Synthesis of aziridine- and oxirane-2-phosphonates spiro-fused with oxindoles

Article abstract of DOI:10.1002/ejoc.201001021

3-(Phosphorylmethylene)oxindoles have been prepared by a straightforward Horner-Wadsworth-Emmons reaction. They were treated with ethyl N-{[(4-nitrophenyl)sulfonyl]oxy}carbamate (NsONHCO₂Et) in the presence of CaO to afford new aziridine-2-phos

Full text of DOI:10.1002/ejoc.201001021

FULL PAPER
DOI: 10.1002/ejoc.201001021
Synthesis of Aziridine- and Oxirane-2-phosphonates Spiro-Fused with
Oxindoles
Tecla Gasperi,[a,b] M. Antonietta Loreto,*[c,d] Antonella Migliorini,[c] and Claudia Ventura[c]
Dedicated to Professor P. Antonio Tardella on the occasion of his 75th birthday
Keywords: Epoxidation / Heterocycles / Indoles / Small ring systems / Spiro compounds / Wittig reactions
3-(Phosphorylmethylene)oxindoles have been prepared by a
straightforward Horner–Wadsworth–Emmons reaction. They
were treated with ethyl N-{[(4-nitrophenyl)sulfonyl]oxy}-
carbamate (NsONHCO2Et) in the presence of CaO to afford
new aziridine-2-phosphonates spiro-fused with oxindole. 3-
(Phosphorylmethylene)oxindoles were also transformed into
novel spiro[oxindole-oxiranes] by reaction with H2O2/NaOH.
of these compounds from oxindoles bearing a methylene or
a vinylcarboxylate group in the α-position.[4] The employed
methodology has already been successfully used in our re-
search group for the preparation of N-(ethoxycarbonyl)-
aziridines from electron-poor olefins, such as α,β-unsatu-
rated esters and phosphonates.[5]
Introduction
The synthesis of molecules containing a spiroheterocycle
moiety has been widely reported.[1] Due to steric strain, the
presence of a spiro carbon atom induces easy rearrange-
ments that can lead to different heterocyclic derivatives. Nu-
merous spirocyclic alkaloids and pharmacologically impor-
tant compounds have a central skeleton based on the spiro-
oxindole system.[2] Spiro[oxindole-oxirane] ring systems are
also of particular interest because of their biological appli-
cations as anticonvulsants, diuretics, sedatives, antifungal,
and antitubercular agents.[3]
In contrast, spiro[aziridine-oxindoles] have not been
much studied. We have recently reported a novel synthesis
Figure 1. Clinically important aziridine- and oxirane-2-phosphon-
ates.
Figure 2. Synthesis of compounds 3 and 4 by starting from oxindoles 5.
Herein, we focused our attention on the synthesis of new
aziridine-2-phosphonates spirofused with oxindoles and in-
vestigated the possibility of obtaining analogous spiro-
[oxindole-oxirane]–phosphonates.
Aziridine- and oxirane-2-phosphonates are important
classes of compounds, and much interest has focused on the
biological activity of some derivatives.[6] For instance, (1,2-
epoxypropyl)phosphonic acid (1; Fosfomycin)[7] is a clini-
cally important drug with wide-spectrum antibiotic activity
[a] Dipartimento di Ingegneria Meccanica Industriale, Università
degli Studi “Roma Tre”,
Via della Vasca Navale 79, 00146 Roma, Italy
[b] CISDiC “Centro Interdipartimentale di Servizi per la Didattica
Chimica”, Università degli Studi “Roma Tre”,
Via della Vasca Navale 79, 00146 Roma, Italy
[c] Dipartimento di Chimica, Università “Sapienza”,
P.le A. Moro 5, 00185 Roma, Italy
Fax: +39-06-490631
E-mail: mariaantonietta.loreto@uniroma1.it
[d] Istituto di Chimica Biomolecolare, Università “Sapienza”,
P.le A. Moro 5, 00185 Roma, Italy
Eur. J. Org. Chem. 2011, 385–391
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
385

M. A. Loreto et al.
FULL PAPER
(Figure 1), whereas 1-alkoxycarbonyl-2-phosphonoazir- 4–6) of NsONHCO2Et and CaO was necessary for com-
idines (2) show antibacterial activity.[8] Aziridine- and oxir- plete disappearance of the starting material and formation
anephosphonates can be also regarded as useful precursors of the expected N-(ethoxycarbonyl)aziridine spiro com-
of a multitude of amino acid mimics after ring opening.[9]
In order to achieve our goal, we designed the synthesis
of compounds 3 and 4 starting from oxindoles 5 bearing a
phosphorylmethylene group in the 3-position (Figure 2).
pounds 3a–f (Scheme 2).
Table 2. Synthesis of spiro[aziridine-oxindoles] 3a–f.
Results and Discussion
Keeping in mind this program, our first objective was
the preparation of substrates 5a–f (Scheme 1), which were
obtained through the Horner–Wadsworth–Emmons reac-
tion,[10] starting from tetraethyl methylenebis(phosphonate)
(6) and isatine derivatives 7a–f having different substituents
either on the nitrogen atom (R1) or on the aromatic ring
(R2).
[a] Ratio of 5/NsONHCO2Et/CaO.
Scheme 2. Synthesis of spiro[aziridine-oxindoles] 3a–f.
In all cases, the crude 1H NMR spectra indicated the
formation of a single isomer, as evidenced by the presence
of a unique aziridine proton signal, which appeared as a
broad doublet (J ≈ 17 Hz, δ = 3–3.5 ppm) due to the char-
acteristic coupling with the phosphorus atom. After
chromatography, products 3a–f were isolated in the re-
ported yields (Table 2) and fully characterized. The stereo-
chemistry of the starting ylidenephosphonate was fully re-
tained in the products, which was clearly shown by 1H
NMR spectroscopic analysis. Indeed, in the region of the
aromatic protons, the characteristic signal from the highly
deshielded 4-H atom was still present. Moreover, the same
stereochemical outcome was previously observed in the az-
iridination of α,β-unsaturated phosphonates.[5] Yields of the
Scheme 1. Synthesis of 3-(phosphorylmethylene)oxindoles 5a–f.
Reasonably good results were achieved with tetra-
hydrofuran (THF) as solvent and lithium diisopropylamide
(LDA) as base (Table 1). The main products, which were
purified by chromatography on silica gel (hexane/ethyl acet-
ate), were always the thermodynamically more stable (E)
1
isomers; their structures were confirmed by H NMR spec-
troscopic analysis. Indeed, as reported for the (E) isomers
of the analogous 3-(oxycarbonylmethylene)oxindoles,[11] the
electronic effect of the phosphonate group markedly de-
shields the 4-H atom with respect to the other aromatic
protons.
1
isolated compounds were modest; however, their H NMR
spectroscopic analysis matched those of the corresponding
spectra of the crude products (70–80% yield).
Concerning the synthesis of spiro-oxirane–phosphonates,
we chose to use classic epoxidation reagents (H2O2,
NaOH), which are usually employed for the preparation of
simple epoxyoxindoles,[12] even though a very poor reactiv-
ity of ylidenephosphonates under such reaction conditions
has been reported.[13] The principal synthetic routes to (1,2-
epoxyalkyl)phosphonates include: the treatment of halo-
hydrines with a base, the reaction of α-halo ketones or α-
tosyloxy ketones with alkali metal derivatives of dialkyl
phosphonates, or the application of Darzens-type reactions
of (halomethyl)phosphonates with aldehydes or ketones.[14]
Using the basic oxidizing conditions (3 equiv. of 30% hy-
Table 1. Synthesis of 3-(phosphorylmethylene)oxindoles 5a–f.
With these new unsaturated phosphonates in hand, we
performed the aziridination reactions with substrates 5a–f drogen peroxide and 0.2 equiv. of sodium hydroxide), we
in CH2Cl2 using the procedure developed previously. Unlike observed an immediate decolourization of the red starting
the aziridination of previously studied α,β-unsaturated solution and, in all cases, the reactions were complete
phosphonates,[5] only 1 or 2 equiv. (Table 2, Entries 1–3 or within 2 h (Scheme 3).
386
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 385–391

Phosphonates Spiro-Fused with Oxindoles
Scheme 3. Synthesis of spiro[oxindole-oxiranes] 4a–f.
Figure 3. NOESY spectrum of cis-4a.
1H NMR analysis revealed the formation of the trans observed for all the trans isomers. The yields and the ratios
and cis diastereomeric spiro-oxiran-2-phosphonates 4. The of the two epoxides are reported in Table 3.
two products were separated by chromatography (hexane/
ethyl acetate), and the minor product was identified as the
Conclusion
cis isomer by NOESY spectroscopic analysis of 4a. Indeed,
NOESY cross peaks were found between the aromatic 4-H
atom (δ = 7.04 ppm) and the epoxide proton (Figure 3). In
contrast, no NOESY cross peaks for the epoxide proton
were found in the major trans isomer 4a. In addition, typi-
cal 1H NMR spectral patterns of the aromatic protons were
We propose two straightforward approaches to new
spiro-oxindole derivatives; in particular, aziridine- and oxir-
ane-2-phosphonates were obtained with moderate to high
yields. The syntheses are stereoselective, and further enan-
tioselective reactions are under investigation. The obtained
compounds are potentially biologically active and consti-
tute key intermediates for the synthesis of hydroxy or amino
phosphonate derivatives.
Table 3. Synthesis of spiro[oxindole-oxiranes] 4a–f.
Experimental Section
General Experimental Methods: Solvents and common reagents
were purchased from commercial sources and used without further
purification. All reactions were monitored by thin layer chromatog-
raphy (TLC) carried out on Merck F-254 silica glass plates and
Eur. J. Org. Chem. 2011, 385–391
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
387

M. A. Loreto et al.
FULL PAPER
visualized with UV light. 1H NMR spectra were recorded with a
Varian Gemini 200 (200 MHz) spectrometer. Chemical shifts (δ) are
expressed in parts per million (ppm) and are referenced to the resid-
ual protons of the NMR solvent (CHCl3: δ = 7.26 ppm); s = singlet,
d = doublet, t = triplet, q = quartet, quint = quintet, sept = septup-
let, dd = double doublet, dt = double triplet, m = multiplet. Cou-
pling constants (J) are expressed in Hz. 13C NMR spectra were
recorded with a Varian Gemini 300 (75 MHz) spectrometer. Chem-
ical shifts (δ) are expressed in parts per million (ppm) and are refer-
enced to the residual carbon atoms of the NMR solvent (CHCl3:
δ = 77.0 ppm). 31P NMR spectra were obtained in CDCl3 with
a Bruker AC 400 spectrometer, with H3PO4 as external standard.
NOESY experiments were recorded with a Bruker AC 300 spec-
trometer. Infrared (IR) spectra were obtained by using a Perkin–
Elmer 1600 (FTIR) spectrometer; data are presented as wave-
numbers (cm–1). HRMS spectra were recorded with a Micromass
Q-TOF Micromass Spectrometer (Waters), coupled to a Micromass
LCT (ESI) with lock spray injector (injection loop mode in an
HPLC system, Waters, Alliance 2695).
Diethyl {[(3E)-1-(2,4-Dichlorobenzyl)-2-oxoindolin-3-ylidene]meth-
yl}phosphonate (5c): Yield: 634 mg (1.44 mmol, 72%); orange solid;
isolated as a single (E) isomer; Rf = 0.42 (hexane/ethyl acetate, 1:1).
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.37 [t, J = 7.1 Hz, 6 H,
(CH3CH2O)2P], 4.10–4.27 [m, 4 H, (CH3CH2O)2P], 5.00 (s, 2 H,
CH2N), 6.62 (d, J = 7.8 Hz, 1 H, ArH), 6.89 (d, JH,P = 13.0 Hz, 1
H, CHP=O), 7.01–7.18 (m, 4 H, ArH), 7.23–7.32 (m, 1 H, ArH),
8.51 (d, J = 7.6 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz,
25 °C): δ = 16.3 (d, JCCOP = 6.4 Hz), 40.9 (NCH2), 62.5 (d, JCOP
= 5.7 Hz), 109.0, 119.9 (d, JCP = 189.6 Hz), 120.3 (d, JCCP
=
6.9 Hz), 123.4, 127.5, 128.0, 128.8, 129.5, 131.3, 132.3, 133.4, 134.1,
140.9 (d, JCCCP = 7.7 Hz), 144.3, 166.8 (d, JCCCP = 25.8 Hz) ppm.
31P NMR: δ = 13.8 ppm. IR (CHCl ): ν = 1717, 1237 cm–1. HRMS:
˜
3
calcd. for C20H20Cl2NNaO4P 462.0405; found 462.0402.
Diethyl {[(3E)-1-Benzyl-2-oxoindolin-3-ylidene]methyl}phosphonate
(5d): Yield: 416 mg (1.12 mmol, 56%); orange solid; isolated as a
single (E) isomer; Rf = 0.46 (hexane/ethyl acetate, 1:1). 1H NMR
(CDCl3, 200 MHz, 25 °C): δ = 1.36 [t, J = 7.0 Hz, 6 H, (CH3CH2-
O)2P], 4.07–4.26 [m, 4 H, (CH3CH2O)2P], 4.93 (s, 2 H, CH2N),
6.69 (d, J = 7.9 Hz, 1 H, ArH), 6.88 (d, JH,P = 13.3 Hz, 1 H,
CHP=O), 7.04 (dt, J = 7.7, 0.96 Hz, 1 H, ArH), 7.21–7.34 (m, 6
H, ArH), 8.47 (d, J = 7.7 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
General Procedure for the Horner–Wadsworth–Emmons Reaction:
To a stirred solution of tetraethyl methylenebis(phosphonate) (1;
2.6 mmol, 749 mg) in anhydrous THF (2 mL) under Ar at 0 °C,
LDA (2 m in THF, 1.43 mL, 2.86 mmol) was added dropwise. After
30 min, the mixture was warmed to room temp., stirred for an ad-
ditional 30 min and cooled again to 0 °C. At this temperature, a
solution of isatine 7 (2 mmol) in anhydrous THF (8 mL) was slowly
added. The reaction mixture was allowed to reach room temp., and
stirred until complete (monitored by TLC; hexane/ethyl acetate).
Saturated aqueous NH4Cl salution was slowly added, and the
aqueous layer was extracted with ethyl acetate (3ϫ50 mL). The
combined organic phases were dried with anhydrous Na2SO4 and
concentrated under reduced pressure to give the crude product,
which was subsequently purified by flash chromatography on silica
gel (hexane/ethyl acetate).
50 MHz, 25 °C): δ = 16.1 (d, JCCOP = 6.3 Hz), 62.3 (d, JCOP
=
5.7 Hz), 109.0, 119.7 (d, JCCP = 6.8 Hz), 120.5 (d, JCP = 189.8 Hz),
122.8, 127.1, 127.5, 127.6, 128.6, 132.0, 135.2, 141.2 (d, JCCCP
=
7.7 Hz), 144.7, 166.4 (d, JCCCP = 25.7 Hz) ppm. 31P NMR: δ =
14.1 ppm. IR (CHCl ): ν = 1714, 1236 cm–1. HRMS: calcd. for
˜
3
C20H22NNaO4P 394.1184; found 394.1181.
Diethyl {[(3E)-1-Benzyl-5-methoxy-2-oxoindolin-3-ylidene]methyl}-
phosphonate (5e): Yield: 562 mg (1.40 mmol, 70%); orange solid;
isolated as a single (E) isomer; Rf = 0.42 (hexane/ethyl acetate, 3:7).
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.37 [t, J = 7.1 Hz, 6 H,
(CH3CH2O)2P], 3.79 (s,
3 H, CH3O), 4.12–4.27 [m, 4 H,
(CH3CH2O)2P], 4.90 (s, 2 H, CH2N), 6.57 (d, J = 8.6 Hz, 1 H,
ArH), 6.73–6.83 (m, 1 H, ArH), 6.87 (d, JHP = 13.0 Hz, 1 H,
CHP=O), 7.27–7.33 (m, 5 H, ArH), 8.24 (d, J = 2.6 Hz, 1 H, ArH)
Diethyl {[(3E)-1-Methyl-2-oxoindolin-3-ylidene]methyl}phosphonate
(5a): Yield: 390 mg (1.32 mmol, 66%); pale-orange solid; isolated
as a single (E) isomer; Rf = 0.36 (hexane/ethyl acetate, 1:1). 1H
NMR (CDCl3, 200 MHz, 25 °C): δ = 1.33 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 1.34 (t, J = 7.1 Hz, 3 H, CH3CH2O), 3.22 (s, 3 H,
CH3N), 4.06–4.23 [m, 4 H, (CH3CH2O)2P], 6.78 (d, J = 7.6 Hz, 1
H, ArH), 6.80 (d, JH,P = 13.4 Hz, 1 H, CHP=O), 7.06 (dt, J = 7.6,
1.1 Hz, 1 H, ArH), 7.36 (m, 1 H, ArH), 8.45 (d, J = 7.6 Hz, 1 H,
ArH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 16.2 (d, JCCOP
ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 16.4 (d, JCCOP
=
6.5 Hz), 44.1, 55.9, 62.5 (d, JCOP = 5.8 Hz), 109.8, 113.3, 118.7,
119.9 (d, JCP = 189.3 Hz), 120.7 (d, JCCP = 6.7 Hz), 121.2, 127.3,
127.8, 128.8, 135.5, 138.4, 156.1, 166.5 (d, JCCCP = 25.4 Hz) ppm.
31P NMR: δ = 14.3 ppm. IR (CHCl ): ν = 1715, 1236 cm–1. HRMS:
˜
3
calcd. for C21H24NNaO5P 424.1290; found 424.1286.
Diethyl {[(3E)-1-Benzyl-5-isopropyl-2-oxoindolin-3-ylidene]methyl}-
phosphonate (5f): Yield: 554 mg (1.34 mmol, 67%); orange solid;
isolated as a single (E) isomer; Rf = 0.46 (hexane/ethyl acetate, 1:1).
1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.22 [d, J = 6.9 Hz, 6 H,
(CH3)2CH], 1.36 [t, J = 7.1 Hz, 6 H, (CH3CH2O)2P], 2.88 [quint,
J = 6.9 Hz, 1 H, (CH3)2CH], 4.12–4.27 [m, 4 H, (CH3CH2O)2P],
4.91 (s, 2 H, CH2N), 6.60 (d, J = 8.1 Hz, 1 H, ArH), 6.86 (d, JH,P
= 13.7 Hz, 1 H, CHP=O), 7.08–7.13 (m, 1 H, ArH), 7.29–7.34 (m,
5 H, ArH), 8.36 (d, J = 1.7 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 16.3 (d, JCCOP = 6.4 Hz), 24.0, 33.7, 43.9, 62.3
(d, JCOP = 5.8 Hz), 108.9, 119.1 (d, JCP = 189.4 Hz), 119.9 (d, JCCP
= 6.8 Hz), 125.9, 127.2, 127.6, 128.7, 130.1, 135.5, 141.8 (d, JCCCP
= 7.8 Hz), 142.9, 143.7, 166.7 (d, JCCCP = 25.7 Hz) ppm. 31P NMR:
= 6.4 Hz), 26.3, 62.5 (d, JCOP = 5.7 Hz), 108.1, 119.6 (d, JCP
=
189.6 Hz), 119.9 (d, JCCP = 7.0 Hz), 123.0, 127.9, 132.2, 141.6 (d,
JCCCP = 7.7 Hz), 145.8, 166.6 (d, JCCCP = 25.7 Hz) ppm. 31P NMR:
δ = 14.2 ppm. IR (CHCl ): ν = 1713, 1236 cm–1. HRMS: calcd. for
˜
3
C14H18NNaO4P 318.0871; found 318.0868.
Diethyl {[(3E)-2-Oxo-1-phenylindolin-3-ylidene]methyl}phosphonate
(5b): Yield: 543 mg (1.52 mmol, 76%); pale-orange solid; isolated
as a single (E) isomer; Rf = 0.45 (hexane/ethyl acetate, 1:1). 1H
NMR (CDCl3, 200 MHz, 25 °C): δ = 1.21 [t, J = 7.1 Hz, 6 H,
(CH3CH2O)2P], 4.13–4.28 [m, 4 H, (CH3CH2O)2P], 6.78 (d, J =
7.9 Hz, 1 H, ArH), 6.91 (d, JH,P = 13.1 Hz, 1 H, CHP=O), 7.10
(dt, J = 7.7, 1.0 Hz, 1 H, ArH), 7.24–7.33 (m, 1 H, ArH), 7.37–
7.46 (m, 3 H, ArH), 7.49–7.58 (m, 2 H, ArH), 8.55 (d, J = 7.7 Hz,
1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 16.3 (d,
δ = 14.4 ppm. IR (CHCl ): ν = 1712, 1236 cm–1. HRMS: calcd. for
˜
3
C23H28NNaO4P 436.1654; found 436.1651.
JCCOP = 6.3 Hz), 62.5 (d, JCOP = 5.7 Hz), 109.5, 119.9 (d, JCCP
6.8 Hz), 120.1 (d, JCP = 189.7 Hz), 122.0, 123.4, 128.1, 128.3, 129.7,
132.1, 134.0, 141.3 (d, JCCCP = 7.8 Hz), 145.8, 165.9 (d, JCCCP
=
General Procedure for the Aziridination Reaction: To a stirred solu-
=
tion of 3-methyleneoxindole 5 (1 mmol) in CH2Cl2 (1 mL),
25.9 Hz) ppm. 31P NMR: δ = 14.1 ppm. IR (CHCl ): ν = 1720, NsONHCO2Et (290 mg, 1 mmol), and CaO (56 mg, 1 mmol) were
˜
3
1236 cm–1. HRMS: calcd. for C19H20NNaO4P 380.1028; found
added portionwise at room temp. every hour, until the molar ratio
380.1023.
of 5/NsONHCO2Et/CaO reported in Table 2 was reached. Because
388
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 385–391

Phosphonates Spiro-Fused with Oxindoles
the reaction is exothermic, during each addition the flask was co-
oled in a water bath to avoid overheating. After 24 h, the reaction
was quenched by adding pentane/CH2Cl2 (8:2). The resulting solid
by-product was filtered and washed with the same solution. The
organic phase was concentrated under reduced pressure and dried
with anhydrous Na2SO4. The crude mixture was purified by
chromatography on silica gel (hexane/ethyl acetate).
7.0 Hz, 3 H, (CH3CH2O)2P], 1.23 [t, J = 7.0 Hz, 3 H, (CH3CH2-
O)2P], 1.43 (t, J = 7.1 Hz, 3 H, CH3CH2OC), 3.40 (d, JH,P
=
17.3 Hz, 1 H, NCH), 3.92–4.12 [m, 2 H, (CH3CH2O)2P], 4.22 (q,
J = 7.1 Hz, 2 H, CH3CH2O), 4.27–4.45 [m, 2 H, (CH3CH2O)2P],
4.82 (d, J = 15.9 Hz, 1 H, NCHaHb), 5.14 (d, J = 15.8 Hz, 1 H,
NCHaHb), 6.77 (d, J = 7.7 Hz, 1 H, ArH), 7.08 (t, J = 7.5 Hz, 1
H, ArH), 7.20–7.49 (m, 6 H, ArH), 7.93 (d, J = 7.6 Hz, 1 H, ArH)
ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.4, 16.4 (d, JCCOP
= 5.9 Hz), 16.7 (d, JCCOP = 6.0 Hz), 44.5 (d, JCP = 207.5 Hz), 44.6,
Ethyl 3-(Diethoxyphosphoryl)-1Ј-methyl-2Ј-oxospiro[aziridine-2,3Ј-
indoline]-1-carboxylate (3a): Yield: 116 mg (0.30 mmol, 30%); yel-
low solid; isolated as the trans isomer; Rf = 0.40 (hexane/ethyl acet-
ate, 2:8). 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.16 [t, J =
7.1 Hz, 3 H, (CH3CH2O)2P], 1.25 [t, J = 7.1 Hz, 3 H, (CH3CH2-
O)2P], 1.42 (t, J = 7.1 Hz, 3 H, CH3CH2OC), 3.29 (s, 3 H, NCH3),
3.32 (d, JH,P = 17.4 Hz, 1 H, NCH), 3.98–4.10 [m, 2 H,
(CH3CH2O)2P], 4.21 (q, J = 7.1 Hz, 2 H, CH3CH2O), 4.28–4.42
[m, 2 H, (CH3CH2O)2P], 6.92 (d, J = 7.7 Hz, 1 H, ArH), 7.12 (dt,
J = 7.7, 1.0 Hz, 1 H, ArH), 7.39 (dt, J = 7.7, 1.3 Hz, 1 H, ArH),
7.92 (d, J = 7.7 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz,
25 °C): δ = 14.4, 16.4 (d, JCCOP = 5.8 Hz), 16.6 (d, JCCOP = 5.9 Hz),
27.1, 44.4 (d, JCP = 207.8 Hz), 48.4 (d, JCCP = 4.5 Hz), 62.9 (d,
JCOP = 6.3 Hz), 63.6, 63.7 (d, JCOP = 4.8 Hz), 108.7, 121.1, 123.3,
48.4 (d, JCCP = 4.1 Hz), 63.0 (d, JCOP = 6.2 Hz), 63.8 (d, JCOP
=
5.7 Hz), 63.8, 109.8, 121.1, 123.4, 126.6, 127.3, 128.0, 129.1, 130.3,
135.2, 144.4, 159.6, 169.9 ppm. IR (CHCl ): ν = 1740, 1721,
˜
3
1253 cm–1. HRMS: calcd. for C23H27N2NaO6P 481.1504; found
481.1500.
Ethyl
1Ј-Benzyl-3-(diethoxyphosphoryl)-5Ј-methoxy-2Ј-oxospiro-
(3e): Yield: 157 mg
[aziridine-2,3Ј-indoline]-1-carboxylate
(0.32 mmol, 32%); yellow solid; isolated as the trans isomer; Rf =
0.42 (hexane/ethyl acetate, 2:8). 1H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.14 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 1.21 [t, J =
7.2 Hz, 3 H, (CH3CH2O)2P], 1.43 (t, J = 7.1 Hz, 3 H, CH3CH2OC),
3.38 (d, JH,P = 17.2 Hz, 1 H, NCH), 3.74 (s, 3 H, CH3O), 3.90–
4.10 [m, 2 H, (CH3CH2O)2P], 4.20 (q, J = 7.1 Hz, 2 H, CH3CH2O),
4.29–4.44 [m, 2 H, (CH3CH2O)2P], 4.76 (d, J = 15.8 Hz, 1 H,
NCHaHb), 5.11 (d, J = 15.8 Hz, 1 H, NCHaHb), 6.64 (d, J =
8.6 Hz, 1 H, ArH), 6.75–6.80 (m, 1 H, ArH), 7.22–7.36 (m, 5 H,
ArH), 7.65 (d, J = 2.6 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ = 14.4, 16.4 (d, JCCOP = 5.9 Hz), 16.6 (d, JCCOP
= 6.0 Hz), 44.4 (d, JCP = 207.7 Hz), 44.6, 48.6 (d, JCCP = 4.1 Hz),
56.0, 63.0 (d, JCOP = 5.7 Hz), 63.8 (d, JCOP = 5.7 Hz), 63.8, 110.5,
112.2, 116.6, 122.2, 127.2, 128.0, 129.0, 135.3, 137.6, 156.4, 159.5,
126.4, 130.4, 145.2, 159.4, 169.6 ppm. IR (CHCl ): ν = 1740, 1722,
˜
3
1257 cm–1. HRMS: calcd. for C17H23N2NaO6P 405.1191; found
405.1188.
Ethyl 3-(Diethoxyphosphoryl)-2Ј-oxo-1Ј-phenylspiro[aziridine-2,3Ј-
indoline]-1-carboxylate (3b): Yield: 187 mg (0.42 mmol, 42%); yel-
low solid; isolated as the trans isomer; Rf = 0.44 (hexane/ethyl acet-
1
ate, 2:8). H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.14–1.31 [m, 6
H, (CH3CH2O)2P], 1.45 (t, J = 7.0 Hz, 3 H, CH3CH2OC), 3.41 (d,
JH,P = 17.3 Hz, 1 H, NCH), 3.97–4.47 [m, 6 H, (CH3CH2O)2P,
CH3CH2O], 6.88 (d, J = 7.7 Hz, 1 H, ArH), 7.15 (t, J = 7.7 Hz, 1
H, ArH), 7.27–7.36 (m, 1 H, ArH), 7.38–7.48 (m, 3 H, ArH), 7.49–
7.62 (m, 2 H, ArH), 7.98 (d, J = 7.7 Hz, 1 H, ArH) ppm. 13C NMR
(CDCl3, 50 MHz, 25 °C): δ = 14.5, 16.4 (d, JCCOP = 5.3 Hz), 16.6
169.6 ppm. IR (CHCl ): ν = 1740, 1719, 1257 cm–1. HRMS: calcd.
˜
3
for C24H29N2NaO7P 511.1610; found 511.1607.
Ethyl
1Ј-Benzyl-3-(diethoxyphosphoryl)-5Ј-isopropyl-2Ј-oxospiro-
(3f): Yield: 240 mg
[aziridine-2,3Ј-indoline]-1-carboxylate
(d, JCCOP = 6.6 Hz), 44.9 (d, JCP = 207.8 Hz), 48.6 (d, JCCP
=
(0.48 mmol, 48%); yellow solid; isolated as the trans isomer; Rf =
0.43 (hexane/ethyl acetate, 2:8). 1H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.11 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 1.16–1.29 [m,
9 H, (CH3CH2O)2P, (CH3)CH], 1.43 (t, J = 7.0 Hz, 3 H,
CH3CH2OC), 2.87 [sept, J = 6.6 Hz, 1 H, (CH3)CH], 3.38 (d, JH,P
= 17.3 Hz, 1 H, NCH), 3.90–4.11 [m, 2 H, (CH3CH2O)2P], 4.22 (q,
J = 7.0 Hz, 2 H, CH3CH2O), 4.28–4.47 [m, 2 H, (CH3CH2O)2P],
4.81 (d, J = 15.7 Hz, 1 H, NCHaHb), 5.09 (d, J = 15.7 Hz, 1 H,
NCHaHb), 6.69 (d, J = 8.1 Hz, 1 H, ArH), 7.07–7.16 (m, 1 H,
4.2 Hz), 63.0 (d, JCOP = 6.1 Hz), 63.7, 63.8 (d, JCOP = 5.6 Hz),
110.0, 121.0, 123.8, 126.7, 126.8, 128.7, 129.9, 130.0, 130.3, 134.1,
145.4, 159.3, 169.2 ppm. IR (CHCl ): ν = 1732, 1720, 1256 cm–1.
˜
3
HRMS: calcd. for C22H25N2NaO6P 467.1348; found 467.1344.
Ethyl 1Ј-(2,4-Dichlorobenzyl)-3-(diethoxyphosphoryl)-2Ј-oxospiro-
[aziridine-2,3Ј-indoline]-1-carboxylate
(3c):
Yield:
153 mg
(0.29 mmol, 29%); yellow solid; isolated as the trans isomer; Rf =
0.43 (hexane/ethyl acetate, 2:8). 1H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.18 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 1.24 [t, J =
7.1 Hz, 3 H, (CH3CH2O)2P], 1.44 (t, J = 7.1 Hz, 3 H, CH3CH2OC),
3.41 (d, JH,P = 17.2 Hz, 1 H, NCH), 3.96–4.12 [m, 2 H,
(CH3CH2O)2P], 4.21 (q, J = 7.1 Hz, 2 H, CH3CH2O), 4.29–4.44
[m, 2 H, (CH3CH2O)2P], 4.94 (d, J = 16.6 Hz, 1 H, NCHaHb), 5.16
(d, J = 16.6 Hz, 1 H, NCHaHb), 6.71 (d, J = 7.4 Hz, 1 H, ArH),
7.04 (t, J = 7.8 Hz, 1 H, ArH), 7.12–7.19 (m, 2 H, ArH), 7.27–7.35
(m, 2 H, ArH), 7.46 (d, J = 2.2 Hz, 1 H, ArH), 7.97 (d, J = 7.8 Hz,
1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 14.5, 16.4
ArH), 7.21–7.44 (m, 5 H, ArH), 7.84–7.91 (m, 1 H, ArH) ppm. 13
C
NMR (CDCl3, 50 MHz, 25 °C): δ = 14.4, 16.4 (d, JCCOP = 5.9 Hz),
16.6 (d, JCCOP = 6.0 Hz), 24.1, 24.4, 34.1, 44.5 (d, JCP = 207.7 Hz),
44.6, 48.4, 62.9 (d, JCOP = 6.1 Hz), 63.6 (d, JCOP = 5.7 Hz), 63.7,
109.5, 121.1, 124.8, 127.3, 128.0, 128.1, 129.0, 135.4, 142.2, 144.3,
159.3, 169.9 ppm. IR (CHCl ): ν = 1737, 1720, 1251 cm–1. HRMS:
˜
3
calcd. for C26H33N2NaO6P 523.1974; found 523.1969.
General Procedure for Nucleophilic Epoxidation: In a round-bot-
tomed flask was placed a solution of 4 (1 mmol, 1 m in EtOH) and
30% aqueous hydrogen peroxide (3 mmol, 0.34 mL). After cooling
with an ice bath to 15 °C, aqueous sodium hydroxide (2 m,
0.125 mL, 0.25 mmol) was slowly added whilst stirring. The re-
sulting mixture was stirred at 20–25 °C until the reaction was com-
plete (TLC) and subsequently poured into saturated aqueous
NH4Cl solution (1.0 mL). The aqueous phase was extracted several
times with EtOAc, and the combined organic phases were washed
with brine, dried with anhydrous Na2SO4 and concentrated under
reduced pressure to give the crude product, which was purified by
(d, JCCOP = 5.9 Hz), 16.6 (d, JCCOP = 6.0 Hz), 41.6, 44.7 (d, JCP
=
208.0 Hz), 48.3 (d, JCCP = 4.2 Hz), 63.0 (d, JCOP = 6.1 Hz), 63.7
(d, JCOP = 5.8 Hz), 63.8, 109.5, 121.1, 123.8, 126.8, 127.8, 128.8,
129.8, 130.5, 131.1, 133.8, 134.5, 143.8, 159.2, 170.1 ppm. IR
(CHCl3):
ν =
˜
1741, 1723, 1243 cm–1. HRMS: calcd. for
C23H25Cl2N2NaO6P 549.0725; found 549.0722.
Ethyl 1Ј-Benzyl-3-(diethoxyphosphoryl)-2Ј-oxospiro[aziridine-2,3Ј-
indoline]-1-carboxylate (3d): Yield: 151 mg (0.33 mmol, 33%); yel-
low solid; isolated as the trans isomer; Rf = 0.40 (hexane/ethyl acet-
ate, 2:8). 1H NMR (CDCl3, 200 MHz, 25 °C): δ = 1.15 [t, J = flash chromatography on silica gel (hexane/ethyl acetate).
Eur. J. Org. Chem. 2011, 385–391
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
389

M. A. Loreto et al.
FULL PAPER
Diethyl trans-1-Methyl-2-oxospiro[indoline-3,2Ј-oxiran]-3Ј-ylphos-
phonate (trans-4a): Yield: 218 mg (0.70 mmol, 70%); pale-yellow
solid; Rf = 0.33 (hexane/ethyl acetate, 3:7). 1H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.21 [t, J = 7.0 Hz, 3 H, (CH3CH2O)2P], 1.41
solid; Rf = 0.25 (hexane/ethyl acetate, 3:7). 1H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.50 [t, J = 7.1 Hz, 6 H, (CH3CH2O)2P], 3.87
(d, JH,P = 27.5 Hz, 1 H, OCH), 4.21–4.57 [m, 4 H, (CH3CH2O)2P],
5.15 (s, 2 H, CH2N), 6.83 (d, J = 7.3 Hz, 1 H, ArH), 7.14–7.52 (m,
[t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 3.26 (s, 3 H, NCH3), 3.73 (d, 6 H, ArH) ppm.
JH,P = 27.6 Hz, 1 H, OCH), 3.95–4.14 [m, 2 H, (CH3CH2O)2P],
Diethyl trans-1-Benzyl-2-oxospiro[indoline-3,2Ј-oxiran]-3Ј-ylphos-
4.20–4.37 [m, 2 H, (CH3CH2O)2P], 6.90 (d, J = 7.9 Hz, 1 H, ArH),
7.1 (dt, J = 7.7, 1.0 Hz, 1 H, ArH), 7.39 (dt, J = 7.9, 1.3 Hz, 1 H,
ArH), 7.99 (d, J = 7.7 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
phonate (trans-4d): Yield: 263 mg (0.68 mmol, 68%); yellow solid;
1
Rf = 0.41 (hexane/ethyl acetate, 3:7). H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.22 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 1.43 [t, J =
7.1 Hz, 3 H, (CH3CH2O)2P], 3.81 (d, JH,P = 27.4 Hz, 1 H, OCH),
4.02–4.14 [m, 2 H, (CH3CH2O)2P], 4.24–4.39 [m, 2 H, (CH3CH2-
O)2P], 4.96 (s, 2 H, CH2N), 6.81 (d, J = 7.6 Hz, 1 H, ArH), 7.07
(t, J = 7.6 Hz, 1 H, ArH), 7.24–7.36 (m, 6 H, ArH), 8.00 (d, J =
7.6 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ =
16.2 (d, JCCOP = 5.7 Hz), 16.4 (d, JCCOP = 5.8 Hz),44.4, 58.1 (d,
JCP = 203.1 Hz), 60.2 (d, JCCP = 1.1 Hz), 62.9 (d, JCOP = 6.0 Hz),
50 MHz, 25 °C): δ = 15.9 (d, JCCOP = 5.8 Hz), 16.0 (d, JCCOP
5.7 Hz), 26.3, 55.5 (d, JCP = 203.5 Hz), 59.7, 62.7 (d, JCOP
=
=
6.3 Hz), 63.1 (d, JCOP = 6.1 Hz), 108.4, 118.9, 122.6, 126.5, 130.6,
145.3, 170.2 ppm. 31P NMR: δ = 14.5 ppm. IR (CHCl ): ν = 1725,
˜
3
1236 cm–1. HRMS: calcd. for C14H18NNaO5P 334.0820; found
334.0816.
Diethyl cis-1-Methyl-2-oxospiro[indoline-3,2Ј-oxiran]-3Ј-ylphosphon-
ate (cis-4a): Yield: 30 mg (0.10 mmol, 10%); pale-yellow solid; Rf 63.3 (d, JCOP = 6.0 Hz), 109.3, 119.2, 122.1, 127.3, 127.5, 127.7,
= 0.23 (hexane/ethyl acetate, 3:7). 1H NMR (CDCl3, 200 MHz, 128.7, 131.7, 135.2, 145.5, 170.7 ppm. 31P NMR: δ = 14.4 ppm. IR
25 °C): δ = 1.35–1.43 [m, 6 H, (CH3CH2O)2P], 3.26 (s, 3 H, NCH3), (CHCl ): ν = 1731, 1262 cm–1. HRMS: calcd. for C H NNaO P
˜
3
20 22
5
3.71 (d, JH,P = 27.4 Hz, 1 H, OCH), 4.18–4.48 [m, 4 H,
(CH3CH2O)2P], 6.89 (d, J = 7.9 Hz, 1 H, ArH), 7.04–7.08 (m, 2
H, ArH), 7.35–7.44 (m, 1 H, ArH) ppm.
410.1133; found 410.1129.
Diethyl cis-1-Benzyl-2-oxospiro[indoline-3,2Ј-oxiran]-3Ј-ylphosphon-
ate (cis-4d): Yield: 46 mg (0.12 mmol, 12%); yellow solid; Rf = 0.27
(hexane/ethyl acetate, 3:7). H NMR (CDCl3, 200 MHz, 25 °C): δ
= 1.33 [t, J = 7.1 Hz, 6 H, (CH3CH2O)2P], 3.69 (d, JH,P = 27.6 Hz,
1 H, OCH), 4.14–4.40 [m, 4 H, (CH3CH2O)2P], 4.90 (s, 2 H,
CH2N), 6.71 (d, J = 7.8 Hz, 1 H, ArH), 6.92–7.02 (m, 2 H, ArH),
1
Diethyl trans-2-Oxo-1-phenylspiro[indoline-3,2Ј-oxiran]-3Ј-ylphos-
phonate (trans-4b): Yield: 233 mg (0.62 mmol, 62%); yellow solid;
1
Rf = 0.42 (hexane/ethyl acetate, 3:7). H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.18 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 1.34 [t, J =
7.1 Hz, 3 H, (CH3CH2O)2P], 3.76 (d, JH,P = 27.6 Hz, 1 H, OCH), 7.16–7.30 (m, 6 H, ArH) ppm.
4.00–4.08 [m, 2 H, (CH3CH2O)2P], 4.18–4.33 [m, 2 H, (CH3CH2-
Diethyl trans-1-Benzyl-5-methoxy-2-oxospiro[indoline-3,2Ј-oxiran]-
O)2P], 6.77 (d, J = 7.6 Hz, 1 H, ArH), 7.05 (t, J = 7.6 Hz, 1 H,
ArH), 7.22 (t, J = 7.6 Hz, 1 H, ArH), 7.35–7.46 (m, 5 H, ArH),
7.96 (d, J = 7.6 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz,
25 °C): δ = 16.0 (d, JCCOP = 5.7 Hz), 16.2 (d, JCCOP = 5.8 Hz), 58.1
3Ј-ylphosphonate (trans-4e): Yield: 333 mg (0.80 mmol, 80%); yel-
1
low solid; Rf = 0.40 (hexane/ethyl acetate, 3:7). H NMR (CDCl3,
200 MHz, 25 °C): δ = 1.23 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 1.43
[t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 3.77 (s, 3 H, OCH3), 3.82 (d,
JH,P = 27.4 Hz, 1 H, OCH), 3.97–4.17 [m, 2 H, (CH3CH2O)2P],
4.24–4.41 [m, 2 H, (CH3CH2O)2P], 4.93 (s, 2 H, CH2N), 6.68 (d, J
= 8.6 Hz, 1 H, ArH), 6.79–6.85 (m, 1 H, ArH), 7.27–7.40 (m, 5 H,
ArH), 7.74 (d, J = 2.6 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
(d, JCP = 203.7 Hz), 60.1, 62.9 (d, JCOP = 6.2 Hz), 63.4 (d, JCOP
=
6.1 Hz), 109.8, 118.8, 123.3, 126.1, 126.9, 128.3, 129.5, 130.6, 133.5,
145.5, 169.8 ppm. 31P NMR: δ = 14.4 ppm. IR (CHCl ): ν = 1716,
˜
3
1265 cm–1. HRMS: calcd. for C19H20NNaO5P 396.0977; found
396.0973.
50 MHz, 25 °C): δ = 16.2 (d, JCCOP = 6.4 Hz), 16.4 (d, JCCOP
=
Diethyl cis-2-Oxo-1-phenylspiro[indoline-3,2Ј-oxiran]-3Ј-ylphosphon-
ate (cis-4b): Yield: 58 mg (0.16 mmol, 16%); yellow solid; Rf = 0.29
(hexane/ethyl acetate, 3:7). H NMR (CDCl3, 200 MHz, 25 °C): δ
= 1.33–1.42 [m, 6 H, (CH3CH2O)2P], 3.79 (d, JH,P = 27.3 Hz, 1 H,
OCH), 4.18–4.45 [m, 4 H, (CH3CH2O)2P], 6.86 (d, J = 7.9 Hz, 1
H, ArH), 7.05–7.14 (m, 2 H, ArH), 7.28–7.39 (m, 1 H, ArH), 7.40–
7.57 (m, 5 H, ArH) ppm.
6.8 Hz), 44.5, 55.8, 58.0 (d, JCP = 189.5 Hz), 60.3 (JCCP = 1.1 Hz),
63.0 (d, JCOP = 5.8 Hz), 63.5 (d, JCOP = 5.7 Hz), 110.3, 112.8,
116.9, 120.4, 127.3, 127.8, 128.8, 135.1, 138.0, 156.1, 170.6 ppm.
1
31P NMR: δ = 14.7 ppm. IR (CHCl ): ν = 1728, 1240 cm–1. HRMS:
˜
3
calcd. for C21H24NNaO6P 440.1239; found 440.1236.
Diethyl cis-1-Benzyl-5-methoxy-2-oxospiro[indoline-3,2Ј-oxiran]-3Ј-
ylphosphonate (cis-4e): Yield: 68 mg (0.16 mmol, 16%); yellow so-
Diethyl
trans-1-(2,4-Dichlorobenzyl)-2-oxospiro[indoline-3,2Ј-ox- lid; Rf = 0.22 (hexane/ethyl acetate, 3:7). 1H NMR (CDCl3,
iran]-3Ј-ylphosphonate (trans-4c): Yield: 307 mg (0.67 mmol, 67%);
yellow solid; Rf = 0.39 (hexane/ethyl acetate, 3:7). 1H NMR
(CDCl3, 200 MHz, 25 °C): δ = 1.23 [t, J = 7.1 Hz, 3 H, (CH3CH2-
200 MHz, 25 °C): δ = 1.39 [t, J = 7.1 Hz, 6 H, (CH3CH2O)2P], 3.71
(d, JH,P = 27.5 Hz, 1 H, OCH), 3.73 (s, 3 H, OCH3), 4.07–4.44 [m,
4 H, (CH3CH2O)2P], 4.93 (s, 2 H, CH2N), 6.62–6.69 (m, 2 H, ArH),
6.75–6.82 (m, 1 H, ArH), 7.27–7.34 (m, 5 H, ArH) ppm.
O)2P], 1.42 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 3.81 (d, JH,P
=
27.4 Hz, 1 H, OCH), 3.97–4.19 [m, 2 H, (CH3CH2O)2P], 4.22–4.39
[m, 2 H, (CH3CH2O)2P], 5.03 (s, 2 H, CH2N), 6.73 (d, J = 7.9 Hz,
1 H, ArH), 7.05–7.20 (m, 3 H, ArH), 7.30–7.34 (m, 3 H, ArH),
7.43 (d, J = 1.9 Hz, 1 H, ArH), 8.00 (d, J = 7.6 Hz, 1 H, ArH)
Diethyl trans-1-Benzyl-5-isopropyl-2-oxospiro[indoline-3,2Ј-oxiran]-
3Ј-ylphosphonate (trans-4f): Yield: 365 mg (0.85 mmol, 85%); yel-
low solid; Rf = 0.42 (hexane/ethyl acetate, 3:7). H NMR (CDCl3,
1
200 MHz, 25 °C): δ = 1.17–1.29 [m, 9 H, (CH3CH2O)2P, (CH3)-
CH], 1.42 [t, J = 7.1 Hz, 3 H, (CH3CH2O)2P], 2.87 [sept, J =
6.6 Hz, 1 H, (CH3)CH], 3.80 (d, JH,P = 27.7 Hz, 1 H, OCH), 4.00–
4.17 [m, 2 H, (CH3CH2O)2P], 4.24–4.41 [m, 2 H, (CH3CH2O)2P],
4.93 (s, 2 H, CH2N), 6.71 (d, J = 7.9 Hz, 1 H, ArH), 7.13 (d, J =
7.9 Hz, 1 H, ArH), 7.29–7.42 (m, 5 H, ArH), 7.35 (d, J = 1.1 Hz,
1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 16.1 (d,
JCCOP = 5.7 Hz), 16.3 (d, JCCOP = 5.7 Hz), 23.9, 24.0, 33.8, 44.4,
ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ = 15.9 (d, JCCOP
=
5.6 Hz), 16.0 (d, JCCOP = 5.5 Hz), 41.1, 57.9 (d, JCP = 203.0 Hz),
59.7 (d, JCCP = 1.1 Hz), 62.6 (d, JCOP = 6.2 Hz), 63.1 (d, JCOP
=
6.2 Hz), 109.2, 118.9, 123.0, 126.8, 127.2, 128.8, 129.2, 130.6, 130.8,
133.2, 133.8, 144.0, 170.6 ppm. 31P NMR: δ = 14.2 ppm. IR
(CHCl3):
ν
˜
=
1733, 1253 cm–1. HRMS: calcd. for
C20H20Cl2NNaO5P 478.0354; found 478.0350.
Diethyl cis-1-(2,4-Dichlorobenzyl)-2-oxospiro[indoline-3,2Ј-oxiran]-
3Ј-ylphosphonate (cis-4c): Yield: 103 mg (0.22 mmol, 22%); yellow
58.1 (d, JCP = 203.1 Hz), 60.2 (d, JCCP = 1.0 Hz), 62.9 (d, JCOP
6.1 Hz), 63.2 (d, JCOP = 6.1 Hz), 109.3, 119.3, 125.2, 127.3, 127.7,
=
390
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 385–391

Phosphonates Spiro-Fused with Oxindoles
128.6, 128.7, 135.2, 142.6, 143.9, 170.8 ppm. 31P NMR: δ =
[5] a) M. Carducci, S. Fioravanti, M. A. Loreto, L. Pellacani, P. A.
Tardella, Tetrahedron Lett. 1996, 37, 3777–3778; b) A. Fazio,
M. A. Loreto, P. A. Tardella, Tetrahedron Lett. 2001, 42, 2185–
2187.
14.9 ppm. IR (CHCl ): ν = 1731, 1236 cm–1. HRMS: calcd. for
˜
3
C23H28NNaO5P 452.1603; found 452.1600.
[6] a) G. S. Singh, M. DЈhooghe, N. De Kimpe, Chem. Rev. 2007,
107, 2080–2135; b) R. Pellicciari, L. Amori, N. Kuznetsova, S.
Zlotsky, A. Gioiello, Tetrahedron Lett. 2007, 48, 4911–4914; c)
C. Stevens, M. Gallant, N. De Kimpe, Tetrahedron Lett. 1999,
40, 3457–3460.
[7] D. Hendlin, E. O. Stapley, M. Jackson, H. Wallik, A. K. Miller,
F. J. Wolf, T. W. Miller, L. Chaiet, F. M. Kahan, E. L. Foltz,
H. B. Woodruff, J. M. Mata, S. Hernandez, S. Mochales, Sci-
ence 1969, 166, 122–123.
Diethyl cis-1-Benzyl-5-isopropyl-2-oxospiro[indoline-3,2Ј-oxiran]-3Ј-
ylphosphonate (cis-4f): Yield: 30 mg (0.07 mmol, 7%); yellow solid;
Rf = 0.24 (hexane/ethyl acetate, 3:7). H NMR (CDCl3, 200 MHz,
25 °C): δ = 1.17 [d, J = 6.8 Hz, 6 H, (CH3)CH], 1.36 [t, J = 7.0 Hz,
6 H, (CH3CH2O)2P], 2.83 [sept, J = 6.8 Hz, 1 H, (CH3)CH], 3.74
(d, JH,P = 27.8 Hz, 1 H, OCH), 4.20–4.44 [m, 4 H, (CH3CH2O)2P],
4.94 (s, 2 H, CH2N), 6.78 (d, J = 8.1 Hz, 1 H, ArH), 6.92 (d, J =
1.6 Hz, 1 H, ArH), 7.11 (d, J = 8.1 Hz, 1 H, ArH), 7.29–7.43 (m,
5 H, ArH) ppm.
1
[8] K. Moonen, I. Laureyn, C. V. Stevens, Chem. Rev. 2004, 104,
6177–6215.
[9] a) F. Palacios, A. M. Ochoa de Retana, J. M. Alonso, J. Org.
Chem. 2005, 70, 8895–8901; b) M. P. Teulade, P. Savignac,
Synth. Commun. 1987, 17, 125–136.
Acknowledgments
[10] M. A. Loreto, C. Pompili, P. A. Tardella, Tetrahedron 2001, 57,
4423–4427.
We thank Dr. Mauro Bassetti (CNR, University “La Sapienza” of
Rome) and Dr. Fabio Sciubba (University “La Sapienza” of Rome)
for their assistance with the 31P NMR spectra. We also thank Dr.
Giovanna Mancini (CNR, University “La Sapienza” of Rome) for
the NOESY experiments.
[11] a) O. R. Suárez-Castillo, M. Sánchez-Zavala, M. Meléndez-
Rodríguez, L. E. Castelán-Duarte, M. S. Morales-Ríos, P.
Joseph-Nathan, Tetrahedron 2006, 62, 3040–3051; b) G. Bar-
tolo, G. Salerno, L. Veltri, M. Costa, C. Massera, Eur. J. Org.
Chem. 2001, 4607–4613; c) M. S. Morales-Ríos, M. García-Vel-
gara, H. Cervantes-Cuevas, C. Alvarez-Cisneros, P. Joseph-Na-
than, Magn. Reson. Chem. 2000, 38, 172–176.
[12] W. C. Anthony, J. Org. Chem. 1966, 31, 77–81.
[13] H.-J. Cristau, X. Y. Mbianda, A. Geze, Y. Beziat, M. B. Gasc,
J. Organomet. Chem. 1998, 571, 189–193.
[14] a) V. Schulz, M. Davoust, M. Lemarié, J.-F. Lohier, J. S. de Ol-
iveira Santos, P. Metzner, J.-F. Briére, Org. Lett. 2007, 9, 1745–
1748; b) B. Iorga, F. Eymery, P. Savignac, Synthesis 1999, 207–
224.
[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] C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209–2219.
[3] A. Dandia, R. Singh, M. Saha, A. Shivpuri, Pharmazie 2002,
57, 602–605.
[4] I. Ammetto, T. Gasperi, M. A. Loreto, A. Migliorini, F. Palma-
relli, P. A. Tardella, Eur. J. Org. Chem. 2009, 6189–6197.
Received: July 19, 2010
Published Online: November 22, 2010
Eur. J. Org. Chem. 2011, 385–391
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
391