One-Pot, Highly Regioselective 1,3-Dipole Cycloaddition Promoted by Montmorillonite for the Synthesis of Spiro[indole-pyrrolizine], Spiro[indole-indolizine], and Spiro[indole-pyrrolidine] gem -Bisphosphonates

Article abstract of DOI:10.1055/s-0035-1560463

Various spiro[indole-pyrrolizine], spiro[indole-indolizine], and spiro[indole-pyrrolidine] gem-bisphosphonates were prepared by multicomponent reactions between isatins, tetraethyl vinylidenebis(phosphonate), and amino acids in the presence of montmorillonite. The one-pot reactions proceeded by 1,3-dipole cycloadditions of azomethine ylides formed in a decarboxylative manner. The proposed mechanism is in line with experimental data that confirmed that the azomethine ylide is formed in a decarboxylative manner; this provides new insight into the underlying mechanisms of such cycloadditions. The method has many notable features, such as a broad substrate scope, high efficiency, and high regioselectivity.

Full text of DOI:10.1055/s-0035-1560463

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3783–3796
paper
3783
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Paper
Synthesis
One-Pot, Highly Regioselective 1,3-Dipole Cycloaddition Promoted
by Montmorillonite for the Synthesis of Spiro[indole-pyrrolizine],
Spiro[indole-indolizine], and Spiro[indole-pyrrolidine] gem-Bis-
phosphonates
Guozhu Li
R1
n
O
P
O
Mingshu Wu*
Fengjiao Liu
Jie Jiang
O
N
O
P
N
O
O
O
O
O
O
R1
O
O
montmorillonite
n
R2
P
P
O
O
+
Key Laboratory of Tropical Medicinal Plant Chemistry of
the Ministry of Education, College of Chemistry &
Chemical Engineering, Hainan Normal University, Gui
Linyang University Town, 2nd Road Xiaoji, 571158,
P. R. of China
+
COOH
O
MeCN, 80 °C
0.5–2 h
N
N
R2
n
H
O
(n = 1,2)
O
N
R1
P
P
O
O
O
O
R1 = H, F, Cl, Br, Me
R2 = H, Bn
wmsh@hainnu.edu.cn
O
N
R2
19 examples
up to 95% yield
Received: 21.06.2015
Accepted after revision: 20.07.2015
Published online: 31.08.2015
N
DOI: 10.1055/s-0035-1560463; Art ID: ss-2015-h0390-op
H
O
H
H
N
Abstract Various spiro[indole-pyrrolizine], spiro[indole-indolizine],
and spiro[indole-pyrrolidine] gem-bisphosphonates were prepared by
multicomponent reactions between isatins, tetraethyl vinyliden-
ebis(phosphonate), and amino acids in the presence of montmorillon-
ite. The one-pot reactions proceeded by 1,3-dipole cycloadditions of
azomethine ylides formed in a decarboxylative manner. The proposed
mechanism is in line with experimental data that confirmed that the
azomethine ylide is formed in a decarboxylative manner; this provides
new insight into the underlying mechanisms of such cycloadditions.
The method has many notable features, such as a broad substrate
scope, high efficiency, and high regioselectivity.
N
H
N
HO
strychnofoline
Me
N
Me
N
MeO
O
O
N
H
N
H
Key words spiro compounds, heterocycles, multicomponent reac-
tions, ylides, catalysis, isatins
horsfiline
coerulescine
Figure 1 Representative natural products containing oxospiroindole
moieties
The core oxospiroindole structure can be found in many
natural compounds, some examples of which are shown in
Figure 1. Oxospiroindoles exhibit a diverse range of biologi-
cal activities and are potentially useful in the treatment of
malaria, HIV, and cancer;1 several members of the family
have been used in human clinical trials.2
As a consequence, we attempted to use isatin and its de-
rivatives in developing an efficient strategy for the synthe-
sis of various spiro[indole-pyrrolizine], spiro[indole-indol-
izine], and spiro[indole-pyrrolidine] gem-bisphosphonates.
Tetraethyl vinylidenebis(phosphonate) (VBP) is a very use-
ful synthon for bisphosphonate derivatives with various
structures.3 However, to the best of our knowledge, this is
the first report of the use of VBP as dienophile for the syn-
thesis of gem-bisphosphonates by 1,3-dipole cycloaddition
with azomethine ylides prepared in a decarboxylative man-
ner.4 This reaction is the basis of one of the most powerful
strategies for the synthesis of various five- or six-mem-
bered heterocycles, although it has received much less at-
tention than methods involving other 1,3-dipoles.5 Most
notably, the targeted molecular that we designed might be
of considerable pharmacological relevance.
Here, we describe our further endeavors and present
examples of a montmorillonite-promoted, one-pot, 1,3-di-
pole cycloaddition of azomethine ylides, formed decarbox-
ylatively, to VBP to provide efficient access to a range of
spiro[indole-pyrrolizine], spiro[indole-indolizine], and
spiro[indole-pyrrolidine] gem-bisphosphonates (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3783–3796

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Synthesis
R1
n
O
P
O
O
N
O
P
N
O
O
O
O
O
R1
O
O
R2
P
O
O
n(n=1,2)
COOH
montmorillonite
+
+
O
MeCN, 80 °C
0.5–2 h
N
N
R2
P
n
H
O
O
O
N
R1
P
O
O
O
P
O
O
N
R2
R
R
1 = H, F, Cl, Br, Me
2 = H, Bn
19 examples
up to 95% yield
Scheme 1 Montmorillonite-promoted one-pot 1,3-dipole cycloaddition for the synthesis of spiro[indole-pyrrolizine], spiro[indole-indolizine], and
spiro[indole-pyrrolidine] gem-bisphosphonates
The learning curve has been steep, although we have
published some primary results.4 This time, we studied the
exact mechanism of this 1,3-dipole cycloaddition on the
basis of our results and reports by other authors.6 We iden-
tified a dimerization product of a 1,3-dipole for the first
time, thereby confirming that the reaction proceeds
through cycloaddition of the 1,3-dipole (or its azomethine
ylide) to VBP.
We initially chose the reaction of VBP (1 mmol) with L-
proline (1.5 mmol) and isatin (1.2 mmol) in toluene under
catalyst-free conditions at 100 °C as our model reaction (Ta-
ble 1, entry 1). After confirming that the target compound 1
was formed, we tested a series of catalysts (entries 2–9).
We therefore chose montmorillonite as the best catalyst
(Table 1, entry 9) for subsequent optimization of the solvent
system (Table 2).
Table 1 Optimization of the Catalyst System
O
O
O
O
O
O
catalyst
toluene, 100 °C
O
P
P
O
O
N
P
O
+
O
+
COOH
O
N
N
P
H
H
HN
O
O
O
Entry
Catalysta
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
–
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
64
68
20
40
48
10
26
62
76
CeO2
MgOc
Sm2O3
CeCl3·7H2O
ZnCl2
Mg(ClO4)2
Yb2O3
montmorillonite
a 10 mol%.
b Determined by column chromatography [silica gel, EtOAc–MeOH (40:1 to 20:1)].
c Nanoparticulate.
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Table 2 Optimization of the Solvent System
O
O
O
O
O
O
P
O
O
P
P
O
O
N
montmorillonite
+
O
O
+
COOH
N
H
N
P
HN
H
O
O
O
Entry
Temp (°C)
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
100
100
reflux
reflux
100
80
xylenes
DMF
0.5
0.5
0.5
0.5
0.5
0.5
46
50
44
72
70
80
THF
MeOH
toluene
MeCN
a Determined by column chromatography [silica gel, EtOAc–MeOH (40:1 to 20:1)].
With the optimum conditions in hand (Table 2, entry 6),
we next examined the scope of the reaction with respect to
the isatin derivative (Table 3). Most of the products were
purified by column chromatography on silica gel, apart
from products 2–4, which precipitated directly from the re-
action system once the reaction had been quenched.
Table 3 Examination of the Scope of the Reaction with Respect to the Isatin Derivative
R1
O
O
O
O
O
R1
O
P
O
montmorillonite
MeCN, 80 °C
O
P
P
O
O
N
+
O
+
COOH
O
N
R2
N
0.5–2 h
P
H
N
R2
O
O
O
Entry
Time (h)
0.5
Product
dra
Yieldb (%)
O
P
O
O
N
O
1
100:14
80
P
HN
O
O
O
1
F
O
O
N
P
O
O
2
0.5
100:6
92
P
HN
O
O
O
2
Cl
O
P
O
O
N
O
3
0.5
100:22
95
P
HN
O
O
O
3
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Table 3 (continued)
Entry
Time (h)
Product
dra
Yieldb (%)
Br
O
P
O
O
N
O
4
5
6
0.5
100:20
93
P
HN
O
O
O
4
O
O
Cl
N
P
O
O
2
100:0
57
P
HN
O
O
O
5
Me
O
O
N
P
O
1
100:24
45
O
P
HN
O
O
O
6
Me
O
P
O
O
N
O
7
2
100:17
47
P
N
O
O
O
Bn
7
O
O
N
P
O
O
8
2
100:18
44
P
N
O
O
O
Bn
8
a dr = (R1R2 + S1S2)/(S1R2 + R1S2); the dr value was determined by 31P NMR; R1R2 and S1S2 were determined by X-ray crystal structure analysis.
b Determined by column chromatography [silica gel, EtOAc–MeOH (40:1 to 20:1)].
Encouraged by our successful examination of the scope
of the isatin derivatives, we decided to extend the generali-
ty of the procedure further by testing the reactivity of two
other amino acids: piperidine-2-carboxylic acid and sarco-
sine (Table 4 and Table 5).
The results presented in Tables 4 and 5 showed that
piperidine-2-carboxylic acid and sarcosine both react
smoothly with isatin or its derivatives. Therefore, the strat-
egy that we developed has a wide reaction scope.
The structures of the products were fully characterized
by spectroscopic analyses (1H, 31P, and 13C NMR, HSQC,
HMBC, and MS).7 The spectra of compound 1 are shown in
Figure 2 and in the Supporting Information.
In the case of compound 1, the diagnostic triplet for P–
1
C–P in the 13C NMR spectrum (δ = 46.21 ppm, JP–C–P
=
135.97 Hz), showing coupling to two phosphorus atoms,
confirmed the presence of a gem-bisphosphonate group.
The peak for the tertiary carbon atom of P–C–CH (δ = 69.63
ppm, 2JP–C–CH = 4.23 Hz) and the quaternary spiro carbon (P–
C–CH2–C; δ = 64.83 ppm, 3J = 5.23 Hz) both appeared as
doublets, rather than the triplets expected for coupling to
two phosphorus atoms. This showed that the two phos-
phoryl groups were magnetically nonequivalent, and only
one phosphorus atom was involved in long-range coupling
with the tertiary carbon or the quaternary spiro carbon. In
the HSQC spectrum of compound 1 (Figure 2), the Ha atom
(δ = 2.953 ppm, ddd, 1 H), and the Hb atom (δ = 3.272 ppm,
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Table 4 The Reactivity of Piperidine-2-carboxylic Acid
R1
O
O
O
O
O
O
P
O
R1
O
montmorillonite
MeCN, 80 °C
N
P
P
O
O
O
+
+
O
P
N
R2
N
COOH
N
R2
O
H
O
O
Entry
Time (h)
Product
dra
Yieldb (%)
O
O
N
P
O
O
1
2
100:46
65
P
HN
O
O
O
9
F
O
P
O
O
N
O
2
3
4
5
6
2
2
2
2
2
100:8
45
P
HN
O
O
O
10
Cl
O
O
N
P
O
O
100:0
100:4
100:8
100:5
40
45
40
35
P
HN
O
O
O
11
Br
O
P
O
O
N
O
P
HN
O
O
O
12
Me
O
O
N
P
O
O
P
N
O
O
O
Bn
13
O
P
O
N
O
O
P
N
Bn
O
O
O
14
a dr = (R1R2 + S1S2)/(S1R2 + R1S2); the dr value was determined by 31P NMR; R1R2 and S1S2 were determined by X-ray crystal structure analysis.
b Determined by column chromatography [silica gel, EtOAc–MeOH (40:1 to 20:1)].
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ddd, 1 H) are not equivalent. This might be because they lie
between the large quaternary spiro carbon and the gem-
phosphoryl groups. The coupling constants for Ha and Hb
are: Ha [3J(31P–H(a or b)) = 20.4Hz, 3J(31P–H(a or b)) = 20.4 Hz,
gem J(Ha–Hb) = 14.8 Hz] and Hb [3J(31P–Ha/b) = 20.8 Hz, gem
J(Ha–Hb) = 14.8 Hz, 3J(31P–Ha/b) = 8.0 Hz]. Furthermore, Ha,
Hb, and the quaternary spiro carbon, and Ha, Hb, and the ter-
minal carbon of the phenyl ring showed strong two- and
three-bond correlations, respectively (Figure 3). Therefore
compound 1 is the sole product and is formed regioselec-
tively. The single-crystal structure of compound 3 (Figure
4)8 confirmed that the results shown in Figure 2 and Figure
3 are reasonable.
Table 5 The Reactivity of Sarcosine
R1
O
O
O
O
O
O
O
R1
N
montmorillonite
MeCN, 80 °C
P
O
P
P
O
O
O
N
COOH
+
+
O
H
P
1–2 h
N
R2
N
R2
O
O
O
Entry
Time (h)
Product
Yielda (%)
O
P
O
O
N
O
1
2
77
P
HN
O
O
O
15
F
O
O
N
P
O
O
2
2
40
P
HN
O
O
O
16
Cl
O
P
O
O
N
O
3
2
50
P
HN
O
O
O
17
Br
O
O
N
P
O
O
4
2
85
P
HN
O
O
O
18
O
P
O
O
N
O
5
2
45
P
N
O
O
O
Bn
19
a Determined by column chromatography [silica gel, EtOAc–MeOH (40:1 to 20:1)].
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Figure 2 The HSQC spectrum of compound 1
Figure 4 The single-crystal structure of compound 3 (see the Support-
ing Information for the cif file)
Because there is more than one chiral center, the hin-
dered rotation of the two phosphoryl groups leads to mag-
netic nonequivalence (see Figure 5). Consequently, the
shapes of the 31P NMR spectra of the products are interest-
ing, with some of the peaks appearing as multiplets. There
are two chiral centers in compound 1–14: the spiro-quater-
nary carbon (R1 and S1) and the tertiary carbon adjacent to
the nitrogen atom of the pyrrolidine backbone (R2 and S2).
That is to say, there are two enantiomeric pairs (the R1S2
and S1R2 isomers and the S1S2 and R1R2 isomers), which are
difficult to separate by column chromatography on silica
gel. However, their ratios can be determined by 31P NMR
spectroscopy. Obviously, it is rational to claim that the two
phosphorus atoms couple with each other with a coupling
constant 2J (31P–31P) of about 14.6 Hz. The heights of peaks
d and e are higher than those of peaks c and f, indicating
that an AB system is present in one pair of enantiomers
(2JP–C–P = 14.58 Hz; Figure 5), whereas the height of peaks a
Figure 5 31P NMR spectrum of compound 1
and b is nearly the same as that of peaks g and h (2JP–C–P
=
11.34 Hz), which shows that an AX system is present in the
other pair of enantiomers (Figure 5), because one phospho-
rus atom is within the deshielding region of the phenyl ring,
leading to a downward displacement of its chemical shift,
whereas the other phosphorus atom is within the shielding
region.
The connectivity and the absolute configuration of the
products were unambiguously determined by X-ray crystal
structure analysis of compound 3 (see Supporting Informa-
tion); this showed that the R1R2-isomer and the S1S2-isomer
are the major isomers. The diastereomeric ratio was deter-
mined by 31P NMR spectroscopy (see Tables 3 and 4). For
several compounds (e.g., compound 5), only one singlet was
observed in the 31P NMR spectrum; this is because the two
phosphoryl groups are equivalent. However, the peaks for
compounds 15–19 were doublets of doublets (dd). This is
because there is only one chiral spiro-quaternary carbon
center (R1 and S1) in these compounds, and because the two
phosphoryl groups are nonequivalent and the two phos-
phorus atoms couple with each other. It is therefore reason-
able to expect to observe the dd peaks in the 31P NMR spec-
tra of compound 15–19.
H
H
O
O
*
N
Ha
P
d
O
*
O
P
HN
O
Hb
O
Figure 3 The main HMBC correlations for compound 1
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Having confirmed the structures of the products, we
went on to propose a reasonable reaction path (Scheme 2)
based on our results and those of other researchers.6 To our
delight, in the absence of VBP, we were able to separate the
coupling product m of the 1,3-dipoles for the first time, and
stituted carbon is increased. For dipolarophiles with elec-
tron-withdrawing groups, the dipole–HOMO/dipolaro-
phile–LUMO interaction is usually dominant.9 At the same
time, the presence of the indole ring at one terminal carbon
of the dipole increases both the HOMO energy and the coef-
ficient at the benzylic carbon. Therefore, according to
frontier molecular orbital theory, our strategy should show
high regioselectivity (Scheme 3).
In conclusion, we have reported a strategy in which VBP
is used as a dienophile to prepare spiro[indole-pyrrolizine],
spiro[indole-indolizine], and spiro[indole-pyrrolidine] gem-
bisphosphonates through 1,3-dipole cycloaddition of the
azomethine ylide formed by decarboxylation, a reaction
that is less commonly studied than those of other 1,3-di-
poles. We have successfully developed this strategy and en-
larged the scope of the starting materials to give the spiro
heterocyclic products with high regioselectivities and mod-
erate to high yields. We have also obtained some insight
into the underlying mechanisms of these cycloadditions for
the first time. The study of the pharmacological properties
of the products is underway in our laboratory.
1
we characterized its structure by H NMR, 13C NMR, and
mass spectrometry and by elemental analysis. This con-
firmed that our proposed reaction path is rational. As a
good Lewis acid, montmorillonite can accelerate the decar-
boxylation process.
In the most common representation, azomethine ylides
have a positive charge located on the nitrogen atom and a
negative charge distributed over the two carbon atoms
(Scheme 2).6a Of all the resonance structures of AMY, struc-
tures k and l (especially k) appear to be the most stable, as
the negative charge can be stabilized by the carbonyl group
and the nitrogen atom, and the positive charge can be stabi-
lized by the lone pair of electrons on the nitrogen. In the
1,3-dipolar cycloaddition reaction, the two phosphonate
groups, which have a remarkable electron-withdrawing
ability, should contribute to decreasing the LUMO energy of
the dipolarophile (VBP), while the coefficient at the unsub-
O
O
O
–
N
– H2O
+
N
+
O
COOH
O
N
O
O
H
N
H
O
N
H
NH
g
h
– CO2
+
–
–
+
+
N
N
–
N
+
N
O
O
O
O
–
NH
NH
NH
NH
k
i
j
l
O
O
P
O
O
+
–
P
O
O
O
O
O
O
N
N
P
P
VBP
O
O
O
O
N
N
1
H
H
O
NH
N
the absence
of VBP
N
HN
O
m
Scheme 2 A plausible reaction path
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LUMO
LUMO
N
HOMO of dipole (AMY)
LUMO of
dipolarophile
HOMO
dipole
HOMO
dipolarophile
HOMOdipole-LUMOdipolarophile
O
P
O
O
O
P
O
O
O
O
O
O
N
P
N
P
VBP
O
O
O
O
N
H
N
1
H
azomethine
ylide + VBP
O
O
O
O
O
P
N
P
O
O
O
N
O
P
O
VBP
P
O
O
O
N
O
H
N
1a
H
Scheme 3 The HOMO (dipole)–LUMO (dipolarophile) interaction
IR (KBr): 1716.79 (C=O), 1224.99 (P=O), 1031.04 (P–O–C) cm–1
.
All compounds were fully characterized by spectroscopic data. The
NMR spectra were recorded on a Bruker Avance III (1H NMR: 400
MHz; 13C NMR: 100 MHz; 31P NMR: 162 MHz, external standard 85%
H3PO4), chemical shifts (δ) are expressed in ppm, and J values are giv-
en in Hz. CDCl3 and DMSO-d6 were used as solvents. The reactions
were monitored by thin-layer chromatography (TLC) using silica gel
GF254. EI-MS (70 eV): esquire HCT-Agilent 1200 mass spectrometer.
Elemental analysis was carried out on Vario EL Cube. IR spectra were
recorded on a Thermo Scientific Nicolet 6700 Fourier Transform IR
spectrometer (ATIR) on samples prepared as KBr pellets. Melting
points were measured with an XS melting-point apparatus made by
Beijing Automation Design and Research Institute and are uncorrect-
ed. All chemicals and solvents were used as received without further
purification unless otherwise stated. Column chromatography was
performed on silica gel (300–400 mesh). Tetraethyl vinylidenebis-
phosphonate (VBP) was prepared according to the literature. Other
materials were purchased from Aladdin Reagent Co., Ltd., Xilong
Chemical Co., Ltd. and China National Medicines Co., Ltd.
1H NMR (400 MHz, CDCl3): δ = 1.27–1.34 (m, 12 H), 1.77–1.84 (m, 1
H), 1.91–2.14 (m, 3 H), 2.20–2.25 (m, 1 H), 2.48–2.53 (m, 1 H), 2.88–
3.01 (m, 1 H), 3.18–3.32 (m, 1 H), 4.15–4.43 (m, 9 H), 6.78 (d, J = 8 Hz,
1 H), 6.93 (t, J = 7.2 Hz, 1 H), 7.09 (t, J = 8.4 Hz, 1 H), 7.62 (d, J = 7.6 Hz,
1 H), 9.31 (s, 1 H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.61 (d, JP–P = 11.34 Hz),
24.30 (d, JP–P = 14.58 Hz), 24.52 (d, JP–P = 14.58 Hz), 26.87 (d, JP–P
=
11.34 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 16.49 (P–O–C–CH3), 16.54 (P–O–C–
CH3), 16.69 (P–O–C–CH3), 16.74 (P–O–C–CH3), 24.42 (d, J = 4.11 Hz, P–
C–CH–CH2), 27.39 (P–C–CH–CH2–CH2), 41.50 (P–C–CH–N–CH2), 45.47
(P–C–CH2), 46.31 (t, J = 135.97 Hz, P–C–P), 62.41 (d, J = 6.61 Hz, P–O–
CH2), 62.61 (d, J = 6.81 Hz, P–O–CH2), 63.01 (d, J = 6.91 Hz, P–O–CH2),
63.32 (d, J = 6.41 Hz, P–O–CH2), 64.83 (d, J = 5.23 Hz, O=C–C), 69.63 (d,
J = 4.23 Hz, P–C–CH), 109.66, 122.52, 125.67, 128.80, 130.69, 141.75,
180.62 (C=O).
MS (EI): m/z = 501.2 [M + H]+, 499.2 [M – H]+, 460.3.
Tetraethyl (2-Oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[indole-3,3′-
pyrrolizine]-1′,1′-diyl)bis(phosphonate) (1); Typical Procedure
Anal. Calcd for C22H34N2O7P2: C, 52.80; H, 6.85; N, 5.60. Found: C,
52.85; H, 6.83; N, 5.64.
A mixture of VBP (1 mmol), L-proline (1.5 mmol), isatin (1.2 mmol),
and montmorillonite (10% mol) in MeCN (2 mL) was heated at 80 °C
for 0.5 h. The mixture was then filtered, and the filtrate was purified
by column chromatography [silica gel, EtOAc–MeOH (40:1 to 20:1)] to
give a white solid; yield: 0.4 g (80%); mp 160.2 °C.
Tetraethyl (5-Fluoro-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[in-
dole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (2)
White solid; yield: 0.48 g (92%); mp 193.5 °C.
IR (KBr): 1715.63 (C=O), 1249.76 (P=O), 1030.55 (P–O–C) cm–1
.
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1H NMR (400 MHz, CDCl3): δ = 1.30–1.39 (m, 12 H), 1.79–1.85 (m, 1
H), 1.98–2.09 (m, 3 H), 2.25–2.29 (m, 1 H), 2.51–2.54 (m, 1 H), 2.90–
3.00 (m, 1 H), 3.24–3.38 (m, 1 H), 4.18–4.43 (m, 9 H), 6.74 (q, J = 4 Hz,
1 H), 6.84 (td, J1 = 8 Hz, J2 = 4 Hz, 1 H), 7.45 (dd, J1 = 8.0 Hz, J2 = 2.4 Hz,
1 H), 9.04 (s, 1 H).
Tetraethyl (5-Bromo-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[in-
dole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (4)
White solid; yield: 0.54 g (93%); mp 198.0 °C.
IR (KBr): 1720.55 (C=O), 1225.82 (P=O), 1030.95 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.16–1.38 (m, 12 H), 1.75–1.81 (m, 1
H), 1.94–2.01 (m, 3 H), 2.17–2.23 (m, 1 H), 2.46–2.51 (m, 1 H), 2.82–
2.97 (m, 1 H), 3.19–3.33 (m, 1 H), 4.13–4.38 (m, 9 H), 6.69–6.74 (m, 1
H), 7.20 (d, J = 2.52 Hz, 1 H), 7.70 (s, 1 H), 9.53 (s, 1 H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.48 (d, JP–P = 11.34 Hz),
24.23 (d, JP–P = 14.58 Hz), 24.28 (d, JP–P = 14.58 Hz), 26.53 (d, JP–P
=
1.34 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 16.58 (P–O–C–CH3), 16.66 (P–O–C–
CH3), 16.77 (P–O–C–CH3), 16.82 (P–O–C–CH3), 24.45 (d, J = 4.02 Hz, P–
C–CH–CH2), 27.54 (P–C–CH–CH2–CH2), 41.39 (P–C–N–CH2), 45.80 (P–
C–CH2), 46.21 (t, J = 137.52 Hz, P–C–P), 62.56 (d, J = 5.94 Hz, P–O–
CH2), 62.79 (d, J = 6.44 Hz, P–O–CH2), 63.15 (d, J = 6.24 Hz, P–O–CH2),
63.53 (d, J = 6.24 Hz, P–O–CH2), 65.07 (d, J = 4.33 Hz, O=C–C), 69.82 (d,
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.44 (d, JP–P = 11.99 Hz),
24.18 (d, JP–P = 15.71 Hz), 24.24 (d, JP–P = 15.71 Hz), 26.19 (d, JP–P
=
11.99 Hz).
13C NMR (100.6 MHz, CDCl3):δ = 16.45 (P–O–C–CH3), 16.50 (P–O–C–
CH3), 16.56 (P–O–C–CH3), 16.70 (P–O–C–CH3), 24.19 (d, J = 5.73 Hz, P–
C–CH–CH2), 24.41 (P–C–CH–CH2–CH2), 41.17 (P–C–N–CH2), 45.80 (P–
C–CH2), 46.07 (t, J = 136.82 Hz, P–C–P), 62.39 (d, J = 6.14 Hz, P–O–
CH2), 62.77 (d, J = 6.34 Hz, P–O–CH2), 63.06 (d, J = 6.44 Hz, P–O–CH2),
63.48 (d, J = 6.14 Hz, P–O–CH2), 64.54 (d, J = 5.13 Hz, O=C–C), 69.63 (d,
J = 3.91 Hz, P–C–CH), 111.34, 115.07, 128.64, 131.63, 132.89, 140.96,
189.90 (C=O).
J = 2.72 Hz, P–C–CH), 110.26 (d, JF–C–CH–CH = 7.65 Hz), 113.61 (d, JF–C–CH
=
24.65 Hz), 115.51 (d, JF–C–CH = 23.74 Hz), 132.62 (d, JF–C–CH–C = 7.65 Hz),
137.45 (d, JF–C–CH–CH–C = 2.01 Hz), 159.52 (d, JF–C = 240.03 Hz), 180.62
(C=O).
MS (EI): m/z = 519.2 [M + H]+, 541.1 [M + Na]+, 517.6 [M – H]+.
Anal. Calcd for C22H33FN2O7P2: C, 52.97; H, 6.42; N, 5.40. Found: C,
53.01; H, 6.43; N, 5.44.
MS (EI): m/z = 579.2 [M + H]+, 577.7 [M – H]+.
Anal. Calcd for C22H33BrN2O7P2: C, 45.61; H, 5.74; N, 4.84. Found: C,
45.69; H, 5.70; N, 4.90.
Tetraethyl (5-Chloro-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[in-
dole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (3)
Tetraethyl (6-Chloro-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[in-
dole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (5)
White solid; yield: 0.51 g (95%); mp 194.5 °C.
IR (KBr): 1718.55 (C=O), 1222.84 (P=O), 1032.91 (P–O–C) cm–1
.
Orange oil; yield: 0.33 g (57%).
1H NMR (400 MHz, CDCl3): δ = 1.26–1.38 (m, 12 H), 1.76–1.82 (m, 1
H), 1.95–2.05 (m, 3 H), 2.20–2.23 (m, 1 H), 2.47–2.49 (m, 1 H), 2.76–
2.98 (m, 1 H), 3.20–3.34 (m, 1 H), 4.13–4.39 (m, 9 H), 6.73–6.78 (m, 1
H), 7.06–7.08 (m, 1 H), 7.59 (d, J = 4.0 Hz, 1 H), 9.44 (s, 1 H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.46 (d, JP–P = 11.83 Hz),
24.22, 26.21 (d, JP–P = 11.83 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 16.51 (P–O–C–CH3), 16.56 (P–O–C–
CH3), 16.63 (P–O–C–CH3), 16.69 (P–O–C–CH3), 24.24 (P–C–CH–CH2),
27.42 (P–C–CH–CH2–CH2), 41.21 (P–C–N–CH2), 45.73 (P–C–CH2),
46.06 (t, J = 137.72 Hz, P–C–P), 62.53 (d, J = 5.73 Hz, P–O–CH2), 62.79
(d, J = 4.83 Hz, P–O–CH2), 63.18 (d, J = 2.92 Hz, P–O–CH2), 63.54 (d,
J = 3.62 Hz, P–O–CH2), 64.69 (d, J = 2.31 Hz, O=C–C), 69.64 (P–C–CH),
110.86, 125.93, 127.89, 128.83, 132.51, 140.33, 180.23 (C=O).
IR (KBr): 1743.08 (C=O), 1247.10 (P=O), 1063.69 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 6.80 Hz, 3 H), 1.19–1.29 (m,
13 H), 1.90 (s, 1 H), 3.02 (tt, J1 = 23.20 Hz, J2 = 7.20 Hz, 1 H), 3.29 (s, 1
H), 3.56 (dd, J1 = 14.00 Hz, J2 = 6.80 Hz, 1 H), 4.03–4.14 (m, 8 H), 4.17–
4.23 (m, 2 H), 6.99 (d, J = 8.00 Hz, 2 H), 7.51 (t, J = 8.00 Hz, 1 H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 19.30.
13C NMR (100.6 MHz, CDCl3): δ = 15.69 (P–O–C–CH3), 15.72 (P–O–C–
CH3), 15.76 (P–O–C–CH3), 15.79 (P–O–C–CH3), 17.76, 20.39, 33.73 (t,
J = 131.99 Hz, P–C–P), 36.78, 49.39, 57.07, 62.66 (P–O–CH2), 62.73 (P–
O–CH2), 63.02 (P–O–CH2), 63.09 (P–O–CH2), 109.09, 114.13, 124.74,
132.94, 138.35, 151.12, 156.90, 179.37 (C=O).
MS (EI): m/z = 535.2 [M + H]+.
MS (EI): m/z = 535.2 [M + H]+, 557.1 [M + Na]+, 533.7 [M – H]+.
Anal. Calcd for C22H33ClN2O7P2: C, 49.40; H, 6.22; N, 5.24. Found: C,
49.45; H, 6.26; N, 5.28.
Anal. Calcd for C22H33ClN2O7P2: C, 49.40; H, 6.22; N, 5.24. Found: C,
49.46; H, 6.23; N, 5.26.
Tetraethyl (5-Methyl-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[in-
dole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (6)
Single crystals of compound 3 were obtained from EtOAc as solvent. A
suitable crystal was selected and examined on an Xcalibur, Atlas,
Gemini ultradiffractometer. The crystal was kept at 293(2) K during
data collection. By using Olex2,10a the structure was solved with the
Superflip structure-solution program10b using charge flipping, and re-
fined with the SHELX refinement package10c using least-squares mini-
mization.
Yellow oil; yield: 0.26 g (45%).
IR (KBr): 1720.55 (C=O), 1225.82 (P=O), 1030.95 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.12 (td, J1 = 7.20 Hz, J2 = 2.00 Hz, 1 H),
1.20–1.30 (m, 12 H), 1.72–1.76 (m, 1 H), 1.94–2.04 (m, 3 H), 2.17 (s, 3
H), 2.32–2.45 (m, 1 H), 2.74–2.93 (m, 1 H), 3.10–3.29 (m, 1 H), 3.94–
4.36 (m, 9 H), 6.60–6.65 (m, 1 H), 6.82 (d, J = 7.60 Hz, 1 H), 7.35 (s, 1
H), 9.32 (s, 1 H).
Monoclinic, space group P21/c (no. 14), a = 13.5990(8) Å,
b = 13.4103(6) Å, c = 14.5865(8) Å, β = 90.674(5)°, V = 2659.9(2) Å3,
Z = 4, T = 293(2) K, μ(Mo Kα) = 0.269 mm–1, Dcalc = 1.162 g/mm3;
13992 reflections measured (4.26 ≤ 2Θ ≤ 59.46), 6460 unique
(Rint = 0.0314), which were used in all calculations. The final R1 was
0.1587 [>2σ(I)] and wR2 was 0.3108 (all data).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.54 (d, JP–P = 11.99 Hz),
24.21 (d, JP–P = 15.71 Hz), 24.51 (d, JP–P = 15.71 Hz), 26.61 (d, JP–P
=
11.99 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 14.08 (P–O–C–CH3), 16.23 (P–O–C–
CH3), 16.35 (P–O–C–CH3), 16.40 (P–O–C–CH3), 21.06 (P–C–CH–CH2),
27.20 (P–C–CH–CH2–CH2), 41.14 (P–C–N–CH2), 45.41 (P–C–CH2),
46.07 (t, J = 138.12 Hz, P–C–P), 62.15 (P–O–CH2), 62.55 (P–O–CH2),
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62.83 (P–O–CH2), 63.19 (P–O–CH2), 64.11 (d, J = 5.23 Hz, O=C–C),
69.36 (d, J = 4.33 Hz, P–C–CH), 109.22, 126.02, 128.92, 130.59, 131.56,
139.31, 180.25 (C=O).
MS (EI): m/z = 515.2 [M + H]+, 513.1 [M – H]+.
Tetraethyl (2-Oxo-1,1′,2,5′,6′,7′,8′,8a′-octahydro-2′H-spiro[indole-
3,3′-indolizine]-1′,1′-diyl)bis(phosphonate) (9)
Orange oil; yield: 0.33 g (65%).
IR (KBr): 1742.28 (C=O), 1238.83 (P=O), 1063.21 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.03–1.42 (m, 15 H), 1.68–1.77 (m, 1
H), 1.93 (d, J = 2.80 Hz, 2 H), 2.11–2.30 (m, 1 H), 2.50–2.90 (m, 1 H),
3.09 (tt, J1 = 23.2 Hz, J2 = 6.8 Hz, 1 H), 3.98–4.25 (m, 10 H), 7.03–7.09
(m, 2 H), 7.48–7.56 (m, 2 H), 9.35 (s, 1 H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 19.58, 23.96 (d, JP–P = 16.20
Hz), 24.62 (d, JP–P = 16.20 Hz).
Anal. Calcd for C23H36N2O7P2: C, 53.69; H, 7.05; N, 5.44. Found: C,
53.71; H, 7.10; N, 5.50.
Tetraethyl (1-Benzyl-5-methyl-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahy-
drospiro[indole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (7)
Yellow oil; yield: 0.28 g (47%).
IR (KBr): 1631.05 (C=O), 1385.09 (P=O), 1095.75 (P–O–C) cm–1
.
13C NMR (100.6 MHz, CDCl3): δ = 15.85 (P–O–C–CH3), 15.92 (P–O–C–
CH3), 16.10 (P–O–C–CH3), 16.15 (P–O–C–CH3), 23.99, 24.75, 28.53 (d,
J = 5.83 Hz, P–C–CH–CH2), 33.93 (t, J = 131.89 Hz, P–C–P), 36.80 (t,
J = 2.82 Hz, P–C–CH2), 38.14 (P–C–CH–N–CH2), 62.78 (P–O–CH2),
62.84 (P–O–CH2), 63.16 (P–O–CH2), 63.23 (P–O–CH2), 63.86 (d,
J = 4.83 Hz, P–C–CH), 69.85 (d, J = 6.04 Hz, O=C–C), 110.80, 123.46,
124.92, 130.95, 138.15, 141.90, 182.69 (C=O).
1H NMR (400 MHz, CDCl3): δ = 1.14 (t, J = 7.20 Hz, 1 H), 1.22–1.33 (m,
11 H), 1.75–1.81 (m, 1 H), 1.92–2.08 (m, 3 H), 2.20 (s, 3 H), 2.44–2.48
(m, 1 H), 2.79 (d, J = 25.20 Hz, 1 H), 2.96 (ddd, J1 = 8.00 Hz, J2 = 16.8
Hz, J3 = 18.4 Hz, 1 H), 3.17–3.37 (m, 1 H), 3.97–4.44 (m, 9 H), 4.73 (dd,
J1 = 82.8 Hz, J2 = 15.6 Hz, 2 H), 6.40 (d, J = 8.00 Hz, 1 H), 6.83 (d,
J = 7.60 Hz, 1 H), 7.09–7.19 (m, 5 H), 7.44 (s, 1 H).
MS (EI): m/z = 515.2 [M + H]+.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.47 (d, JP–P = 12.15 Hz),
24.13 (d, JP–P = 15.55 Hz), 24.43 (d, JP–P = 15.55 Hz), 26.62 (d, JP–P
12.15 Hz).
=
Anal. Calcd for C23H36N2O7P2: C, 53.69; H, 7.05; N, 5.44. Found: C,
53.73; H, 7.06; N, 5.48.
13C NMR (100.6 MHz, CDCl3): δ = 14.08 (P–O–C–CH3), 16.40 (P–O–C–
CH3), 16.44 (P–O–C–CH3), 16.51 (P–O–C–CH3), 21.02 (CH3), 24.05 (d,
J = 4.43 Hz, P–C–CH–CH2), 27.26 (P–C–CH–CH2–CH2), 41.03 (P–C–CH–
N–CH2), 43.22 (PhCH2), 45.81 (P–C–CH2), 45.96 (t, J = 138.12 Hz, P–C–
P), 62.03 (P–O–CH2), 62.47 (P–O–CH2), 62.79 (P–O–CH2), 63.23 (P–O–
CH2), 63.50 (d, J = 5.83 Hz, O=C–C), 69.48 (d, J = 4.63 Hz, P–C–CH),
108.25, 125.95, 126.97, 127.05, 127.31, 128.57, 128.60, 128.92,
129.93, 132.22, 136.07, 140.28, 177.65 (C=O).
Tetraethyl (5-Fluoro-2-oxo-1,1′,2,5′,6′,7′,8′,8a′-octahydro-2′H-
spiro[indole-3,3′-indolizine]-1′,1′-diyl)bis(phosphonate) (10)
Yellow oil; yield: 0.24 g (45%).
IR (KBr): 1752.12 (C=O), 1252.81 (P=O), 1064.69 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.15–1.95 (m, 16 H), 1.95 (d, J = 10.8
Hz, 1 H), 3.03 (tt, J1 = 24.00 Hz, J2 = 7.2 Hz, 1 H), 4.00–4.24 (m, 13 H),
7.07 (dd, J1 = 8.4 Hz, J2 = 3.2 Hz, 1 H), 7.22 (dd, J1 = 7.8 Hz, J2 = 3.2 Hz, 1
H), 7.29 (td, J1 = 8.8 Hz, J2 = 2.8 Hz, 1 H), 9.21 (s, 1 H).
MS (EI): m/z = 605.2 [M + H]+.
Anal. Calcd for C30H42N2O7P2: C, 59.60; H, 7.00; N, 4.63. Found: C,
59.65; H, 7.06; N, 4.68.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 19.50.
13C NMR (100.6 MHz, CDCl3): δ = 13.93, 15.94 (P–O–C–CH3), 15.98 (P–
O–C–CH3), 16.01 (P–O–C–CH3), 16.05 (P–O–C–CH3), 20.58, 20.72,
34.01 (t, J = 131.89 Hz, P–C–P), 37.10 (t, J = 3.01 Hz, P–C–CH2), 60.09
(P–C–CH–N–CH2), 62.03 (d, J = 7.14 Hz, O=C–C), 62.50 (t, J = 2.92 Hz,
P–C–CH), 62.79 (P–O–CH2), 62.85 (P–O–CH2), 63.19 (P–O–CH2), 63.26
(P–O–CH2), 110.26 (d, JF–C–CH–CH = 7.14 Hz), 111.96 (d, JF–C–CH = 24.24
Hz), 124.64 (d, JF–C–CH = 24.14 Hz), 146.45 (d, JF–C–CH–C = 1.91 Hz),
157.85 (d, JF–C–CH–CH–C = 1.41 Hz), 160.17 (d, JF–C = 245.56 Hz), 182.23
(C=O).
Tetraethyl (1-Benzyl-2-oxo-1,1′,2,2′,5′,6′,7′,7a′-octahydrospiro[in-
dole-3,3′-pyrrolizine]-1′,1′-diyl)bis(phosphonate) (8)
Yellow oil; yield: 0.26 g (44%).
IR (KBr): 1715.24 (C=O), 1248.00 (P=O), 1031.65 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.08–1.29 (m, 13 H), 1.75–1.79 (m, 1
H), 1.89–2.08 (m, 3 H), 2.15–2.20 (m, 1 H), 2.43 (br s, 1 H), 2.86–3.00
(m, 1 H), 3.16–3.37 (m, 1 H), 3.89–4.43 (m, 9 H), 4.72 (dd, J1 = 84.40
Hz, J2 = 15.60 Hz, 2 H), 6.50 (d, J = 7.70 Hz, 1 H), 6.90 (t, J = 7.20 Hz, 1
H), 7.00 (t, J = 7.60 Hz, 1 H), 7.08–7.16 (m, 4 H), 7.61 (d, J = 7.20 Hz, 1
H).
MS (EI): m/z = 533.2 [M + H]+.
Anal. Calcd for C23H35FN2O7P2: C, 51.88; H, 6.63; N, 5.26. Found: C,
51.98; H, 6.66; N, 5.29.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.51 (d, JP–P = 11.18 Hz),
24.19 (d, JP–P = 14.90 Hz), 24.36 (d, JP–P = 14.90 Hz), 26.74 (d, JP–P
11.18 Hz).
=
Tetraethyl (5-Chloro-2-oxo-1,1′,2,5′,6′,7′,8′,8a′-octahydro-2′H-
spiro[indole-3,3′-indolizine]-1′,1′-diyl)bis(phosphonate) (11)
13C NMR (100.6 MHz, CDCl3): δ = 14.00 (P–O–C–CH3), 16.31 (P–O–C–
CH3), 16.36 (P–O–C–CH3), 16.46 (P–O–C–CH3), 24.05 (d, J = 3.92 Hz, P–
C–CH–CH2), 27.20 (P–C–CH–CH2–CH2), 41.08 (P–C–CH–N–CH2), 43.14
(PhCH2), 45.62 (P–C–CH2), 45.88 (t, J = 138.12 Hz, P–C–P), 62.08 (P–
O–CH2), 62.39 (P–O–CH2), 62.83 (P–O–CH2), 63.11 (P–O–CH2), 64.08
(d, J = 5.03 Hz, O=C–C), 69.43 (d, J = 3.92 Hz, P–C–CH), 108.46, 122.76,
125.18, 126.98, 127.30, 128.53, 128.65, 129.78, 135.84, 142.56,
177.69 (C=O).
Dark-red oil; yield: 0.22 g (40%).
IR (KBr): 1743.79 (C=O), 1249.41 (P=O), 1063.11 (P–O–C) cm–1
1H NMR (400 MHz, CDCl3): δ = 1.06–1.18 (m, 15 H), 1.86 (d, J = 10.8
Hz, 1 H), 2.70 (s, 1 H), 2.81 (s, 1 H), 2.94 (tt, J1 = 23.2 Hz, J2 = 7.2 Hz, 1
H), 3.90–4.14 (m, 13 H), 6.97 (d, J = 8.4 Hz, 1 H), 7.37 (s, 1 H), 7.43 (d,
J = 8.4 Hz, 1 H).
.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 19.45.
MS (EI): m/z = 591.2 [M + H]+.
13C NMR (100.6 MHz, CDCl3): δ = 16.03 (P–O–C–CH3), 16.07 (P–O–C–
CH3), 16.10 (P–O–C–CH3), 16.14 (P–O–C–CH3), 20.70, 20.84, 29.48,
31.26, 34.05 (t, J = 131.89 Hz, P–C–P), 36.38, 37.17 (t, J = 3.02 Hz, P–C–
Anal. Calcd for C29H40N2O7P2: C, 58.98; H, 6.83; N, 4.74. Found: C,
59.05; H, 6.79; N, 4.68.
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CH2), 60.18 (O=C–C), 62.89 (P–O–CH2), 62.96 (P–O–CH2), 63.29 (P–O–
CH2), 63.36 (P–O–CH2), 112.44, 124.83, 129.25, 137.55, 148.71,
157.58, 181.85 (C=O).
MS (EI): m/z = 549.2 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 1.25–1.32 (m, 16 H), 1.71–1.77 (m, 1
H), 1.93 (d, J = 4.00 Hz, 1 H), 2.14–2.31 (m, 2 H), 2.54–2.70 (m, 1 H),
2.76–2.90 (m, 1 H), 3.44 (dd, J1 = 14.00 Hz, J2 = 6.80 Hz, 1 H), 3.73–
3.89 (m, 1 H), 4.04–4.12 (m, 8 H), 4.75 (dd, J1 = 68.00 Hz, J2 = 15.60 Hz,
2 H), 6.52 (d, J = 7.60 Hz, 1 H), 6.91–6.96 (m, 1 H), 7.00–7.06 (m, 1 H),
7.12–7.22 (m, 3 H), 7.20 (d, J = 7.20 Hz, 1 H), 7.56 (d, J = 7.20 Hz, 1 H).
Anal. Calcd for C23H35ClN2O7P2: C, 50.33; H, 6.43; N, 5.10. Found: C,
50.39; H, 6.46; N, 5.14.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 21.29 (d, J1 = 26.73 Hz), 24.03
(d, J2 = 16.04 Hz), 24.64 (d, J2 = 15.88 Hz).
Tetraethyl (5-Bromo-2-oxo-1,1′,2,5′,6′,7′,8′,8a′-octahydro-2′H-
spiro[indole-3,3′-indolizine]-1′,1′-diyl)bis(phosphonate) (12)
13C NMR (100.6 MHz, CDCl3):δ = 16.03 (P–O–C–CH3), 16.15 (P–O–C–
CH3), 16.29 (P–O–C–CH3), 16.35 (P–O–C–CH3), 24.04 (CH2), 24.89
(CH2), 28.66 (d, J = 5.23 Hz, P–C–CH–CH2), 38.70 (t, J = 3.42 Hz, P–C–
CH2), 43.04 (PhCH2), 46.12 (P–C–CH–N–CH2), 49.32 (t, J = 136.01 Hz,
P–C–P), 61.90 (P–O–CH2), 62.47 (P–O–CH2), 62.66 (P–O–CH2), 63.24
(P–O–CH2), 64.18 (d, J = 4.63 Hz, P–C–CH), 69.69 (d, J = 5.23 Hz, O=C–
C), 108.18, 122.82, 124.93, 127.01, 127.26, 128.47, 128.55, 135.89,
142.89, 149.07, 177.36 (C=O).
Yellow oil; yield: 0.27 g (45%).
IR (KBr): 1745.30 (C=O), 1254.94 (P=O), 1025.92 (P–O–C) cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.16–1.30 (m, 16 H), 1.96 (s, 2 H), 3.01
(tt, J1 = 23.2 Hz, J2 = 6.80 Hz, 1 H), 4.00–4.23 (m, 13 H), 6.99 (d, J = 8.40
Hz, 1 H), 7.61 (d, J = 2.00 Hz, 1 H), 7.67 (dd, J1 = 8.40 Hz, J2 = 2.00 Hz, 1
H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 19.45.
MS (EI): m/z = 605.2 [M + H]+.
13C NMR (100.6 MHz, CDCl3): δ = 14.10, 16.01 (P–O–C–CH3), 16.15 (P–
O–C–CH3), 16.18 (P–O–C–CH3), 16.22 (P–O–C–CH3), 20.91, 34.18 (t,
J = 131.48 Hz, P–C–P), 34.35, 37.28 (t, J = 2.92 Hz, P–C–CH2), 60.24
(O=C–C), 62.90 (P–O–CH2), 62.97 (P–O–CH2), 63.31 (P–O–CH2), 63.38
(P–O–CH2), 72.73, 112.86, 116.37, 118.71, 127.80, 140.42, 149.23,
157.46, 181.75 (C=O).
Anal. Calcd for C30H42N2O7P2: C, 59.60; H, 7.00; N, 4.63. Found: C,
59.65; H, 7.06; N, 4.69.
Tetraethyl (1′-Methyl-2-oxo-1,2-dihydrospiro[indole-3,2′-pyrroli-
dine]-4′,4′-diyl)bis(phosphonate) (15)
Yellowish oil; yield: 0.46 g (77%).
MS (EI): m/z = 593.2 [M + H]+.
IR (KBr): 1745.30 (C=O), 1254.94 (P=O), 1025.92 (P–O–C).
Anal. Calcd for C23H35BrN2O7P2: C, 46.55; H, 5.95; N, 4.72. Found: C,
46.58; H, 5.99; N, 4.79.
1H NMR (400 MHz, CDCl3): δ = 1.22–1.35 (m, 14 H), 2.02 (s, 3 H), 3.09
(tt, J1 = 24.00 Hz, J2 = 7.20 Hz, 1 H), 4.09–4.29 (m, 10 H), 7.06–7.12 (m,
2 H), 7.56–7.61 (m, 2 H).
Tetraethyl (1-Benzyl-5-methyl-2-oxo-1,1′,2,5′,6′,7′,8′,8a′-octahy-
dro-2′H-spiro[indole-3,3′-indolizine]-1′,1′-diyl)bis(phosphonate)
(13)
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 19.74.
13C NMR (100.6 MHz, CDCl3): δ = 16.38 (P–O–C–CH3), 16.42 (P–O–C–
CH3), 16.44 (P–O–C–CH3), 16.49 (P–O–C–CH3), 21.24 (CH3), 34.55 (t,
J = 131.99 Hz, P–C–P), 37.41 (t, J = 3.42 Hz, CH2), 60.59 (CH2), 62.88 (t,
J = 2.82 Hz, O=C–C), 63.15 (P–O–CH2), 63.22 (P–O–CH2), 63.55 (P–O–
CH2), 63.62 (P–O–CH2), 111.21, 123.90, 125.54, 138.54, 150.76,
158.46, 183.24 (C=O).
Yellow oil; yield: 0.24 g (40%).
IR (KBr): 1715.24 (C=O), 1248.00 (P=O), 1031.65 (P–O–C).
1H NMR (400 MHz, CDCl3): δ = 1.12–1.39 (m, 16 H), 1.69–1.78 (m, 1
H), 1.91 (m, 1 H), 2.12–2.27 (m, 5 H), 2.52–2.64 (m, 1 H), 2.74–3.02
(m, 1 H), 3.78 (dt, J1 = 33.60 Hz, J2 = 12.00 Hz, 1 H), 3.98–4.20 (m, 9 H),
4.70 (dd, J1 = 67.20 Hz, J2 = 15.20 Hz, 2 H), 6.38 (d, J = 7.60 Hz, 1 H),
6.81 (d, J = 6.00 Hz, 1 H), 6.98–7.15 (m, 4 H), 7.35 (s, 1 H).
MS (EI): m/z = 475.2 [M + H]+.
Anal. Calcd for C20H32N2O7P2: C, 50.63; H, 6.80; N, 5.90. Found: C,
50.68; H, 6.86; N, 5.95.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.78 (d, JP–P = 12.96 Hz),
24.15 (d, JP–P = 16.20 Hz), 24.85 (d, JP–P = 16.20 Hz), 27.02 (d, JP–P
12.96 Hz).
=
Tetraethyl (5-Fluoro-1′-methyl-2-oxo-1,2-dihydrospiro[indole-
3,2′-pyrrolidine]-4′,4′-diyl)bis(phosphonate) (16)
13C NMR (100.6 MHz, CDCl3): δ = 16.15 (P–O–C–CH3), 16.34 (P–O–C–
CH3), 16.40 (P–O–C–CH3), 16.56 (P–O–C–CH3), 21.00 (CH3), 24.18
(CH2), 28.83 (d, J = 5.23 Hz, P–C–CH–CH2), 29.55 (CH2), 38.87 (t,
J = 3.92 Hz, P–C–CH2), 43.17 (PhCH2), 49.54 (t, J = 136.11 Hz, P–C–P),
60.20 (P–C–CH–N–CH2), 61.90 (P–O–CH2), 62.57 (P–O–CH2), 62.64
(P–O–CH2), 62.77 (P–O–CH2), 63.37 (d, J = 6.64 Hz, P–C–CH), 69.92 (d,
J = 5.13 Hz, O=C–C), 108.04, 125.78, 127.10, 127.31, 128.55, 128.90,
130.55, 132.32, 136.11, 140.64, 177.44 (C=O).
Yellow oil; yield: 0.20 g (40%).
IR (KBr): 1750.30 (C=O), 1244.94 (P=O), 1035.92 (P–O–C).
1H NMR (400 MHz, CDCl3): δ = 1.16–1.33 (m, 12 H), 2.01 (s, 3 H),
2.36–3.03 (m, 2 H), 3.43–3.51 (m, 1 H), 3.71–3.90 (m, 1 H), 4.02–4.27
(m, 8 H), 6.65–7.05 (m, 2 H), 7.41 (dd, J1 = 8.40 Hz, J2 = 2.40 Hz, 1 H),
9.16 (s, 1 H).
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.81 (d, J = 11.34 Hz), 26.51
(d, J = 11.34 Hz).
MS (EI): m/z = 619.2 [M + H]+.
Anal. Calcd for C31H44N2O7P2: C, 60.19; H, 7.17; N, 4.53. Found: C,
60.26; H, 7.19; N, 4.59.
13C NMR (100.6 MHz, CDCl3): δ = 16.37 (P–O–C–CH3), 16.50 (P–O–C–
CH3), 16.55 (P–O–C–CH3), 16.63 (P–O–C–CH3), 21.12 (CH3), 40.01 (t,
J = 3.02 Hz, CH2), 45.63 (t, J = 138.93 Hz, P–C–P), 57.56 (d, J = 4.33 Hz,
CH2), 63.21 (P–O–CH2), 63.28 (P–O–CH2), 63.40 (P–O–CH2), 63.46 (P–
O–CH2), 71.34 (d, J = 5.03 Hz, O=C–C), 110.22 (d, J = 24.75 Hz), 113.93
(d, J = 24.75 Hz), 115.52 (d, J = 23.64 Hz), 132.05 (d, J = 7.75 Hz),
137.71 (d, J = 1.91 Hz), 160.59 (d, J = 240.03 Hz), 179.629 (C=O).
Tetraethyl (1-Benzyl-2-oxo-1,1′,2,5′,6′,7′,8′,8a′-octahydro-2′H-
spiro[indole-3,3′-indolizine]-1′,1′-diyl)bis(phosphonate) (14)
Brown oil; yield: 0.21 g (35%).
IR (KBr): 1715.90 (C=O), 1247.89 (P=O), 1034.82 (P–O–C) cm–1
.
MS (EI): m/z = 493.2 [M + H]+.
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Anal. Calcd for C20H31FN2O7P2: C, 48.78; H, 6.35; N, 5.69. Found: C,
48.87; H, 6.36; N, 5.77.
57.46 (d, J = 4.53 Hz, CH2), 62.59 (P–O–CH2), 63.00 (P–O–CH2), 63.10
(P–O–CH2), 63.22 (P–O–CH2), 70.49 (d, J = 3.82 Hz, O=C–C), 108.52,
123.00, 125.61, 127.14, 128.61, 128.84, 129.37, 135.88, 142.79,
149.26, 177.12 (C=O).
Tetraethyl (5-Chloro-1′-methyl-2-oxo-1,2-dihydrospiro[indole-
3,2′-pyrrolidine]-4′,4′-diyl)bis(phosphonate) (17)
MS (EI): m/z = 565.2 [M + H]+.
Yellow oil; yield: 0.25 g (50%).
Anal. Calcd for C27H38N2O7P2: C, 57.44; H, 6.78; N, 4.96. Found: C,
57.55; H, 6.86; N, 4.99.
IR (KBr): 1718.56 (C=O), 1284.94 (P=O), 1070.16 (P–O–C).
1H NMR (400 MHz, CDCl3): δ = 1.15–1.34 (m, 12 H), 1.96 (s, 2 H), 2.03
(s, 1 H), 2.60–3.03 (m, 2 H), 3.43–3.51 (m, 1 H), 3.71–3.85 (m, 1 H),
3.97–4.26 (m, 8 H), 6.68–6.83 (m, 1 H), 6.99–7.10 (m, 1 H), 7.21–7.41
(m, 1 H), 9.63 (s, 1 H).
1′,2′,3′,5a′,6′,7′,8′,10a′-Octahydrodispiro[indole-3,5′-dipyrrolo[1,2-
a:1′,2′-d]pyrazine-10′,3′′-indole]-2,2′′(1H,1′′H)-dione (Compound
m)
White solid; yield: 0.28 g (70%); mp 169.6 °C.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.73 (d, J = 12.31 Hz), 26.29
(d, J = 12.31 Hz).
1H NMR (400 MHz, DMSO): δ = 1.34–1.41 (m, 2 H), 1.51–1.66 (m, 3
H), 1.75–1.77 (m, 2 H), 1.99 (q, J = 8.40 Hz, 2 H), 2.36 (t, J = 8.40 Hz, 2
H), 3.16 (d, J = 5.20 Hz, 1 H), 3.48–3.55 (m, 2 H), 6.43 (d, J = 7.60 Hz, 2
H), 6.80 (t, J = 7.60 Hz, 2 H), 7.00 (t, J = 7.60 Hz, 2 H), 7.20 (d, J = 7.20
Hz, 2 H), 10.18 (s, 2 H).
13C NMR (100.6 MHz, DMSO): δ = 20.57, 27.14, 46.98, 58.40, 67.68,
108.86, 121.08, 125.86, 126.26, 129.04, 142.36, 175.30.
13C NMR (100.6 MHz, CDCl3): δ = 16.17 (P–O–C–CH3), 16.23 (P–O–C–
CH3), 16.29 (P–O–C–CH3), 16.35 (P–O–C–CH3), 20.90 (CH3), 39.77 (t,
J = 2.82 Hz, CH2), 45.10 (t, J = 137.02 Hz, P–C–P), 57.29 (d, J = 4.43 Hz,
CH2), 63.00 (P–O–CH2), 63.07 (P–O–CH2), 63.23 (P–O–CH2), 63.27 (P–
O–CH2), 70.92 (d, J = 5.03 Hz, O=C–C), 110.70, 125.91, 128.78, 131.83,
140.64, 168.01, 178.94 (C=O).
MS (EI): m/z = 509.2 [M + H]+.
MS (EI): m/z =401.2 [M + H]+, 423.1 [M + Na]+, 399.6 [M – H]+.
Anal. Calcd for C20H31ClN2O7P2: C, 47.21; H, 6.14; N, 5.51. Found: C,
47.25; H, 6.06; N, 5.59.
Anal. Calcd for C24H24N4O2: C, 71.98; H, 6.04; N, 13.99. Found: C,
71.09; H, 6.06; N, 14.04.
Tetraethyl (5-Bromo-1′-methyl-2-oxo-1,2-dihydrospiro[indole-
3,2′-pyrrolidine]-4′,4′-diyl)bis(phosphonate) 18
Acknowledgment
Yellow oil; yield: 0.47 g (85%).
IR (KBr): 1728.06 (C=O), 1228.59 (P=O), 1064.14 (P–O–C) cm–1
1H NMR (400 MHz, CDCl3): δ = 1.17–1.34 (m, 12 H), 1.96 (s, 1 H), 2.03
(s, 2 H), 2.65–3.12 (m, 2 H), 3.42–3.52 (m, 1 H), 3.70–3.85 (m, 1 H),
4.01–4.25 (m, 8 H), 6.72 (d, J = 8.00 Hz, 1 H), 7.12 (dd, J1 = 8.40 Hz,
J2 = 2.00 Hz, 1 H), 7.69 (d, J = 0.8 Hz, 1 H), 9.59 (s, 1 H).
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (No. 21162008), the Graduate Innovative
Research Project of Hainan Normal University (Nos. Hsyx2014-38 and
Hsyx2014-39), and the Undergraduate Innovative Research Project of
Hainan Normal University (Nos. cxcyxj2015004 and cxcyxj2015024).
.
31P NMR (162.0 MHz, CDCl3/H3PO4): δ = 23.75 (d, J = 12.64 Hz), 26.28
(d, J = 12.64 Hz).
Supporting Information
13C NMR (100.6 MHz, CDCl3): δ = 16.22 (P–O–C–CH3), 16.36 (P–O–C–
CH3), 16.42 (P–O–C–CH3), 16.52 (P–O–C–CH3), 20.96 (CH3), 39.84 (t,
J = 4.02 Hz, CH2), 45.45 (t, J = 138.43 Hz, P–C–P), 57.32 (d, J = 4.02 Hz,
CH2), 63.01 (P–O–CH2), 63.17 (P–O–CH2), 63.25 (P–O–CH2), 63.36 (P–
O–CH2), 70.90 (d, J = 4.73 Hz, O=C–C), 111.23, 114.95, 128.69, 131.70,
132.27, 141.16, 178.72 (C=O).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560463.
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MS (EI): m/z = 553.2 [M + H]+.
Anal. Calcd for C20H31BrN2O7P2: C, 43.41; H, 5.65; N, 5.06. Found: C,
43.45; H, 5.66; N, 5.09.
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Tetraethyl (1-Benzyl-1′-methyl-2-oxo-1,2-dihydrospiro[indole-
3,2′-pyrrolidine]-4′,4′-diyl)bis(phosphonate) (19)
References
Yellow oil; yield: 0.25 g (45%).
IR (KBr): 1713.13 (C=O), 1247.40 (P=O), 1065.78 (P–O–C) cm–1
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(s, 2 H), 2.69–2.97 (m, 1 H), 3.48–3.56 (m, 1 H), 3.66–3.92 (m, 1 H),
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