2CH3),
21.7 (CH2CCH3), 29.9 (CH2CH2C), 34.6 (NCH3), 35.9 (NCH2),
57.9 (OCH2CH3), 64.4 (CH2CCH3), 159.2 (NCO2), 178.4
(NCH3CO) ppm. GC-MS: m/z (%) = 200 (7) [M]+, 111 (100).
HRMS: calcd. for C9H16N2NaO3 223.1059; found 223.1056.
Ethyl [(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)methyl]carbamate
(12): Compound 12 was prepared from 11 (50 mg, 0.20 mmol), ac-
cording to the procedure described for 3b. The mixture was stirred
at room temperature under argon for 1 h, and the crude product
was purified by chromatography on silica gel (hexane/ethyl acetate,
[16] C. B. Cui, H. Kakeya, G. Okada, R. Onose, H. Osada, J. Anti-
biot. 1996, 49, 527–533.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2365–2371

Novel Spiroheterocycles by Aziridination of α-Methylene-γ- and -δ-lactams
FULL PAPER
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Received: November 29, 2006
Published Online: March 2, 2007
Eur. J. Org. Chem. 2007, 2365–2371
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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