Synthesis of functionalized spiroaziridine-oxindoles from 3-ylideneoxindoles: an easy route to 3-(aminoalkyl)oxindoles

Article abstract of DOI:10.1002/ejoc.200900891

Novel potentially bioactive spiroaziridine-oxindoles have been prepared by treatment of easily accessible 3-ylidene-oxindoles with N-{[(4-nitrophenyl) sulfonyl]oxy}carbamate (NsONHCO₂Et) in the presence of CaO. These compounds gave new 3-(amino

Full text of DOI:10.1002/ejoc.200900891

FULL PAPER
DOI: 10.1002/ejoc.200900891
Synthesis of Functionalized Spiroaziridine-oxindoles from 3-Ylideneoxindoles:
An Easy Route to 3-(Aminoalkyl)oxindoles
I. Ammetto,[a] T. Gasperi,[b] M. Antonietta Loreto,*[a,c] A. Migliorini,[a,c] F. Palmarelli,[a]
and P. Antonio Tardella[a]
Keywords: Aziridination / Spiro compounds / Nitrogen heterocycles
Novel potentially bioactive spiroaziridine-oxindoles have
been prepared by treatment of easily accessible 3-ylidene-
oxindoles with N-{[(4-nitrophenyl)sulfonyl]oxy}carbamate
(NsONHCO2Et) in the presence of CaO. These compounds
gave new 3-(aminoalkyl)oxindole derivatives through easy
and regioselective reductive aziridine ring-opening reac-
tions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Because of their highly remarkable biological activities,
heterocyclic spiro compounds occupy a key place among
the various classes of organic molecules.[1] The synthetic
interest in compounds of this type arises from the presence
of the spiro carbon atom, which induces a relative steric
strain and allows easy rearrangements, yielding new hetero-
cycle derivatives.[2] A well-known class of spirocyclic mole-
cules are based on the spirooxindole system, which repre-
sents a common main feature of a variety of medicinal
agents and natural products. Such exceptional characteris-
tics have inspired many efforts directed towards their syn-
thesis.[3] The spiro architectures of many of these com-
pounds are based on a variety of heterocyclic moieties.
Spirotryprostatins A (1, Figure 1) and B (2), for example,
isolated from the fermentation broth of Aspergillus fumi-
gatus, are pentacyclic compounds with potential antineo-
Figure 1. Natural products containing the spirooxindole system.
plastic activity,[4] synthesized by Danishefsky’s[5a] and Wil- addition to the biological importance of compounds char-
liams’s[5b,5c] groups, respectively. Several total syntheses of acterized by aziridine rings,[9] the reactivities of these three-
the structurally simpler tricyclic horsfiline (3) have also membered heterocycles in modern organic chemistry are
been reported,[6] and its derivatives have been identified as also well documented; ring-opening, for instance, can be
cancer cell growth inhibitors.[5a]
effected by various carbon and heteroatom nucleophiles,
Otherwise, spirooxindoles in which the oxindole core is even in regiocontrolled processes to produce a variety of
fused with an aziridine ring have not been dealt with until functionalized amino compounds.[10]
now, except for one synthesis of spiroaziridine-oxindole de-
As part of our ongoing research into aziridines derived
rivatives by Renuka.[7] On the other hand, aziridines spiro- from electron-poor olefins, we have accomplished the syn-
fused with cyclic moieties have been widely described.[8] In thesis of N-(ethoxycarbonyl)spiroaziridines from unsatu-
rated heterocycles such as α-ylidene-γ-lactones[11] and α-
methylene-γ- and -δ-lactams[8e] with the aid of
[a] Dipartimento di Chimica, Università “La Sapienza”,
Piazzale Aldo Moro 5, Roma 00185, Italy
Fax: +39-06-490-631
NsONHCO2Et and CaO. Our first investigation of applica-
tion of the aziridination protocol to N-methyl-3-methyl-
eneoxindole was successful.[8e] By subsequent reductive az-
iridine ring-opening we obtained the corresponding 3-(ami-
nomethyl)oxindole derivative (Scheme 1, R = Me; R1 = H;
R2 = H; R3 = Et).
E-mail: mariaantonietta.loreto@uniroma1.it
[b] Dipartimento di Ingegneria Meccanica e Industriale, Università
degli Studi Roma Tre,
Via della Vasca Navale 79, 00146 Roma, Italy
[c] Istituto di Chimica Biomolecolare, Università “La Sapienza”,
Piazzale Aldo Moro 5, Roma 00185, Italy
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. A. Loreto et al.
FULL PAPER
Scheme 1. Reaction conditions: i) NsONHCO2R3, CaO, CH2Cl2;
Scheme 3. Synthesis of 3-ylideneoxindoles 5d–m. Reaction condi-
–
+
ii) Pd/C, HCO2 NH4
.
tions: i) R2O2CCH2PO(OR2)2, K2CO3, H2O/THF.
The effectiveness of the aziridination protocol and the
interest of spirooxindoles mentioned above paved the way
to the synthesis of spiroaziridino oxindoles 4 from the start-
ing 3-ylideneoxindoles 5 with different substituents either
on the aza group or on the double bond (Scheme 1). In
addition, the amino oxindole derivatives 6, quite remark-
able targets,[12] could easily be obtained by the reductive
ring-opening reaction.
Table 1. Synthesis of 3-ylideneoxindoles 5d–m.
Entry 7[a]
R
R1
5[a]
R2
% Yield
1
2
3
4
5
6
7
8
b
Me
Me
H
H
d[16a]
Et
90
77
71
77
70
70
50
61
b
e[16b]
Me
Me
Et
Me
Me
Me
Me
c[14]
c[14]
d[17a]
e[17a]
f[17a]
g[17b]
CH2CO2Et H
CH2CO2Et H
Bn
Bn
Bn
Ph
f
g
H
h[16c]
OMe
iPr
H
i
l
m
[a] The spectroscopic data for 7c–g, 5d, 5e and 5h were in agree-
ment with those reported in the literature.
Results and Discussion
The synthesis of the 3-methyleneoxindoles 5a–c was
achieved by a slightly modified Rossiter procedure.[13] Opti-
mization of the reported synthetic protocol was necessary
in order to avoid the polymerization of the desired products
5a–c (Scheme 2). We found that the substrates had to be
rapidly used once synthesized, without complete evapora-
tion of the solvent (dichloromethane) involved in the work-
up.[8e] The two-step procedure that we followed starts di-
rectly from the commercially available isatin (7a, R = H)
and N-methylisatin (7b, R = CH3), whereas the precursor
7c (R = CH2CO2Et) had to be prepared by a N-alkylation
reaction reported in the literature.[14] It is noteworthy that
the intermediates 8a–c were isolated and that the new
alcohol 8c has been fully characterized.
Compounds 5d–m are very stable and were purified by
chromatography on silica gel (hexane/AcOEt). Their struc-
1
tures were confirmed by H NMR and 13C NMR analysis.
The aziridination reactions were carried out with sub-
strates 5a–m in CH2Cl2 as in the reported procedure by por-
tionwise addition of NsONHCO2R3 and CaO (Scheme 4,
Table 2).[8e]
Scheme 4. Synthesis of spiroaziridine-oxindoles 4a–r. Reaction con-
ditions: i) NsONHCO2R3, CaO, CH2Cl2, r.t.
The reactions of 5a–c were quantitative with use of only
one equivalent of each reagent, whereas when starting from
5d–m two equivalents were required. The aziridines 4a–m
were easily isolated by chromatography on silica gel (hex-
ane/AcOEt) in the reported yields (Table 2).
With the aim of accessing aziridine derivatives bearing a
more easily removable protecting group on the nitrogen, we
carried out the optimized aziridination reaction with
Scheme 2. Synthesis of substrates 5a–c. Reaction conditions i) Me3-
SiCH2MgCl, THF anhydrous, –78 °CǞroom temp.; ii) BF3·OEt2,
CH2Cl2, –78 °CǞ0 °C.
Substrates 5d–m (Scheme 3), each bearing an alkoxycarb- NsONHCO2tBu as aminating agent.[18] With the 3-methyl-
onyl group on the double bond, were obtained by Horner– eneoxindoles 5a–c, aziridination was successful with
Wadsworth–Emmons reactions[15] between 7b–g and tri- 2 equiv. of reagent and 3 equiv. of base. The N-Boc-pro-
ethyl phosphonoacetate (R2 = CH2CH3) or trimethyl phos- tected spiroaziridines 4n–p (Entries 12–14) were obtained as
phonoacetate (R2 = CH3). Quite good results were achieved pure materials in good yields (70% to 92%) without any
with THF as solvent and aqueous K2CO3 as base (Table 1). need for further purification.
The main product was always the E isomer (5d–m),[16]
The presence of a carboxylate group on the double bond
whereas the minor Z isomers (9d–m) rapidly turned into (Entries 15–16) reduced the reactivities of the 3-ylideneox-
the corresponding E ones during the workup. The parent indoles. Indeed, on application of the described amination
substrates 7d–g were prepared as described in the litera- protocol to the substrates 5d and 5e the reactions were very
ture.[17]
sluggish and the desired products were detected only in
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Eur. J. Org. Chem. 2009, 6189–6197

Spiroaziridine-oxindoles from 3-Ylideneoxindoles
Table 2. Synthesis of spiroaziridine-oxindoles 4.
Entry
5
R
R1
Z
Molar ratio[a]
4
R3
% Yield
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
Me
CH2CO2Et
Me
Me
CH2CO2Et
CH2CO2Et
Bn
Bn
Bn
Ph
H
Me
CH2CO2Et
Me
H
H
H
H
H
H
H
H
OMe
iPr
H
H
H
H
H
H
H
H
H
1:1:1
1:1:1
1:1:1
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:3
1:2:3
1:2:3
1:6:6
1:8:8
a
b
c
d
e
f
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
tBu
tBu
tBu
tBu
tBu
62
72
62
52
51
48
49
57
44
60
59
70
CO2Et
CO2Me
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
H
H
H
CO2Et
CO2Me
g
h
i
g
h
i
9
10
11
12
13
14
15
16
l
l
m
a
b
c
d
e
m
n
o
p
q
r
92
90
trace[b]
trace[b]
Me
1
[a] 5/NsONHCO2R3/CaO. [b] Evaluated by H NMR analysis of the crude reaction mixture.
traces even though 8 equiv. of reactants were employed. We isolated by chromatography as syn/anti mixtures in 1:1 ra-
therefore did not examine the other hindered 3-ylideneox- tios (Scheme 6) as shown by their spectroscopic data. In-
indoles 5f–m.
deed, by means of shift correlation spectroscopy experi-
With the spiroaziridine-oxindoles 4a–p to hand, we pro- ments (COSY, HMQC, HMBC) we clearly identified the
ceeded with the ring-opening reactions, which were carried diagnostic signals of each stereoisomer.
out with ammonium formate and Pd/C,[19] conditions al-
ready successfully used for compound 4b.[8e] The reactions
always proved fruitful and regioselective, giving only 3-
(aminoalkyl)oxindole derivatives (Scheme 5).
Conclusions
In conclusion, we have developed a versatile strategy to
obtain novel spiroaziridine-oxindoles, potentially biolo-
gically active molecules, starting from easily accessible 3-
ylideneoxindoles. Moreover, the easy and regioselective
aziridine ring-opening reactions proved to be a straightfor-
ward tool for the preparation of the new 3-(aminoalkyl)-
oxindole derivatives 6a–m. The application of this method-
ology to asymmetric 3-ylideneoxindoles is currently under
investigation.
Scheme 5. Ring-opening reactions. Reaction conditions:
–
i) HCO2 NH4+, Pd/C.
Experimental Section
When the reactions were carried out on 4a–c and 4n–p,
the corresponding N-ethoxycarbonyl-3-(aminoalkyl)ox- General Methods: Solvents and common reagents were purchased
from a commercial source and were used without further purifica-
tion. All reactions were monitored by GC-MS with a HP 5890 sys-
tem fitted with a phenylmethylsilicone capillary column (15 m,
0.15 mm i.d.) and by thin-layer chromatography (TLC) carried out
on Merck F-254 a silica glass plates and visualized with the aid
of UV light and I2. 1H NMR spectra were recorded with Varian
Gemini 200 (200 MHz) and Bruker AVS 400 instruments. Chemical
shifts are expressed in parts per million (δ scale) and are referenced
to the residual protons of the NMR solvent (CHCl3: δ = 7.26 ppm):
(br. s) = broad singlet, (br. d) = broad doublet, (s) = singlet, (d) =
doublet, (t) = triplet, (q) = quartet, (dd) = double doublet, (sept)
= septuplet, (m) = multiplet. Coupling constants (J) are expressed
in Hz. 13C NMR spectra were recorded with a Varian Gemini 200
(50 MHz) instrument. Chemical shifts are expressed in parts per
million (δ scale) and are referenced to the carbon of the NMR
solvent (CHCl3: δ = 77.0 ppm). Most of the signals were assigned
by 2D NMR experiments (H-H-COSY, HMQC, HMBC), recorded
with Bruker AVS 400, Bruker DRX 400 or Bruker DRX 500 in-
struments. Infrared (IR) spectra were obtained with a Perkin–
indoles were formed as single compounds after 1 h. The
structures were confirmed by 1H NMR and 13C NMR
analyses.
With the spiroaziridines 4d–m the ring-opening reactions
were complete within 2 h. These reactions afforded mix-
tures of racemic amino diasteroisomers 6d–m, which were
Scheme 6. Ring-opening reactions. Reaction conditions:
–
i) HCO2 NH4+, Pd/C.
Eur. J. Org. Chem. 2009, 6189–6197
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6191

M. A. Loreto et al.
FULL PAPER
Elmer 1600 (FT-IR) instrument; data are presented as the fre-
quencies of absorption. HRMS spectra were recorded with a
Micromass Q-TOF micro Mass Spectrometer (Waters) and a
Micromass LCT (ESI) with Lock-Spray-Injector (Injection Loop-
Modus in a HPLC system, Waters, Alliance 2695). Microanalyses
were carried out with a CE Instruments EA1110 machine.
144.7, 165.9, 167.2, 167.5 ppm. IR (CHCl ): ν = 1740, 1618 cm–1.
HRMS: calcd. for C15H15NNaO5 312.0848; found 312.0845.
˜
3
Diethyl (2ЈE)-2,2Ј-(2-Oxo-1H-indol-1-yl-3-ylidene)diacetate (5g):
Compound 5g was prepared from 7c (818 mg, 3.5 mmol) and tri-
ethyl phosphonoacetate (851 mg, 3.8 mmol) by the procedure de-
scribed for 5f. After solvent evaporation, the crude mixture was
chromatographed over silica gel (hexane/ethyl acetate 7:3) to pro-
vide the isomer (E)-5g (816 mg, 2.7 mmol, 77% yield) as an orange
Ethyl [3-Hydroxy-2-oxo-3-(trimethylsilyl)methyl-2,3-dihydroindol-1-
yl]acetate (8c): Ethyl (2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate
(7c, 500 mg, 2.15 mmol) was suspended in dry THF (8.6 mL) and
the resulting mixture was cooled to –78 °C. [(Trimethylsilyl)meth-
yl]magnesium chloride (2.1 mL of a 1  solution in diethyl ether,
2.1 mmol) was added with stirring. The mixture was stirred at
–78 °C for 15 min and was then allowed to warm to room tempera-
ture, with stirring, for a further 3 h. The reaction was quenched
with methanol, and then the mixture was concentrated in vacuo to
give a brown viscous liquid, which was triturated first with hexane/
ethyl acetate 1:1 and then with ethyl acetate. After filtration, the
combined organic phases were concentrated in vacuo to give pure
8c as an orange viscous liquid. (587 mg, 1.83 mmol, 85% yield). 1H
NMR (CDCl3, 200 MHz, 25 °C): δ = –0.25 [s, 9 H, Si(CH3)3], 1.26
(t, J = 7.3 Hz, 3 H, CH3CH2), 1.56 (s, 2 H, SiCH2), 2.56 (br. s, 1
H, OH), 4.22 (q, J = 7.3 Hz, 2 H, CH3CH2), 4.34 (d, J = 17.2 Hz,
1 H, NCHH), 4.51 (d, J = 17.2 Hz, 1 H, NCHH), 6.71 (d, J =
7.8 Hz, 1 H, CHarom), 7.09 (m, 1 H, CHarom) 7.24–7.42 (m, 2 H,
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = –1.1, 14.1,
28.2, 41.5, 61.7, 75.5, 108.6, 123.3, 124.2, 129.6, 131.1, 141.7, 167.4,
1
solid. H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.26 (t, J = 7.1 Hz,
3 H, CH2CH3), 1.37 (t, J = 7.1 Hz, 3 H, CH2CH3), 4.22 (q, J =
7.1 Hz, 2 H, CH2CH3), 4.30 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.48
(s, 2 H, NCH2), 6.70 (d, J = 7.7 Hz, 1 H, CHarom), 6.94 (s, 1 H,
CH=), 7.01–7.45 (m, 2 H, CHarom), 8.90 (d, J = 7.7 Hz, 1 H,
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 13.6, 13.7,
53.2, 59.2, 59.6, 120.3, 123.4, 124.0, 126.4, 126.8, 127.9, 135.9,
150.3, 162.3, 165.0, 171.0 ppm. IR (CHCl ): ν = 1731, 1613 cm–1.
˜
3
HRMS: calcd. for C16H17NNaO5 326.1004; found 326.1008.
Methyl (2E)-(1-Benzyl-5-methoxy-2-oxo-1,2-dihydro-3H-indol-3-
ylidene)ethanoate (5i): Compound 5i was prepared from 7e
(500 mg, 1.8 mmol) and trimethyl phosphonoacetate (364 mg,
2.0 mmol) by the procedure described for 5f. After solvent evapora-
tion, the crude mixture was chromatographed over silica gel (hex-
ane/ethyl acetate 7:3) to provide the isomer (E)-5i (408 mg,
1.2 mmol, 70% yield) as an orange solid. 1H NMR (CDCl3,
200 MHz, 25 °C): δ = 3.77 (s, 3 H, OCH3), 3.86 (s, 3 H, CO2CH3),
4.86 (s, 2 H, NCH2), 6.55 (d, J = 8.5 Hz, 1 H, CHarom), 6.78 (dd,
J = 8.5, 2.5 Hz, 1 H, CHarom), 6.94 (s, 1 H, CH=), 7.28 (m, 5 H,
CHarom), 8.27 (d, J = 2.5 Hz, 1 H, CHarom) ppm. 13C NMR
(CDCl3, 50 MHz, 25 °C): δ = 43.7, 51.9, 55.6, 109.4, 114.4, 118.1,
120.4, 122.0, 127.0, 127.5, 128.6, 135.4, 138.3, 155.6, 165.7,
178.1 ppm. IR (CHCl ): ν = 3605, 1740, 1700 cm–1. GC-MS: m/z
˜
3
(%) = 321 (12) [M]+, 158 (100). HRMS: calcd. for C16H23NNaO4Si
344.1294; found 344.1290.
Ethyl (3-Methylidene-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate (5c):
Ethyl (3-hydroxy-2-oxo-3-(trimethylsilyl)methyl-2,3-dihydroindol-
1-yl)acetate (8c, 350 mg, 1.1 mmol) in dry CH2Cl2 (28 mL) was co-
oled to –78 °C and boron trifluoride diethyl etherate (774 mg,
2.5 mmol) was added. The mixture was stirred at –78 °C for 2 h
and then at 0 °C for another 1 h. The mixture was poured into
saturated aqueous NaHCO3 solution and extracted with CH2Cl2
(4ϫ50 mL). The combined organic layers were washed with
NaHCO3 and dried with NaSO4, and the solvent was partially
evaporated to give a concentrated solution of pure product 5c,
which was immediately treated as described below. An analytical
sample was concentrated to dryness for 1H NMR spectroscopic
confirmation. 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.26 (t, J
= 7.3 Hz, 3 H, CH3CH2), 4.22 (q, J = 7.3 Hz, 2 H, CH3CH2), 4.49
(s, 2 H, NCH2), 6.15 (s, 1 H, C=CHH), 6.43 (s, 1 H, C=CHH),
6.71 (d, J = 7.8 Hz, 1 H, CHarom), 7.06 (m, 1 H, CHarom), 7.23–
7.54 (m, 2 H, CHarom) ppm.
167.2 ppm. IR (CHCl ): ν = 1742, 1607 cm–1. HRMS: calcd. for
˜
3
C19H19NNaO4 346.1055; found 346.1052.
Methyl (2E)-[1-Benzyl-2-oxo-5-(propan-2-yl)-1,2-dihydro-3H-indol-
3-ylidene]ethanoate (5l): Compound 5l was prepared from 7f
(500 mg, 1.7 mmol) and trimethyl phosphonoacetate (364 mg,
2.0 mmol) by the procedure described for 5f. After solvent evapora-
tion, the crude mixture was chromatographed over silica gel (hex-
ane/ethyl acetate 7:3) to provide the isomer (E)-5l (285 mg,
0.8 mmol, 50% yield) as an orange solid. H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.24 [d, J = 6.9 Hz, 6 H, (CH3)2CH], 2.90
[sept, J = 6.9 Hz, 1 H, (CH3)2CH], 3.89 (s, 3 H, CO2CH3), 4.91 (s,
2 H, NCH2), 6.62 (d, J = 8.1 Hz, 1 H, CHarom), 6.97 (s, 1 H, CH=),
7.13 (dd, J = 8.1, 1.7 Hz, 1 H, CHarom), 7.29 (m, 5 H, CHarom),
8.51 (d, J = 1.7 Hz, 1 H, CHarom) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 23.9, 33.6, 44.2, 52.2, 111.0, 117.9, 123.3,
127.6, 128.2, 129.2, 134.9, 136.8, 141.2, 143.8, 145.0, 149.0, 158.7,
162.3 ppm. IR (CHCl ): ν = 1739, 1623 cm–1. HRMS: calcd. for
˜
3
Ethyl Methyl (2ЈE)-2,2Ј-(2-Oxo-1H-indol-1-yl-3-ylidene)diacetate
(5f): Trimethyl phosphonoacetate (546 mg, 3.0 mmol) and a solu-
tion of K2CO3 (1.2 g, 8.7 mmol) in water (1.8 mL) were added at
0 °C to a stirred solution of 7c (640 mg, 2.7 mmol) in THF (9 mL).
The mixture was stirred at 0 °C for 15 min. After the system had
been kept for 3 h at room temperature, diethyl ether (50 mL) was
added and the organic phase was washed with brine and dried with
anhydrous Na2SO4. After solvent evaporation the crude mixture
was chromatographed on silica gel (hexane/ethyl acetate 7:3) to
provide (E)-5f as an orange solid (555 mg, 1.9 mmol, yield 71%).
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.25 (t, J = 7.3 Hz, 3 H,
C21H21NNaO3 358.1419; found 358.1422.
Methyl (2E)-(2-Oxo-1-phenyl-1,2-dihydro-3H-indol-3-ylidene)eth-
anoate (5m): Compound 5m was prepared from 7g (500 mg,
2.2 mmol) and trimethyl phosphonoacetate (448 mg, 2.4 mmol) by
the procedure described for 5f. After solvent evaporation, the crude
mixture was chromatographed over silica gel (hexane/ethyl acetate
7:3) to provide the isomer (E)-5m (375 mg, 1.3 mmol, 61% yield)
1
as an orange solid. H NMR (CDCl3, 200 MHz, 25 °C): δ = 3.85
(s, 3 H, OCH3), 6.76 (d, J = 8.0 Hz, 1 H, CHarom), 6.96 (s, 1 H,
CH=), 7.06 (m, 1 H, CHarom), 7.27 (m, 1 H, CHarom), 7.33–7.57
CH2CH3), 3.87 (s, 3 H, CO2CH3), 4.22 (q, J = 7.3 Hz, 2 H, (m, 5 H, CHarom), 8.64 (d, J = 7.7 Hz, 1 H, CHarom) ppm. 13C
CH2CH3), 4.48 (s, 2 H, NCH2), 6.69 (d, J = 7.7 Hz, 1 H, CHarom), NMR (CDCl3, 50 MHz, 25 °C): δ = 51.8, 109.0, 119.5, 122.0,
6.94 (s, 1 H, CH=), 7.02–7.44 (m, 2 H, CHarom), 8.59 (d, J = 7.7 Hz,
123.0, 126.2, 127.9, 128.7, 129.4, 132.1, 133.6, 137.6, 145.7, 165.7,
1 H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.0, 166.5 ppm. IR (CHCl ): ν = 1741, 1615 cm–1. HRMS: calcd. for
˜
3
41.5, 52.1, 61.8, 108.2, 119.9, 122.4, 123.2, 128.9, 132.4, 137.5,
6192
C17H13NNaO3 302.0793; found 302.0791.
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Eur. J. Org. Chem. 2009, 6189–6197

Spiroaziridine-oxindoles from 3-Ylideneoxindoles
Ethyl 2Ј-Oxo-1Ј,2Ј-dihydro-1H-spiro[aziridine-2,3Ј-indole]-1-carbox-
ylate (4a): NsONHCO2Et (246 mg, 0.8 mmol) and CaO (48 mg,
0.8 mmol) were added portionwise to a stirred solution of the sub-
strate 5a (123 mg, 0.8 mmol) in CH2Cl2 (0.5 mL). After 1 h, pen-
tane was added and the mixture was stirred for an additional hour.
The organic phase was filtered and the solid residue was washed
first with pentane/CH2Cl2 (8:2) and then with pentane/CH2Cl2
(1:1). The combined organic phases were concentrated under vac-
uum and the crude mixture was chromatographed on silica gel
(hexane/ethyl acetate 7:3) to provide the product 4a (116 mg,
0.5 mmol, 62% yield) as a yellow solid. 1H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.23 (t, J = 7.3 Hz, 3 H, OCH2CH3), 2.85
(d, J = 1.5 Hz, 1 H, NCHH), 3.12 (d, J = 1.5 Hz, 1 H, NCHH),
4.20 (q, J = 7.3 Hz, 2 H, OCH2CH3), 6.97 (d, J = 8.2 Hz, 1 H,
CHarom), 7.01–7.35 (m, 3 H, CHarom), 8.46 (br. s, 1 H, NH) ppm.
13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.2, 39.2, 45.1, 63.0,
110.7, 121.8, 122.7, 124.0, 129.6, 141.9, 160.1, 172.7 ppm. IR
H, CO2CH2CH3), 6.92 (m, 1 H, CHarom), 7.08 (m, 1 H, CHarom),
7.34–7.44 (m, 2 H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz,
25 °C): δ = 14.3, 26.9, 48.0, 49.1, 52.7, 63.6, 108.8, 120.8, 123.2,
124.4, 130.4, 145.3, 158.3, 165.6, 168.8 ppm. IR (CHCl ): ν = 1738,
˜
3
1720, 1631 cm–1. HRMS calcd. for C15H16N2NaO5 327.0957;
found 327.0955. C15H16N2O5 (304.30): calcd. C 59.21, H 5.30, N
9.21; found C 59.24, H 5.32, N 9.18.
1-Ethyl 3-Methyl 1Ј-(2-Ethoxy-2-oxoethyl)-2Ј-oxo-1Ј,2Ј-dihydro-1H-
spiro[aziridine-2,3Ј-indole]-1,3-dicarboxylate (4f): Compound 4f was
prepared from 5f (82 mg, 0.2 mmol) by the procedure described for
4d. The crude product was purified by chromatography over silica
gel (hexane/ethyl acetate 7:3) to provide a yellow solid (36 mg,
0.1 mmol, 48% yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.22 (m, 6 H, NCO2CH2CH3, CH2CO2CH2CH3), 3.74 (s, 3 H,
CO2CH3), 3.86 (s, 1 H, NCHCO), 4.19 (m, 4 H, NCO2CH2CH3,
CH2CO2CH2CH3), 4.42 (d, J = 17.5 Hz, 1 H, CHHCO2CH2CH3),
4.53 (d, J = 17.5 Hz, 1 H, CHHCO2CH2CH3), 6.79 (d, J = 7.8 Hz,
1 H, CHarom), 7.06 (m, 1 H, CHarom), 7.25–7.45 (m, 2 H,
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 13.9, 14.0,
41.9, 48.0, 48.7, 52.6, 61.9, 63.5, 108.8, 120.4, 123.4, 124.6, 130.3,
(CHCl3):
ν =
˜
3217, 1716, 1623 cm–1. HRMS: calcd. for
C12H12N2NaO3 255.0746; found 255.0742. C12H12N2O3 (232.23):
calcd. C 62.06, H 5.21, N 12.06; found C 62.04, H 5.20, N 12.02.
143.9, 165.3, 166.7, 169.0, 176.5 ppm. IR (CHCl ): ν = 1742,
˜
Ethyl 1Ј-(2-Ethoxy-2-oxoethyl)-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro[azir-
idine-2,3Ј-indole]-1-carboxylate (4c): Compound 4c was prepared
from 5c (231 mg, 1.0 mmol) by the procedure described for 4a. The
product was obtained as a yellow solid (197 mg, 0.6 mmol, 62%
yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.22 (t, J = 7.1 Hz,
3 H, CO2CH2CH3), 1.27 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 2.87
(d, J = 1.5 Hz, 1 H, NCHH), 3.15 (d, J = 1.5 Hz, 1 H, NCHH),
4.13–4.28 (m, 4 H, NCO2CH2CH3, CH2CO2CH2CH3), 4.42 (d, J
= 17.6 Hz, 1 H, NCHHCO2), 4.61 (d, J = 17.6 Hz, 1 H,
NCHHCO2), 6.81 (d, J = 7.8 Hz, 1 H, CHarom), 7.06–7.13 (m, 2
H, CHarom), 7.29–7.42 (m, 1 H, CHarom) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 14.1, 14.2, 39.3, 41.8, 44.6, 61.8, 63.0, 108.7,
121.7, 123.2, 123.5, 129.6, 143.4, 166.8, 170.4, 173.9 ppm. IR
3
1630 cm–1. HRMS calcd. for C18H20N2NaO7 399.1168; found
399.1165. C18H20N2O7 (376.36): calcd. C 57.44, H 5.36, N 7.44;
found C 57.40, H 5.31, N 7.40.
Diethyl 1Ј-(2-Ethoxy-2-oxoethyl)-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro[az-
iridine-2,3Ј-indole]-1,3-dicarboxylate (4g): Compound 4g was pre-
pared from 5g (776 mg, 2.5 mmol) by the procedure described for
4d. The crude product was purified by chromatography over silica
gel (hexane/ethyl acetate 7:3) to provide a yellow solid (477 mg,
1.2 mmol, 49% yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.16–1.29 (m, 9 H, CO2CH2CH3), 3.85 (s, 1 H, NCH), 4.11–4.27
(m, 4 H, CO2CH2CH3), 4.43 (d, J = 17.5 Hz, 1 H, NCHH), 4.54
(d, J = 17.5 Hz, 1 H, NCHH), 6.80 (d, J = 7.8 Hz, 1 H, CHarom),
7.06 (m, 1 H, CHarom), 7.27–7.49 (m, 2 H, CHarom) ppm. 13C NMR
(CDCl3, 50 MHz, 25 °C): δ = 13.7, 13.8, 41.5, 47.8, 48.4, 61.5, 61.8,
63.1, 108.6, 120.2, 123.0, 124.2, 130.0, 143.6, 158.0, 164.5, 166.5,
(CHCl3):
ν =
˜
1732, 1710, 1621 cm–1. HRMS: calcd. for
C16H18N2NaO5 341.1113; found 341.1110. C16H18N2O5 (318.32):
calcd. C 60.37, H 5.70, N 8.80; found C 60.34, H 5.72, N 8.79.
168.7 ppm. IR (CHCl ): ν = 1741, 1618 cm–1. HRMS calcd. for
˜
3
Diethyl
1Ј-Methyl-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro[aziridine-2,3Ј-
C19H22N2NaO7 413.1325; found 413.1329. C19H22N2O7 (390.39):
calcd. C 58.46, H 5.68, N 7.18; found C 58.47, H 5.69, N 7.17.
indole]-1,3-dicarboxylate (4d): Compound 4d was prepared from 5d
(450 mg, 1.9 mmol) by the procedure described for 4a, with a sub-
strate/NsONHCO2Et/CaO molar ratio of 1:2:2 being reached. The
crude product was chromatographed on silica gel (hexane/ethyl ace-
tate 7:3) to provide a yellow solid (300 mg, 0.9 mmol, 52% yield).
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.25 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 1.26 (t, J = 7.1 Hz 3 H, CO2CH2CH3), 3.28 (s, 3 H,
NCH3), 3.86 (s, 1 H, NCHCO), 4.11 (q, J = 7.1 Hz, 2 H,
CO2CH2CH3), 4.22 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 6.92 (d, J
= 8.9 Hz, 1 H, CHarom), 7.08 (m, 1 H, CHarom), 7.34–7.44 (m, 2 H,
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 13.9, 14.0,
26.6, 47.8, 48.7, 61.9, 63.3, 108.6, 120.5, 122.9, 124.1, 130.2, 145.0,
158.2, 164.8, 168.6 ppm. IR (CHCl ): ν = 1740, 1715, 1623 cm–1.
1-Ethyl 3-Methyl 1Ј-Benzyl-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro[aziridine-
2,3Ј-indole]-1,3-dicarboxylate (4h): Compound 4h was prepared
from 5h[16c] (104 mg, 0.35 mmol) by the procedure described for 4d.
The crude product was purified by chromatography over silica gel
(hexane/ethyl acetate 7:3) to provide a yellow solid (76 mg,
0.2 mmol, 57% yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.24 (t, J = 7.3 Hz, 3 H, CH2CH3), 3.79 (s, 3 H, CO2CH3), 3.95 (s,
1 H, NCHCO), 4.23 (q, J = 7.3 Hz, 2 H, CH2CH3), 4.83 (d, J =
15.8 Hz, 1 H, NCHHPh), 5.11 (d, J = 15.8 Hz, 1 H, NCHHPh),
6.79 (d, J = 7.6 Hz, 1 H, CHarom), 7.04 (m, 1 H, CHarom), 7.22–
7.46 (m, 7 H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ
= 14.1, 44.2, 47.9, 48.9, 52.6, 66.5, 109.7, 120.8, 123.2, 124.4, 127.1,
127.8, 128.8, 130.2, 134.9, 144.3, 158.3, 165.5, 169.0 ppm. IR
˜
3
HRMS calcd. for C16H18N2NaO5 341.1113; found 341.1116.
C16H18N2O5 (318.32): calcd. C 60.37, H 5.70, N 8.80; found C
60.35, H 5.68, N 8.81.
(CHCl ): ν = 1738, 1620 cm–1. HRMS: calcd. for C H N NaO
˜
3
21 20
2
5
403.1270; found 403.1272. C21H20N2O5 (380.39): calcd. C 66.31, H
5.30, N 7.36; found C 66.34, H 5.30, N 7.32.
1-Ethyl 3-Methyl 1Ј-Methyl-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro[aziridine-
2,3Ј-indole]-1,3-dicarboxylate (4e): Compound 4e was prepared
from 5e (450 mg, 2.0 mmol) by the procedure described for 4a, with
a substrate/NsONHCO2Et/CaO molar ratio of 1:2:2 being reached.
The crude product was purified by chromatography over silica gel
(hexane/ethyl acetate 7:3) to provide a yellow solid (325 mg,
1.0 mmol, 51% yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1-Ethyl 3-Methyl 1Ј-Benzyl-5Ј-methoxy-2Ј-oxo-1Ј,2Ј-dihydro-1H-
spiro[aziridine-2,3Ј-indole]-1,3-dicarboxylate (4i): Compound 4i was
prepared from 5i (250 mg, 0.9 mmol) by the procedure described
for 4d. The crude product was purified by chromatography over
silica gel (hexane/ethyl acetate 7:3) to provide a yellow solid
1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 3.28 (s, 3 H, NCH3), 3.78 (165 mg, 0.4 mmol, 44% yield). 1H NMR (CDCl3, 200 MHz,
(s, 3 H, CO2CH3), 3.86 (s, 1 H, NCHCO), 4.24 (q, J = 7.1 Hz, 2 25 °C): δ = 1.25 (t, J = 7.1 Hz, 3 H, CH2CH3), 3.74 (s, 3 H,
Eur. J. Org. Chem. 2009, 6189–6197
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6193

M. A. Loreto et al.
FULL PAPER
COCH3), 3.80 (s, 3 H, CO2CH3), 3.95 (s, 1 H, NCHCO), 4.24 (q,
J = 7.1, Hz, 2 H, CH2CH3), 4.80 (d, J = 15.8 Hz, 1 H, NCHHPh),
tert-Butyl 1Ј-Methyl-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro[aziridine-2,3Ј-
indole]-1-carboxylate (4o): NsONHCO2tBu (127 mg, 0.4 mmol)
5.10 (d, J = 15.8 Hz, 1 H, NCHHPh), 6.64–6.83 (m, 2 H, CHarom), and CaO (22 mg, 0.4 mmol) were added portionwise every hour to
7.06 (d, J = 2.5 Hz, 1 H, CHarom), 7.26–7.36 (m, 5 H, CHarom) ppm. a stirred solution of the substrate 5b (64 mg, 0.4 mmol) in CH2Cl2
13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.1, 44.4, 47.9, 49.1, 52.6,
55.7, 63.5, 110.3, 110.8, 115.6, 121.9, 127.1, 127.7, 128.7, 135.0,
(1 mL), with a substrate/NsONHCO2tBu/CaO molar ratio of up to
1:2:3 being reached. After 3 h, pentane was added and the mixture
was stirred for an additional hour. The organic phase was filtered
and the solid residue was washed first with pentane/CH2Cl2 (8:2)
and then with pentane/CH2Cl2 (1:1). The organic phases were con-
centrated under vacuum to provide 4o as a yellow solid (101 mg,
0.3 mmol, 92% yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.42 [s, 9 H, C(CH3)3], 2.78 (d, J = 1.8 Hz, 1 H, NCHH), 3.04 (d,
J = 1.8 Hz, 1 H, NCHH), 3.26 (s, 3 H, NCH3), 6.90 (d, J = 7.8 Hz,
1 H, CHarom), 7.04 (m, 2 H, CHarom), 7.33 (m, 1 H, CHarom) ppm.
13C NMR (CDCl3, 50 MHz, 25 °C): δ = 27.8, 29.6, 38.9, 44.7, 82.3,
108.5, 121.5, 122.6, 123.9, 129.4, 144.6, 158.4, 170.5 ppm. IR
137.5, 156.2, 158.3, 165.4, 168.7 ppm. IR (CHCl ): ν = 1743,
˜
3
1602 cm–1. HRMS: calcd. for C22H22N2NaO6 433.1376; found
433.1374. C22H22N2O6 (410.42): calcd. C 64.38, H 5.40, N 6.83;
found C 64.34, H 5.42, N 6.80.
1-Ethyl 3-Methyl 1Ј-Benzyl-2Ј-oxo-5Ј-(propan-2-yl)-1Ј,2Ј-dihydro-
1H-spiro[aziridine-2,3Ј-indole]-1,3-dicarboxylate (4l): Compound 4l
was prepared from 5l (468 mg, 1.4 mmol) by the procedure de-
scribed for 4d. The crude product was purified by chromatography
over silica gel (hexane/ethyl acetate 7:3) to provide a yellow solid
(359 mg, 0.8 mmol, 60% yield). 1H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.13–1.30 [m, 9 H, (CH3)2CH, CH2CH3], 2.85 [sept, J
= 6.8 Hz, 1 H, (CH3)2CH], 3.79 (s, 1 H, NCHCO), 3.80 (s, 3 H,
CO2CH3), 4.24 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.82 (d, J = 15.7 Hz,
(CHCl ): ν = 1776, 1615 cm–1. HRMS: calcd. for C H N NaO
˜
3
15 18
2
3
297.1215; found 297.1213. C15H18N2O3 (274.31): calcd. C 65.68, H
6.61, N 10.21; found C 65.69, H 6.60, N 10.22.
1 H, NCHHPh), 5.06 (d, J = 15.7 Hz, 1 H, NCHHPh), 6.71 (d, J tert-Butyl 1Ј-(2-Ethoxy-2-oxoethyl)-2Ј-oxo-1Ј,2Ј-dihydro-1H-spiro-
= 8.1 Hz, 1 H, CHarom), 7.11 (dd, J = 8.1, 1.8 Hz, 1 H, CHarom), [aziridine-2,3Ј-indole]-1-carboxylate (4p): Compound 4p was pre-
7.26–7.36 (m, 6 H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz, pared from 5c (46 mg, 0.2 mmol) by the procedure described for 4o,
25 °C): δ = 14.0, 23.7, 24.0, 33.6, 44.3, 47.8, 49.0, 52.5, 63.3, 109.4,
with a substrate/NsONHCO2tBu/CaO molar ratio of 1:2:3 being
reached. The organic phases were concentrated under vacuum to
provide 4p as a yellow solid (62 mg, 0.18 mmol, yield 90%). 1H
111.8, 120.6, 122.2, 127.1, 127.6, 128.7, 135.0, 142.0, 144.0, 158.3,
165.4, 168.8 ppm. IR (CHCl ): ν = 1721, 1618 cm–1. HRMS: calcd.
˜
3
for C24H26N2NaO5 445.1739; found 445.1743. C24H26N2O5 NMR (CDCl3, 200 MHz, 25 °C): δ = 1.26 (t, J = 7.1 Hz, 3 H,
(422.47): calcd. C 68.23, H 6.20, N 6.63; found C 68.24, H 6.22, N
6.62.
CH3CH2), 1.43 [s, 9 H, C(CH3)3], 2.82 (d, J = 1.7 Hz, 1 H, NCHH),
3.11 (d, J = 1.7 Hz, 1 H, NCHH), 4.22 (q, J = 7.1 Hz, 2 H,
CH2CH3), 4.44 (d, J = 17.5 Hz, 1 H, NCHHCO2), 4.60 (d, J =
17.5 Hz, 1 H, 1 H, NCHHCO2), 6.80 (d, J = 7.8 Hz, 1 H, CHarom),
7.04–7.13 (m, 2 H, CHarom), 7.25–7.37 (m, 1 H, CHarom) ppm. 13C
NMR (CDCl3, 50 MHz, 25 °C): δ = 14.1, 27.8, 39.3, 41.7, 44.7,
61.7, 82.5, 108.6, 121.7, 123.0, 123.7, 129.5, 143.4, 158.4, 167.2,
1-Ethyl 3-Methyl 2Ј-Oxo-1Ј-phenyl-1Ј,2Ј-dihydro-1H-spiro[aziridine-
2,3Ј-indole]-1,3-dicarboxylate (4m): Compound 4m was prepared
from 5m (386 mg, 1.3 mmol) by the procedure described for 4d.
The crude product was purified by chromatography over silica gel
(hexane/ethyl acetate 7:3) to provide a yellow solid (280 mg,
0.8 mmol, 59% yield). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.26 (t, J = 7.1 Hz, 3 H, CH2CH3), 3.82 (s, 3 H, CO2CH3), 3.96 (s,
1 H, NCHCO), 4.23 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.90 (d, J =
7.8 Hz, 1 H, CHarom), 7.12 (m, 1 H, CHarom), 7.27–7.60 (m, 7 H,
170.6 ppm. IR (CHCl ): ν = 1723, 1617 cm–1. HRMS: calcd. for
˜
3
C18H22N2NaO5 369.1426; found 369.1423. C18H22N2O5 (346.38):
calcd. C 62.42, H 6.40, N 8.09; found C 62.44, H 6.44, N 8.11.
Ethyl [(2-Oxo-2,3-dihydro-1H-indol-3-yl)methyl]carbamate (6a):
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 13.3, 44.5, Anhydrous ammonium formate (64.8 mg, 1.0 mmol) was added in
45.7, 55.4, 57.2, 120.6, 125.4, 126.5, 127.1, 127.5, 127.8, 128.3,
a single portion to a stirred suspension of 4a (84 mg, 0.36 mmol)
and Pd/C (10%, 144 mg) in dry methanol (1.8 mL), and the re-
sulting mixture was stirred at room temperature under argon for
1 h. The catalyst was removed by filtration through a celite pad
and washed with methanol. The filtrate was concentrated under
reduced pressure and then purified by chromatography on silica
gel (hexane/ethyl acetate 6:4) to provide the product 6a (56 mg,
0.24 mmol, yield 66%). 1H NMR (CDCl3, 200 MHz, 25 °C): δ =
1.19 (t, J = 7.1 Hz, OCH2CH3), 3.38–3.95 (m, 2 H, CHCH2NH),
3.76–3.98 (m, 1 H, CHCH2NH), 4.07 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 5.69 (br. s, 1 H, NHCO2CH2), 6.88 (d, J = 7.6 Hz, 1
H, CHarom), 6.98–7.05 (m, 1 H, CHarom), 7.15–7.38 (m, 2 H,
CHarom), 9.17 (br. s, 1 H, NHCOCH) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 14.5, 41.1, 46.1, 61.2, 110.0, 123.0, 124.4,
133.4, 139.3, 145.3, 159.3, 171.1, 172.0 ppm. IR (CHCl ): ν = 1776,
˜
3
1615 cm–1. HRMS: calcd. for C20H18N2NaO5 389.1113; found
389.1117. C20H18N2O5 (366.37): calcd. C 65.57, H 4.95, N 7.65;
found C 65.54, H 4.97, N 7.63.
tert-Butyl
2Ј-Oxo-1Ј,2Ј-dihydro-1H-spiro[aziridine-2,3Ј-indole]-1-
carboxylate (4n): NsONHCO2tBu (120 mg, 0.38 mmol) and CaO
(32 mg, 0.58 mmol) were added portionwise every hour to a stirred
solution of 5a (46 mg, 0.32 mmol) in CH2Cl2 (2.0 mL), with a sub-
strate/NsONHCO2tBu/CaO molar ratio of up to 1:2:3 being
reached. After 2 h, pentane was added and the mixture was stirred
for an additional hour. The organic phase was filtered and the solid
residue was washed first with pentane/CH2Cl2 (8:2) and then with
pentane/CH2Cl2 (1:1). The combined organic phases were concen-
trated under vacuum to give the product 4n as a yellow solid
(58 mg, 0.2 mmol, 70% yield). 1H NMR (CDCl3, 200 MHz, 25 °C):
δ = 1.44 [s, 9 H, C(CH3)3], 2.80 (d, J = 1.7 Hz, 1 H, NCHH), 3.07
126.6, 128.5, 141.7, 156.6, 179.3 ppm. IR (CHCl ): ν = 3424, 1705,
˜
3
1609 cm–1. HRMS: calcd. for C12H14N2NaO3 257.0902; found
257.0899. C12H14N2O3 (234.25): calcd. C 61.53, H 6.02, N 11.96;
found C 61.55, H 6.00, N 11.92.
(d, J = 1.7 Hz, 1 H, NCHH), 6.94 (d, J = 7.8 Hz, 1 H, CHarom
)
7.03 (m, 2 H, CHarom), 7.23–7.33 (m, 1 H, CHarom), 9.09 (br. s, 1
Ethyl (3-{[(Ethoxycarbonyl)amino]methyl}-2-oxo-2,3-dihydro-1H-
H, NHCO) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 27.9, indol-1-yl)acetate (6c): Compound 6c was prepared from 4c
39.0, 45.1, 82.5, 110.6, 121.9, 122.7, 124.3, 129.6, 141.9, 158.6,
(147 mg, 0.46 mmol) by the procedure described for 6a. The prod-
172.8 ppm. IR (CHCl ): ν = 1730, 1620 cm–1. HRMS: calcd. for uct 6c was obtained as a yellow solid (53 mg, 0.2 mmol, yield 50%).
˜
3
C14H16N2NaO3 283.1059; found 283.1055. C14H16N2O3 (260.29): 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.19 (t, J = 7.1 Hz, 3 H,
calcd. C 64.60, H 6.20, N 10.76; found C 64.64, H 6.22, N 10.72.
6194
CO2CH2CH3), 1.26 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 3.55 (m, 1
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6189–6197

Spiroaziridine-oxindoles from 3-Ylideneoxindoles
H, CHCHHNH), 3.65 (m, 1 H, CHCH2NH), 3.95 (m, 1 H,
same as had been followed for the preparation of compound 6a.
CHCHHNH), 4.07 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 4.21 (q, J The product 6f was isolated as a syn/anti mixture (1:1) of two dia-
= 7.1 Hz, 4 H, CO2CH2CH3), 4.37 (d, J = 17.5 Hz, 1 H,
NCHHCO2), 4.53 (d, J = 17.5 Hz, 1 H, NCHHCO2), 5.42 (br. s, 1
H, NH), 6.72 (m, 1 H, CHarom), 7.08 (m, 1 H, CHarom), 7.30 (m, 2
stereoisomers (147 mg, 0.4 mmol, 50% yield). 1H NMR (CDCl3,
400 MHz, 25 °C): δ = 1.10–1.30 (m, 12 H, 4ϫOCH2CH3), 3.73 (s,
3 H, OCH3), 3.75 (s, 3 H, OCH3), 4.02 (m, 1 H, CHCHNH), 3.99–
H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.0, 4.28 (m, 5 H, 2ϫOCH2CH3, CHCHNH), 4.32 (d, J = 17.6 Hz, 1
14.5, 41.2, 41.3, 45.4, 60.9, 61.8, 108.1, 123.0, 124.5, 125.7, 128.5,
H, NCHHCO2), 4.45 (m, 2 H, NCH2CO2), 4.57 (d, J = 17.6 Hz, 1
H, NCHHCO2), 5.14 (dd, J = 8.3, 3.1 Hz, 1 H, CHCHNH), 5.19
(dd, J = 9.1, 3.3 Hz, 1 H, CHCHNH), 5.43 (br. d, J = 9.1 Hz, 1
H, NH), 5.49 (br. d, J = 8.3 Hz, 1 H, NH), 6.71 (m, 2 H, CHarom),
7.07 (m, 2 H, CHarom), 7.14–7.39 (m, 4 H, CHarom) ppm. 13C NMR
(CDCl3, 100 MHz, 25 °C): δ = 14.2, 14.5, 41.5, 47.0, 47.9, 53.0,
53.9, 54.3, 61.4, 61.5, 61.9, 62.0, 108.2, 108.6, 123.2, 123.3, 123.4,
124.5, 124.7, 128.8, 129.2, 143.3, 143.6, 156.2, 156.3, 167.3, 167.4,
143.0, 156.6, 167.4, 176.8 ppm. IR (CHCl ): ν = 3420, 1711,
˜
3
1615 cm–1. HRMS: calcd. for C16H20N2NaO5 343.1270; found
343.1267. C16H20N2O5 (320.34): calcd. C 59.99, H 6.29, N 8.74;
found C 60.04, H 6.30, N 8.72.
Ethyl
[(Ethoxycarbonyl)amino](1-methyl-2-oxo-2,3-dihydro-1H-
indol-3-yl)acetate (6d): Anhydrous ammonium formate (315 mg,
5.0 mmol) was added in a single portion to a stirred suspension of
4d (317 mg, 1.0 mmol) and Pd/C (10%, 315 mg) in dry methanol
(13 mL), and the resulting mixture was stirred at room temperature
under argon for 1 h. The workup of the reaction was the same as
had been followed for the preparation of compound 6a. Product
6d was isolated as a syn/anti mixture (1:1) of two diastereoisomers
(176 mg, 0.5 mmol, 55% yield). 1H NMR (CDCl3, 400 MHz,
25 °C): δ = 0.95–1.35 (m, 12 H, 4ϫOCH2CH3), 3.20 (s, 6 H,
2ϫNCH3), 3.88 (br. s, 1 H, CHCHNH), 4.07–4.16 (m, 9 H,
4ϫOCH2CH3, CHCHNH), 5.09 (m, 2 H, 2ϫCHCHNH), 5.50
(br. d, J = 8.1 Hz, 1 H, NH), 5.60 (br. d, J = 10.5 Hz, 1 H, NH),
6.80 (d, J = 7.7 Hz, 1 H, CHarom), 6.83 (d, J = 7.7 Hz, 1 H,
CHarom), 7.03 (m, 2 H, CHarom), 7.15–7.35 (m, 4 H, CHarom) ppm.
13C NMR (CDCl3, 100 MHz, 25 °C): δ = 13.9, 14.5, 26.3, 47.0,
48.1, 54.0, 54.3, 61.5, 61.8, 62.0, 108.1, 108.5, 122.6, 122.8, 123.9,
124.3, 124.5, 124.9, 128.8, 129.1, 144.7, 144.9, 156.1, 156.2, 169.6,
170.2, 170.7, 174.5, 174.7 ppm. IR (CHCl ): ν = 3424, 1713,
˜
3
1613 cm–1. HRMS: calcd. for C18H22N2NaO7 401.1325; found
401.1328. C18H22N2O7 (378.38): calcd. C 57.14, H 5.86, N 7.40;
found C 57.12, H 5.88, N 7.42.
Ethyl [(Ethoxycarbonyl)amino][1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-
dihydro-1H-indol-3-yl]acetate (6g): Anhydrous ammonium formate
(403 mg, 6.4 mmol) was added in a single portion to a stirred sus-
pension of 4g (500 mg, 1.2 mmol) and Pd/C (10%, 396 mg) in dry
methanol (16 mL), and the resulting mixture was stirred at room
temperature under argon for 1 h. Workup of the reaction was the
same as had been followed for the preparation of compound 6a.
The product 6g was isolated as a syn/anti mixture (1:1) of two dia-
stereoisomers (240 mg, 0.6 mmol, yield 48% yield). 1H NMR
(CDCl3, 200 MHz, 25 °C): δ = 1.12–1.28 (m, 18 H, 6ϫOCH2CH3),
3.98–4.26 (m, 14 H, 6ϫOCH2CH3, 2ϫCHCHNH), 4.27–4.61 (m,
4 H, 2ϫNCH2), 5.12–5.21 (m, 2 H, 2ϫCHCHNH), 5.40–5.41 (m,
2 H, 2ϫNH), 6.67–6.69 (m, 2 H, CHarom), 7.12–7.38 (m, 6 H,
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 13.9, 14.0,
14.3, 14.5, 41.5, 47.0, 47.7, 53.1, 53.9, 54.3, 61.3, 61.5, 61.9, 62.1,
108.3, 108.6, 123.5, 124.5, 124.8, 129.2, 143.3, 143.5, 156.2, 156.3,
170.3, 174.3, 174.9 ppm. IR (CHCl ): ν = 3426, 1711, 1612 cm–1.
˜
3
HRMS: calcd. for C16H20N2NaO5 343.1270; found 343.1269.
C16H20N2O5 (320.34): calcd. C 59.99, H 6.29, N 8.74; found C
59.95, H 6.27, N 8.72.
Methyl
[(Ethoxycarbonyl)amino](1-methyl-2-oxo-2,3-dihydro-1H-
167.3, 167.5, 170.2, 170.7, 174.5, 174.6 ppm. IR (CHCl ): ν = 3426,
˜
3
1713, 1613 cm–1. HRMS: calcd. for C19H24N2NaO7 415.1481;
found 415.1480. C19H24N2O7 (392.40): calcd. C 58.16, H 6.16, N
7.14; found C 58.14, H 6.14, N 7.12.
indol-3-yl)acetate (6e): Anhydrous ammonium formate (362 mg,
5.7 mmol) was added in a single portion to a stirred suspension of
4e (350 mg, 1.1 mmol) and Pd/C (10%, 356 mg) in dry methanol
(15 mL), and the resulting mixture was stirred at room temperature
under argon for 1 h. Workup of the reaction was the same as had
been followed for the preparation of compound 6a. Products 6e
was isolated as a syn/anti mixture (1:1) of two diastereoisomers
(197 mg, 0.6 mmol, 56% yield). 1H NMR (CDCl3, 400 MHz,
25 °C): δ = 1.13–1.27 (m, 6 H, 2ϫOCH2CH3), 3.20 (s, 3 H, NCH3),
3.21 (s, 3 H, NCH3), 3.70 (s, 3 H, CO2CH3), 3.71 (s, 3 H, CO2CH3),
3.89 (m, 1 H, CHCHNH), 4.02–4.14 (m, 4 H, 2ϫOCH2CH3), 4.15
(m, 1 H, CHCHNH), 5.08–5.20 (m, 2 H, 2ϫCHCHNH), 5.39 (br.
d, J = 7.0 Hz, 1 H, NH), 5.53 (br. d, J = 9.0 Hz, 1 H, NH), 6.82
(d, J = 7.7 Hz, 1 H, CHarom), 6.85 (d, J = 7.7 Hz, 1 H, CHarom),
7.06 (m, 2 H, CHarom), 7.20–7.38 (m, 4 H, CHarom) ppm. 13C NMR
(CDCl3, 100 MHz, 25 °C): δ = 13.3, 13.7, 35.0, 35.4, 43.5, 43.7,
50.4, 51.0, 56.7, 56.9, 58.1, 109.0, 121.3, 124.3, 124.6, 127.6, 127.7,
130.0, 130.4, 142.1, 142.6, 157.4, 157.5, 166.2, 167.0, 171.7,
Methyl
(1-Benzyl-2-oxo-2,3-dihydro-1H-indol-3-yl)[(ethoxycarb-
onyl)amino]acetate (6h): Anhydrous ammonium formate (319 mg,
5.0 mmol) was added in a single portion to a stirred suspension of
4h (450 mg, 1.0 mmol) and Pd/C (10%, 312 mg) in dry methanol
(13 mL), and the resulting mixture was stirred at room temperature
under argon for 1 h. The workup was the same as had been fol-
lowed for the preparation of compound 6a. The product 6h was
isolated as a syn/anti mixture (1:1) of two diastereoisomers
(247 mg, 0.5 mmol, 55% yield). 1H NMR (CDCl3, 400 MHz,
25 °C): δ = 1.14–1.24 (m, 6 H, 2ϫOCH2CH3), 3.62 (s, 3 H,
CO2CH3), 3.69 (s, 3 H, CO2CH3), 4.01 (m, 1 H, CHCHNH), 4.03–
4.28 (m, 5 H, 2ϫOCH2CH3, CHCHNH), 4.76 (d, J = 15.5 Hz, 1
H, NCHHPh), 4.84 (d, J = 15.5 Hz, 1 H, NCHHPh), 4.96 (d, J =
15.5 Hz, 1 H, NCHHPh), 5.07 (d, J = 15.5 Hz, 1 H, NCHHPh),
5.17 (m, 1 H, CHCHNH), 5.25 (dd, J = 9.5, 3.9 Hz, 1 H,
CHCHNH), 5.50 (br. d, J = 7.3 Hz, 1 H, NH), 5.54 (br. d, J =
9.5 Hz, 1 H, NH), 6.72 (m, 2 H, CHarom), 7.01 (m, 2 H, CHarom),
7.12–7.37 (m, 14 H, CHarom) ppm. 13C NMR (CDCl3, 100 MHz,
25 °C): δ = 14.5, 14.6, 43.9, 44.0, 47.1, 48.4, 52.8, 52.9, 54.0, 54.2,
61.5, 61.6, 109.1, 109.6, 122.7, 122.9, 123.7, 124.2, 124.7, 124.8,
127.4, 127.6, 127.8, 127.9, 128.8, 128.9, 129.1, 135.6, 135.7, 143.8,
171.9 ppm. IR (CHCl ): ν = 3424, 1713, 1613 cm–1. HRMS: calcd.
˜
3
for C15H18N2NaO5 329.1113; found 329.1111. C15H18N2O5
(306.31): calcd. C 58.82, H 5.92, N 9.15; found C 58.84, H 5.90, N
9.12.
Methyl [(Ethoxycarbonyl)amino][1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3-
dihydro-1H-indol-3-yl]acetate (6f): Anhydrous ammonium formate
(251 mg, 3.9 mmol) was added in a single portion to a stirred sus-
pension of 4f (300 mg, 0.8 mmol) and Pd/C (10%, 244 mg) in dry
methanol (10 mL), and the resulting mixture was stirred at room
temperature under argon for 1 h. Workup of the reaction was the
144.0, 156.2, 170.3, 170.8, 174.4, 174.9 ppm. IR (CHCl ): ν = 3412,
˜
3
1719, 1613 cm–1. HRMS calcd. for C21H22N2NaO5 405.1426;
found 405.1429. C21H22N2O5 (382.41): calcd. C 65.96, H 5.80, N
7.33; found C 65.98, H 5.83, N 7.32.
Eur. J. Org. Chem. 2009, 6189–6197
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6195

M. A. Loreto et al.
FULL PAPER
Methyl [(Ethoxycarbonyl)amino](1-benzyl-5-methoxy-2-oxo-2,3-di-
hydro-1H-indol-3-yl)acetate (6i): Anhydrous ammonium formate
(166 mg, 2.6 mmol) was added in a single portion to a stirred sus-
100 MHz, 25 °C): δ = 14.5, 47.2, 48.5, 53.0, 54.5, 54.7, 61.6, 109.5,
109.8, 123.2, 123.3, 124.4, 124.8, 126.4, 126.7, 128.3, 128.4, 128.8,
129.1, 129.7, 129.8, 134.3, 144.7, 145.0, 156.2, 170.1, 170.7, 173.7,
pension of 4i (250 mg, 0.5 mmol) and Pd/C (10%, 160 mg) in dry 174.7 ppm. IR (CHCl ): ν = 3417, 1720, 1615 cm–1. HRMS: calcd.
˜
3
methanol (6 mL), and the resulting mixture was stirred at room
temperature under argon for 1 h. By the same workup as for com-
pound 6a, the product 6i was isolated as a syn/anti mixture (1:1)
for C20H20N2NaO5 391.1270; found 391.1269. C20H20N2O5
(368.38): calcd. C 65.21, H 5.47, N 7.60; found C 65.25, H 5.44, N
7.65.
1
of two diastereoisomers (238 mg, 0.3 mmol, yield 56%). H NMR
tert-Butyl
[(2-Oxo-2,3-dihydro-1H-indol-3-yl)methyl]carbamate
(CDCl3, 400 MHz, 25 °C): δ = 1.24 (t, J = 7.1 Hz, 6 H,
2ϫOCH2CH3), 3.63 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.74 (s,
3 H, OCH3), 3.75 (s, 3 H, OCH3), 3.98 (m, 1 H, CHCHNH), 4.07–
4.27 (m, 5 H, 2ϫOCH2CH3, CHCHNH), 4.73 (d, J = 15.8 Hz, 1
H, NCHHPh), 4.82 (d, J = 15.8 Hz, 1 H, NCHHPh), 4.92 (d, J =
15.8 Hz, 1 H, NCHHPh), 5.04 (d, J = 15.8 Hz, 1 H, NCHHPh),
5.14 (m, 1 H, CHCHNH), 5.22 (dd, J = 9.7, 3.6 Hz, 1 H,
CHCHNH), 5.50 (br. d, J = 7.3 Hz, 1 H, NH), 5.54 (br. d, J =
9.7 Hz, 1 H, NH), 6.55–6.97 (m, 6 H CHarom), 7.24–7.32 (m, 10 H,
CHarom) ppm. 13C NMR (CDCl3, 100 MHz, 25 °C): δ = 14.6, 44.1,
47.5, 52.8, 54.0, 55.8, 61.6, 109.5, 110.0, 111.7, 112.0, 112.3, 113.2,
113.3, 125.1, 127.4, 127.6, 127.7, 128.8, 128.9, 135.6, 135.8, 137.2,
(6n): Compound 6n was prepared from 4n (104 mg, 0.4 mmol) by
the procedure described for 6a. The product 6n was obtained as
a yellow solid (58 mg, 0.2 mmol, 55% yield). 1H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.41 [s, 9 H, C(CH3)3], 3.38–3.95 (m, 2 H,
CHCH2NH), 3.76–3.98 (m, 1 H, CHCH2NH), 5.69 (br. s, 1 H,
NHCO2tBu), 6.88 (m, 1 H, CHarom), 6.98–7.05 (m, 1 H, CHarom),
7.15–7.38 (m, 2 H, CHarom), 9.17 (br. s, 1 H, NHCOCH) ppm. 13C
NMR (CDCl3, 50 MHz, 25 °C): δ = 28.0, 41.1, 46.1, 82.5, 109.7,
123.3, 124.4, 126.7, 128.3, 155.0, 156.7, 177.3 ppm. IR (CHCl ): ν
˜
3
= 3425, 1705, 1609 cm–1. HRMS: calcd. for C14H18N2NaO3
285.1215; found 285.1219. C14H18N2O3 (262.30): calcd. C 64.10, H
6.92, N 10.68; found C 64.14, H 6.90, N 10.66.
137.4, 155.9, 156.0, 156.2, 170.7, 174.7 ppm. IR (CHCl ): ν = 3416,
˜
3
1725, 1617 cm–1. HRMS: calcd. for C22H24N2NaO6 435.1532;
found 435.1537. C22H24N2O6 (412.43): calcd. C 64.07, H 5.87, N
6.79; found C 64.04, H 5.89, N 6.80.
Ethyl [(1-Methyl-2-oxo-2,3-dihydro-1H-indol-3-yl)methyl]carbamate
(6o): Compound 6o was prepared from 4o (82 mg, 0.3 mmol) by
the procedure described for 6a. The product 6o was obtained as
a yellow solid (33 mg, 0.12 mmol, 40% yield). 1H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.40 [s, 9 H, C(CH3)3], 3.18 (s, 3 H, NCH3),
3.32 (m, 1 H, CHCHHNH), 3.65 (m, 1 H, CHCH2NH), 3.84–4.04
(m, 1 H, CHCHHNH), 5.42 (br. s, 1 H, NH), 6.84 (d, J = 7.8 Hz,
1H CHarom), 7.06 (m, 1 H, CHarom), 7.30 (m, 2 H, CHarom) ppm.
13C NMR (CDCl3, 50 MHz, 25 °C): δ = 26.2, 27.3, 41.2, 45.8, 82.5,
108.0, 123.2, 124.4, 125.6, 128.4, 144.3, 156.5, 176.6 ppm. IR
Methyl
[(Ethoxycarbonyl)amino][1-benzyl-2-oxo-5-(propan-2-yl)-
2,3-dihydro-1H-indol-3-yl]acetate (6l): Anhydrous ammonium for-
mate (116 mg, 1.8 mmol) was added in a single portion to a stirred
suspension of 4l (160 mg, 0.4 mmol) and Pd/C (10%, 129 mg) in
dry methanol (5 mL), and the resulting mixture was stirred at room
temperature under argon for 1 h. By the same workup as for com-
pound 6a, product 6l was isolated as a syn/anti mixture (1:1) of two
diastereoisomers (77 mg, 0.2 mmol, 48% yield). 1H NMR (CDCl3,
(CHCl3):
ν =
˜
3420, 1709, 1613 cm–1. HRMS: calcd. for
C15H20N2NaO3 299.1372; found 299.1370. C15H20N2O3 (276.33):
calcd. C 65.20, H 7.30, N 10.14; found C 65.04, H 7.28, N 10.12.
200 MHz, 25 °C):
δ = 1.11–1.28 [m, 18 H, 2ϫ(CH3)2CH,
2ϫOCH2CH3], 2.75–2.90 [m, 2 H, 2ϫ(CH3)2CH], 3.63 (s, 3 H,
CO2CH3), 3.66 (s, 3 H, CO2CH3), 3.97 (m, 1 H, CHCHNH), 4.01–
4.27 (m, 5 H, 2ϫOCH2CH3, CHCHNH), 4.72 (d, J = 15.2 Hz, 1
H, NCHHPh), 4.82 (d, J = 15.5 Hz, 1 H, NCHHPh), 4.92 (d, J =
15.5 Hz, 1 H, NCHHPh), 5.03 (d, J = 15.2 Hz, 1 H, NCHHPh),
5.15 (m, 1 H, CHCHNH), 5.23 (m, 1 H, CHCHNH), 5.48 (br. d,
J = 8.1 Hz, 1 H, NH), 5.64 (br. d, J = 9.4 Hz, 1 H, NH), 6.64
(m, 2 H, CHarom), 7.01 (m, 2 H, CHarom), 7.14–7.38 (m, 12 H,
CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.6, 24.3,
33.9, 34.0, 44.1, 47.3, 52.7, 52.9, 54.2, 61.6, 108.9, 109.4, 122.6,
123.1, 124.9, 125.4, 127.5, 127.7, 127.8, 128.9, 135.8, 136.0, 141.8,
Ethyl (3-{[(Ethoxycarbonyl)amino]methyl}-2-oxo-2,3-dihydro-1H-
indol-1-yl)acetate (6p): Compound 6p was prepared from 4p
(138 mg, 0.4 mmol) by the procedure described for 6a. The product
6p was obtained as a yellow solid (67 mg, 0.2 mmol, yield 48%).
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.23 (t, J = 7.1 Hz, 3 H,
CH3CH2), 1.38 [s, 9 H, C(CH3)3], 3.53–3.56 (m, 1 H, CHCHHNH),
3.65 (m, 1 H, CHCH2NH), 3.93–3.56 (m, 1 H, CHCHHNH), 4.21
(q, J = 7.1 Hz, 4 H, OCH2CH3), 4.37 (d, J = 17.0 Hz, 1 H,
NCHHCO2), 4.53 (d, J = 17.0 Hz, 1 H, 1 H, NHCHHCO2), 5.40
(br. s, 1 H, NH), 6.70 (m, 1 H, CHarom), 7.08 (m, 1 H, CHarom),
7.32 (m, 2 H, CHarom) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ
= 14.0, 27.9, 41.2, 42.3, 45.4, 61.8, 82.5, 108.2, 123.1, 124.1, 125.7,
143.6, 157.3, 167.2, 172.0 ppm. IR (CHCl ): ν = 3417, 1720,
˜
3
1615 cm–1. HRMS: calcd. for C24H26N2NaO5 447.1896; found
447.1899. C24H26N2O5 (422.47): calcd. C 68.23, H 6.20, N 6.63;
found C 68.26, H 6.25, N 6.65.
127.3, 142.5, 155.6, 167.1, 176.0 ppm. IR (CHCl ): ν = 3418, 1711,
˜
3
1615 cm–1. HRMS: calcd. for C18H24N2NaO5 371.1583; found
371.1585. C18H24N2O5 (348.39): calcd. C 62.05, H 6.94, N 8.04;
found C 62.02, H 6.97, N 8.02.
Methyl
[(Ethoxycarbonyl)amino](2-oxo-1-phenyl-2,3-dihydro-1H-
indol-3-yl)acetate (6m): Anhydrous ammonium formate (166 mg,
2.7 mmol) was added in a single portion to a stirred suspension of
4m (190 mg, 0.5 mmol) and Pd/C (10%, 165 mg) in dry methanol
(7 mL), and the resulting mixture was stirred at room temperature
under argon for 1 h. By the same workup as for compound 6a,
product 6m was isolated as a syn/anti mixture (1:1) of two dia-
stereoisomers (58 mg, 0.16 mmol, 30% yield). 1H NMR (CDCl3,
400 MHz, 25 °C): δ = 1.23 (t, J = 7.1 Hz, 6 H, 2ϫOCH2CH3),
3.69 (s, 6 H, 2ϫCO2CH3), 4.03 (m, 1 H, CHCHNH), 4.08–4.17
(m, 4 H, 2ϫOCH2CH3), 4.35 (m, 1 H, CHCHNH), 5.19–5.27 (m,
2 H, 2ϫCHCHNH), 5.57 (br. d, J = 7.0 Hz, 1 H, NH), 5.82 (br.
d, J = 10.5 Hz, 1 H, NH), 6.68–6.73 (m, 2 H, CHarom), 7.05–7.12
(m, 2 H, CHarom), 7.19–7.27 (m, 2 H, CHarom), 7.35–7.45 (m, 8
H, CHarom), 7.47–7.55 (m, 4 H, CHarom) ppm. 13C NMR (CDCl3,
[1] a) M. H. Chen, P. Pollard, A. Patchett, K. Cheng, L. Wei, W.-
S. Chan, B. Butler, T. M. Jacks, R. G. Smith, Bioorg. Med.
Chem. Lett. 1999, 9, 1261–1266; b) R. K. Behera, A. K. Be-
hera, R. Pradhan, A. Pati, M. Patra, Synth. Commun. 2006,
36, 3729–3742.
[2] a) C. Roussel, R. Fihi, K. Ciamala, J. Vebrel, T. Zair, C. Riche,
Org. Biomol. Chem. 2003, 1, 2689–2698; b) R. K. Howe, B. R.
Shelton, J. Org. Chem. 1990, 55, 4603–4607.
[3] a) G. Shanthi, G. Subbulakshmi, P. T. Perumal, Tetrahedron
2007, 63, 2057–2063; b) C. Marti, E. M. Carreira, J. Am. Chem.
Soc. 2005, 127, 11505–11515; c) S. T. Hilton, T. C. T. Ho, G.
Pljevaljcic, K. Jones, Org. Lett. 2000, 2, 2639–2641; d) C.
Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209–2219; e)
6196
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 6189–6197

Spiroaziridine-oxindoles from 3-Ylideneoxindoles
C. V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed. 2007, 46, [10]
8748–8758.
[4] C. B. Cui, H. Kakeya, G. Okada, R. Onose, H. Osada, J. Anti-
biot. 1996, 49, 527–533.
[5] a) S. Edmonson, S. J. Danishefsky, L. Sepp-Lorenzino, N.
a) G. S. Singh, M. DЈhooghe, N. De Kimpe, Chem. Rev. 2007,
107, 2080–2135; b) M. Pineschi, Eur. J. Org. Chem. 2006, 4979–
4988; c) K. B. Hansen, N. S. Finney, E. N. Jacobsen, Angew.
Chem. Int. Ed. Engl. 1995, 34, 676–678; d) P. Crotti, V. Di Bus-
solo, L. Favero, M. Pineschi, Tetrahedron 1997, 53, 1417–1438.
Rosen, J. Am. Chem. Soc. 1999, 121, 2147–2155; b) P. R. Seba-
har, R. M. Williams, J. Am. Chem. Soc. 2000, 122, 5666–5667;
c) P. R. Sebahar, H. Osada, T. Usui, R. M. Williams, Tetrahe-
dron 2002, 58, 6311–6322.
[11]
[12]
a) T. Gasperi, M. A. Loreto, P. A. Tardella, E. Veri, Tetrahe-
dron Lett. 2003, 44, 4953–4956; b) T. Gasperi, M. A. Loreto,
A. Migliorini, P. A. Tardella, Heterocycles 2005, 65, 1447–1454.
a) S. P. Marsden, E. L. Watson, S. A. Raw, Org. Lett. 2008, 10,
2905–2908; b) S. J. O’Connor, Z. Liu, Synlett 2003, 2135–2138.
S. Rossiter, Tetrahedron Lett. 2002, 43, 4671–4673.
S. Muthusamy, S. A. Babu, M. Nethaji, Tetrahedron 2003, 59,
8117–8127.
[6] a) G. Cravotto, G. B. Giovenzana, T. Pilati, M. Sisti, G. Palmis-
ano, J. Org. Chem. 2001, 66, 8447–8453; b) G. Lakshmaiah, T.
Kawabata, M. H. Shang, K. Fuji, J. Org. Chem. 1999, 64,
1699–1704; c) G. Palmisano, R. Annunziata, G. Papeo, M. Si-
sti, Tetrahedron: Asymmetry 1996, 7, 1–4; d) C. Pellegrini, C.
Strässler, M. Weber, H. J. Borschberg, Tetrahedron: Asymmetry
1994, 5, 1979–1992.
[13]
[14]
[15] R. Shimazawa, M. Kurijama, R. Shirai, Bioorg. Med. Chem.
Lett. 2008, 18, 3350–3353.
[7] J. Renuka, Ind. J. Hetrocycl. Chem. 1992, 2, 59–60.
[8] a) P. Kapferer, V. Birault, J.-F. Poisson, A. Vasella, Helv. Chim.
Acta 2003, 86, 2210–2227; b) C. Mazal, J. Jonas, Z. Zak, Tetra-
hedron 2002, 58, 2729–2733; c) A. Rulev, J. Maddaluno, Eur. J.
Org. Chem. 2001, 2569–2576; d) D. Donati, S. Fusi, F. Pon-
ticelli, Tetrahedron Lett. 2002, 43, 9527–9530; e) M. A. Loreto,
A. Migliorini, P. A. Tardella, A. Gambacorta, Eur. J. Org.
Chem. 2007, 2365–2371.
[9] a) K.-I. Harada, K. Tomita, K. Fujii, K. Masuda, Y. Mikami,
K. Yazawa, H. Komaki, J. Antibiot. 2004, 57, 125–135; b) Y.
Nakao, M. Fujita, K. Warabi, S. Matsunaga, N. Fusetani, J.
Am. Chem. Soc. 2000, 122, 10462–10463; c) T. Schirmeister, M.
Peric, Bioorg. Med. Chem. 2000, 8, 1281–1291; d) M. Kasai,
M. Kono, Synlett 1992, 778–790; e) S. Kinoshita, K. Uzu, K.
Nakano, M. Shimizu, T. Takahashi, J. Med. Chem. 1971, 14,
103–109; f) K. R. Kunz, B. S. Iyengar, R. T. Dorr, D. S. Alberts,
W. A. Remers, J. Med. Chem. 1991, 34, 2281–2286; g) T. Kur-
oda, K. Hisamura, I. Matsukuma, Y. Osawa, T. Sugaya, H.
Nishikawa, M. Morimoto, T. Ahizawa, N. Nakamizo, Y. Ot-
suji, J. Heterocycl. Chem. 1992, 29, 1133–1142.
[16] a) C.-L. Fang, S. Horne, N. Taylor, R. Rodrigo, J. Am. Chem.
Soc. 1994, 116, 9480–9486; b) F. H. Osman, F. A. El-Samahy,
I. S. Ahmed Farag, Monatsh. Chem. 2004, 135, 823–831; c) B.
Gabriele, G. Salerno, L. Veltri, M. Costa, C. Massera, E. J.
Org. Chem 2001, 4607–4613.
[17] a) R. P. Singh, U. Maijumder, J. M. Shreeve, J. Org. Chem.
2001, 66, 6263–6267; b) M. G. Bursavich, A. M. Gilbert, S.
Lombardi, K. E. Georgiadis, E. Reifenberg, C. R. Flannery,
E. A. Morris, Bioorg. Med. Chem. Lett. 2007, 17, 5630–5633.
[18] The aminating agent NsONHCO2tBu was obtained by Lwows-
ki’s procedure: W. Lwowski, T. J. Maricich, J. Am. Chem. Soc.
1965, 87, 3630–3637. Physical and spectroscopic data are in
agreement with those reported: M. R. Banks, J. I. G. Cadogan,
I. Gosney, P. K. G. Hodgson, P. R. R. Langridge-Smith,
J. R. A. Millar, A. T. J. Taylor, J. Chem. Soc., Chem. Commun.
1995, 885–886.
[19] D. Y. Kim, D. Y. Rhie, Tetrahedron 1997, 53, 13603–13608.
Received: August 4, 2009
Published Online: October 23, 2009
Eur. J. Org. Chem. 2009, 6189–6197
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