1,3-Dipolar Cycloaddition of 3-Amino Oxindole-Based Azomethine Ylides and O-Vinylphosphonylated Salicylaldehydes for Diastereoselective Synthesis of Oxindole Spiro-P, N-polycyclic Heterocycles

Article abstract of DOI:10.1055/s-0039-1691597

An efficient stereoselective assembly strategy for the construction of pyrrolidin-2,3′-oxindole cis-fused phosphadihydrocoumarins was established. The process involves the condensation of O-vinylphosphonylated salicylaldehydes and 3-amino oxindoles followed by intermolecular cycloaddition with high diastereoselectivity and atom economy.

Full text of DOI:10.1055/s-0039-1691597

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–K
paper
A
en
T. Huang et al.
Paper
Synthesis
1,3-Dipolar Cycloaddition of 3-Amino Oxindole-Based Azomethine
Ylides and O-Vinylphosphonylated Salicylaldehydes for Diastereo-
selective Synthesis of Oxindole Spiro-P,N-polycyclic Heterocycles
Tiao Huanga
Li Liua
R3
R4
Qinghe Wanga
Mingshu Wu*a
Dulin Kong*b
O
O
NH2•HCl
O
N
R2
P
H
R4
CHO
4 Å MS
NaHCO3
0
0
0
0-0
0
0
2-0
6
1
1-
8
2
7
5
R1
OEt
HN
H
O
R1
+
THF, r.t., 4 h
O
P
O
a Key Laboratory of Tropical Medicinal Resource Chemistry of
the Ministry of Education, Hainan Normal University, Haikou
571158, P. R. of China
wmsh@hainnu.edu.cn
b School of Pharmaceutical Sciences, Hainan Medical University,
Haikou 571199, Hainan Province, P. R. of China
R3
OEt
N
R2
28 examples, up to 96% yield
Only cis-selective intarmolecular dipolar cycloaddition
R = MeO, Cl, Br, F, alkyl, H Bn
Three new bonds (C–N, 2 C–C), two new P,N-heterocycles
Mild reaction conditions
Potential biological activity of the products
Received: 04.11.2019
Accepted after revision: 21.01.2020
Published online: 12.02.2020
egy for drug discovery, we envisioned that the integration
of these two frameworks of pyrrolidin-2,3′-oxindoles and
phosphadihydrocoumarins would produce structurally
complex and diverse new molecules.
DOI: 10.1055/s-0039-1691597; Art ID: ss-2019-h0613-op
Abstract An efficient stereoselective assembly strategy for the con-
struction of pyrrolidin-2,3′-oxindole cis-fused phosphadihydrocouma-
rins was established. The process involves the condensation of O-vinyl-
phosphonylated salicylaldehydes and 3-amino oxindoles followed by
intermolecular cycloaddition with high diastereoselectivity and atom
economy.
H
N
N
OH
H
O
O
O
H
N
Cl
NH
F
O
O
Key words 3-amino oxindole, azomethine ylide, dipolar cycloaddi-
tion, pyrrolidin-2,3′-oxindoles, cis-fused phosphadihydrocoumarins, O-
vinylphosphonylated salicylaldehyde
N
H
MeO
N
H
Cl
a) MDM2-p53 inhibitors
b) Spirotryprostatin A
O
O
O
RO
RO
O
Important challenges of contemporary synthetic chem-
istry include the creation of complex molecular entities
with potential bioactivities by employing atom- and step-
economical reaction routes. The application of efficient
convergent assembly strategies should be one of the most
useful ways of achieving these goals.1
P
P
OCH3
OR
OH
H3C
C
CH3
O
NH CH3
OR
c) Phostine Antitumor
d) Antimicrobial
Figure 1 Representative bioactive molecules containing the spiro-
[pyrrolidin-2,3′-oxindole] or oxaphosphinanes core
Pyrrolidin-2,3′-oxindoles, as a representative of spiro-
oxindole compounds, are notable heterocyclic frameworks
because of their widespread occurrence in numerous natu-
ral products2 and synthetic compounds exhibiting versatile
bioactivities, such as anticancer,3 antibacterial,4 and MDM2
inhibitor action (Figure 1).5 On the other hand, phosphorus-
containing heterocyclic compounds have also been fascinat-
ing because of their ubiquity in biological systems and be-
cause new bioactivities have been discovered.6 For example,
phosphadihydrocoumarin or phosphonosugar possess
phosphinolactone structural cores, which can be regarded
as a surrogate of lactol and have shown various biological
activities, such as antitumor,7 phosphorylase inhibitor,8 and
antiproliferative activities (Figure 1).9 Considering that as-
sembling these dissimilar privileged scaffolds in a single
framework to yield hybrid molecules is an interesting strat-
Owing to its significant medicinal implications, many
methods have been developed for the synthesis of spirocy-
clic oxindole over the past decades.10 Among the varied
synthetic approaches to these compounds, the 1,3-dipolar
cycloaddition reactions of 3-aminooxindole-derived
azomethine ylides with various dipolarophiles such as ni-
troalkenes,11
,-enones,12
,-ynones,13
3-nitro-
chromenes14 and indolenines15 for the construction of the
spirocyclic frameworks has provided the most efficient and
direct methods (Scheme 1). However, reports on a consecu-
tive condensation/intramolecular cycloaddition of 3-ami-
nooxindole-derived azomethine ylides and bifunctional di-
polarophiles to access the oxindole-fused spiro-P,N-hetero-
cycles are scarce. Our group has been interested in using
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Huang et al.
Paper
Synthesis
O-vinyl phosphonylated salicylaldehydes as bifunctional di-
polarophiles though a condensation/intramolecular cyclo-
addition cascade reaction for the synthesis of complex
phosphorus-containing fused heterocycles.16 Herein, we
describe our latest work on condensation of O-vinylphoph-
onylated salicylaldehydes and 3-aminooxindoles followed
by intramolecular 1,3-dipoar cycloaddition to efficiently
generate such scaffolds with high diastereoselectivity
(Scheme 1).
Originally, the reaction conditions from our previously
published work16 were adopted as the starting point for the
development of this cascade condensation/intramolecular
cycloaddition of 3-amino oxindole hydrochloride salt 1a
and O-vinylphosphylated salicylaldehyde 2a. The reaction
was carried out at room temperature in THF for 4 hours; the
base (NaHCO3) was used to scavenge HCl. To our delight, the
product 3a was obtained in 66% yield with high diastereo-
selectivity (99:1 d.r.; Table 1, entry 1), which prompted us
Previous work: cycloaddition of 3-amino oxindole-derived azomethine ylides with electron-deficient alkenes
a) Zhang et al.11
R2
HN
NO2
R3
NH2•HCl
O
N
R1
R1
R1
Et3N
NO2
R2CHO
+
+
R3
O
CHCl3, reflux
N
R2
R3
HN
b) Wang et al.12
O
R5
NH2•HCl
O
N
R1
R4
O
NaHCO3
R2
R2
O
R3CHO
R4
R5
+
+
+
+
N
R1
MgSO4, CH2Cl2, r.t.
c) Wang et al.13
O
R3
HN
CPA 1g (5 mol%)
MgSO4 (200 mg)
NaHCO3 (1.5 equiv)
Ph
NH2•HCl
O
N
R2
R1
R1
O
Ph
O
R3CHO
Ph
+
Ph
CH2Cl2, 25 °C
N
R2
d) Wang et al.14
R2
NO2
catalytic agent
NaHCO3
(1.5 equiv)
X
NH2•HCl
HN
R1
NO2
R1
R3
R2CHO
O
+
N
3 Å MS, toluene, 25 °C
35 h
X
O
N
Bn
Bn
R3
HN
e) Zhu et al.15
N
NH2•HCl
O
R4
R4
NaHCO3
R2
O
R3CHO
R2
+
+
N
R1
N
R1
CH2Cl2, r.t.
N
f ) This work: intramolecular cycloadditions of 3-amino oxindole-derived azomethine ylides with
O-vinylphosphylated salicylaldehydes
R3
R4
NH•HCl
O
4 Å MS
O
R4
CHO
P
NaHCO3
H
R1
O
OEt
+
HN
H
O
N
R2
THF, r.t., 4 h
O
P
O
R3
R1
OEt
N
R2
1
2
3
Scheme 1 Previous and proposed work
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

C
T. Huang et al.
Paper
Synthesis
to further improve the reaction conditions. First, we tried to
use different type of additives in THF (entries 2–8). When
molecular sieves (4 Å) were added into the reaction system,
the yield of 3a clearly increased (entry 2), which indicated
that molecular sieves were beneficial, probably by promot-
ing the dehydration during the condensation of 1a and 2a.
Subsequently, considering that the Lewis acidic catalyst
might promote the reaction, we replaced molecular sieves
4 Å with Cu (CF3SO3)2, CuCl2, CuI, ZnCl2, AlCl3, and BF3·Et2O,
but found no significant improvement in the yield (entries
3–8). Next, we tested the effect of the temperature on the
condensation/intramolecular cyclization (entries 9 and 10).
Lowering the reaction temperature to 10 °C led to a lower
yield (entry 10), while elevating the reaction temperature
to 50 °C resulted in a slight decrease of the yield (entry 9).
Finally, we also tried other solvents including CH2Cl2, CHCl3,
CH3CN, CH3OH and toluene at room temperature in the
presence of molecular sieves (4 Å), but they did not give
more satisfactory results than in THF (entries 11–15). Thus,
the optimal reaction conditions were selected as summa-
rized in Table 1, entry 2. Notably, these conditions seeming-
ly have no clear influence on the diastereomeric ratios.
After establishing the optimal reaction conditions, we
next examined the scope of this tandem reaction by varia-
tion of the substitution patterns on the O-vinylphospho-
such as fluoro, bromo, and methyl groups at the 5-position
reacted smoothly to afford the desired products with excel-
lent yields and diastereoselectivities (3v–z and 3p–u),
while a nitro group at the same position fail to afford the
desired product. Furthermore, both the N-unprotected and
N-benzyl protected 3-aminooxindoles 1 were found to re-
act smoothly with good yields. Notably, only one cis-diaste-
reoisomer was formed for most of the above cases, although
the products contained four stereocenters including three
carbon and one phosphorus stereocenters. The relative con-
figuration of 3a was unequivocally assigned by X-ray dif-
fraction (Figure 2; see also the Supporting Information),16
and those of other products 3 were determined by analogy.
The structures of all products 3 were unambiguously as-
signed by 1H, 13C and 31P NMR spectroscopy and HRMS. The
1H NMR spectrum of all products 3 showed a double dou-
blet at  = 5.04–5.23 ppm and double quartet at  = 3.14–
3.28 ppm, respectively, for the vicinal two atoms H3 and H6
in the oxophosphorus heterocycle moiety due to coupling
with adjacent phosphorus atoms (3JP–C–C–H value of 12.2–
Table 1 Optimization of the Reaction Conditionsa
O
O
NH2•HCl
O
P
H
CHO
nylated salicylaldehydes
2 and 3-amino oxindoles 1
NaHCO3
OEt
HN
H
(Scheme 2). In general, variation of the different substitu-
tion patterns on the phenyl ring of O-vinylphosphonylated
salicylaldehydes (R3, R4 groups) gave structurally diversified
spiropyrrolidin-2,3′-oxindoles cis-fused phosphadihydro-
coumarin derivatives 3 in satisfactory yields. Regardless of
the substituent position (ortho, meta or para) and the
electronic nature (electron-donating MeO or electron-
withdrawing Cl) of the substituent on the phenyl ring moiety,
the desired products 3a–z were obtained in good yields
(67–96%) and with excellent diastereoselectivity (d.r. > 99:1)
as the cis-fused diastereomer. In detail, the electron-donat-
ing O-vinylphosphonylated salicylaldehydes afforded mod-
erately lower yields (3x, 3i, 3q). The linear or branched ali-
phatic groups on O-vinylphosphonylated salicylaldehydes 2
are also competent, giving excellent results (3e, 3k, 3l). The
scope of the reaction with respect to the bis-substituted
substituents on the O-vinylphosphonylated salicylaldehyde
2 was then studied. The substrates containing electron-
donating groups (methyl groups) on the phenyl ring im-
posed no clear effect on the reactivity and gave excellent
yields and similar high diastereoselectivities (3g, 3t), while
substrates with electron-withdrawing groups (Cl, Br) did
not work. In addition, 2-O-vinylphosphonylated naphthal-
dehyde 2z2, derived from -hydroxy-naphthaldehyde also
participated in the reaction smoothly with good yield to
give single diastereomers (3z2). Next, we switched to ex-
plore the effect on the results of the substituents (R1) on the
benzene ring of 3-aminooxindoles 1. 3-Aminooxindoles 1
with electron-withdrawing or electron-donating groups
+
N
O
P
O
H
O
OEt
N
H
1a
2a
3a
Entry Solvent
Additiveb
Temp (°C) Time (h) Yield (%)cdrd
1
2
THF
none
r.t
r.t
r.t
r.t.
r.t
r.t
r.t
r.t
50
10
r.t
r.t.
r.t
r.t
r.t
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
66
87
80
72
60
70
60
70
80
60
70
65
77
61
40
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
THF
4 Å MS
3
THF
Cu (CF3SO3)2
CuCl2
4
THF
5
THF
CuI
6
THF
ZnCl2
7
THF
AlCl3
8
THF
BF3·Et2O
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
9
THF
10
11
12
13
14
15
THF
CH2Cl2
CHCl3
MeCN
MeOH
toluene
a Reaction conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol 1 equiv),
NaHCO3 (0.2 mmol, 1 equiv) and catalyst (20 mmol%) in anhydrous solvent
(2 mL).
b Reactions 8–11,14 conditions: 100 mg 4 Å MS; Lewis acid 20 mmol%.
c Isolated yield.
d The dr was determined by 31PNMR spectroscopic analysis of the crude
products.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

D
T. Huang et al.
Paper
Synthesis
R3
R4
O
R4
CHO
NH2•HCl
O
H3
P
R1
4 Å MS, NaHCO3
THF, r.t., 4 h
OEt
H6
O
HN
+
O
R1
O
P
O
N
R2
R3
OEt
N
2
1
R2
3
R3
R4
3a: R3 = H, R4 = H, 87% yield
R4
3h: R4 = Me, 88% yield
3i: R4 = OMe, 72% yield
3j: R4 = Et, 93% yield
3k: R4 = iPr, 86% yield
3l: R4 = tBu, 89% yield
3m: R4 = Cl, 94% yield
3b: R3 = H, R4 = Me, 82% yield
3c: R3 = H, R4 = Et, 96% yield
O
O
O
O
H3
P
H3
3d: R3 = H, R4 = OMe, 90% yield
3e: R3 = H, R4 = iPr, 96% yield
3f: R3 = H, R4 = Cl, 88% yield
3g: R3 = Me, R4 = Me, 88% yield
P
OEt
OEt
H6
O
HN
H6
HN
O
N
N
H
Bn
R3
R3
R4
R4
3p: R3 = H, R4 = H, 95% yield
3q: R3 = H, R4 = Me, 78% yield
3r: R3 = H, R4 = Et, 96% yield
3s: R3 = H, R4 = Cl, 95% yield
3t: R3 = Me, R3 = Me, 92% yield
3u: R3 = OMe, R4 = H, 96% yield
O
O
O
O
H3
H3
P
3n: R3 = Me, R4 = Me, 91% yield
3o: R3 = OMe, R4 = H, 90% yield
P
OEt
OEt
H6
O
HN
HN
H6
Me
O
N
N
Bn
Bn
R4
O
3v: R1 = Br, R2 = Bn, R4 = Me, 93% yield
3w: R1 = Br, R2 = Bn, R4 = Et, 92% yield
3x: R1 = Br, R2 = Bn, R4 = OMe, 67% yield
3y: R1 = Br, R2 = Bn, R4 = Cl, 85% yield
3z: R1 = F, R2 = H, R4 = Me, 95% yield
3z1: R1 = F, R2 = H, R4 = Et, 96% yield
O
O
O
H3
HN
P
H3
HN
P
OEt
3z2: 90% yield
OEt
H6
O
H6
O
R1
N
N
R2
Bn
Scheme 2 Reaction scope. Reagents and conditions: 1 (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1 equiv), NaHCO3 (0.2 mmol, 1 equiv) and 100 mg 4 Å MS in
anhydrous THF solvent (2 mL) at room temperature for 4 h; isolated yields are given.
16.9 Hz; JH3–H6 value of 7.4–8.4 Hz). The 13C NMR signal of
the carbon atom close to phosphorus was a doublet at  =
35.1–36.7 ppm with 1JC–P values of 134–135.8 Hz. Based on
the above spectra analysis and deducing from the smaller
coupling constant value of the ring juncture protons (JH3–H6
= 7.4–8.4 Hz), the relative configurations of product 3 was
comes the preferential intermediate. Subsequently, intra-
molecular endo-cycloaddition reaction takes place in only a
cis-selective mode to produce pyrrolidin-2,3′-oxindoles cis-
fused phosphadihydrocoumarin 3. Finally, the epimeriza-
tion of the cycloadducts at the phosphorus stereocenter
1
assigned as cis at the newly formed ring junction. The H
NMR spectral data was also consistent with the structure
derived from the X-ray diffraction data (Figure 2).
Based on the above results and on previous reports,17
we propose a possible mechanism (Scheme 3). The reaction
is initiated through the condensation reaction between O-
vinylphosphonylated salicylaldehyde 2 and 3-aminooxin-
dole 1 to give ‘S’-shaped E-form azomethine ylide interme-
diates, which presumably exists in two transient states:
exo-form (exo-TS) and endo-form (endo-TS). The endo-form
is more stable than the exo-form because it experiences less
steric hindrance and electrostatic repulsions, and it be-
O
O
P
H3
OEt
H6
O
HN
≡
N
H
Figure 2 The single-crystal X-ray structure of compound 3a
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

E
T. Huang et al.
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Synthesis
O
O
H3
H6
O
P
O
OEt
P
HN
NH2•HCl
H3
HN
OEt
H6
trans-selectivity
O
O
O
N
R
N
exo-cycloaddition
N
R
R
3
1
S-shaped E-form exo-TS
Steric hindrance
condensation
Unfavored
+
4 Å MS
– H2O
Unfavored TS
CHO
O
O
O
P
P
O
O
H3
H3
OEt
P
cis-selectivity
O
3 + 3'
OEt
OEt
H6
H6
O
HN
HN
2
endo-cycloaddition
P-epimerization
O
N
N
R
R
3
S-shaped E-form endo-TS
No steric hindrance
Favored TS
Favored
Scheme 3 A plausible reaction pathway
results in the two diastereomers 3 and 3′ with cis-
configuration.
1H NMR (400 MHz, CDCl3):  = 8.66 (s, 1 H), 7.39 (dd, J = 7.7, 1.7 Hz,
1 H), 7.29–7.18 (m, 1 H), 7.13–7.03 (m, 2 H), 7.00 (dd, J = 8.2, 1.2 Hz,
3
1 H), 6.91–6.80 (m, 2 H), 6.75 (d, J = 7.7 Hz, 1 H), 5.09 (dd, JP–C–C–H
=
In summary, we have developed an efficient method for
the construction of pyrrolidin-2,3′-oxindole cis-fused phos-
phadihydrocoumarin frameworks through a cascade con-
densation / intermolecular 1,3-dipolar cycloaddition reac-
tion of 3-aminooxindoles with O-vinylphosphonylated sa-
licylaldehydes. This cascade reaction creates two new P,N-
heterocycles with four stereocenters by generating two C–C
bonds and one C–N bond under mild reaction conditions,
with high diastereoselectivity and atom economy.
3
14.1, JH–C–C–H = 7.8 Hz, 1 H), 4.42–4.08 (m, 2 H), 3.44–3.11 (m, 1 H),
2.68–2.39 (m, 3 H), 1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 182.0, 149.9 (d, 2JP–O–C = 6.5 Hz), 140.6,
131.5, 130.9, 129.7, 129.1, 125.8 (d,3JP–O–C–C = 11.5 Hz), 124.6, 124.2,
3
3
123.3, 119.5 (d, JP–O–C–C = 6.5 Hz), 110.0, 67.8 (d, JP–C–C–C = 10.7 Hz),
2
2
62.6 (d, JP–O–C = 7.1 Hz), 61.1 (d, JP–C–C = 3.7 Hz), 37.7, 35.8 (d, JP–C
=
134.6 Hz), 16.4 (d, 3JP–O–C–C = 5.6 Hz).
31P NMR (162 MHz, CDCl3):  = 25.42 (s).
HRMS (ESI): m/z [M + H]+ calcd for C19H20N2O4P: 371.1155; found:
371.1177.
The reactions were monitored by thin-layer chromatography (TLC)
using silica gel GF254. All compounds were fully characterized based
on their spectroscopic data. The NMR spectra were recorded with a
Bruker Avance III (1H NMR: 400 MHz, 13C NMR: 100 MHz, 31P NMR:
162 MHz external standard 85% H3PO4), chemical shifts () are ex-
pressed in ppm, and J values are given in Hz. CDCl3 and DMSO-d6 were
used as solvents. High-resolution mass spectra (HRMS) were recorded
with an LCMS-IT-TOF. All chemicals and solvents were used as re-
ceived without further purification unless otherwise stated. Column
chromatography was performed on silica gel (200–300 mesh).
(±)-4-Ethoxy-8-methyl-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]-
oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3b)
Yield: 63.0 mg (82%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 9.10 (s, 1 H), 7.23 (d, J = 2.2 Hz, 1 H),
7.16–7.04 (m, 2 H), 7.01–6.90 (m, 2 H), 6.90–6.85 (m, 1 H), 6.81 (d, J =
7.7 Hz, 1 H), 5.11 (dd, 3JP–C–C–H = 14.7, 3JH–C–C–H = 7.9 Hz, 1 H), 4.30–4.15
(m, 2 H), 3.30–3.16 (m, 1 H), 2.68–2.51 (m, 3 H), 2.27 (s, 3 H), 1.28 (t,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 182.1, 147.8 (d, 2JP–O–C = 6.3 Hz), 140.9,
3
134.2, 131.4, 131.1, 130.3, 129.1, 125.3 (d, JP–O–C–C = 11.5 Hz), 124.1,
3
3
123.1, 119.2 (d, JP–O–C–C = 6.4 Hz), 110.1, 67.9 (d, JP–C–C–C = 10.5 Hz),
Synthesis of 3; General Procedure
2
2
62.5 (d, JP–O–C = 7.0 Hz), 61.1 (d, JP–C–C = 3.7 Hz), 37.6, 35.8 (d, JP–C
=
In a Schlenk tube, anhydrous THF (2 mL) was added to a mixture of 3-
aminooxindole 1 (0.3 mmol), ethyl (2-formylphenyl) vinylphospho-
nate 2 (0.2 mmol), NaHCO3 (0.2 mmol), and 4 Å MS (100 mg) under a
nitrogen atmosphere. The mixture was stirred at r.t. for 4 h (2 was
completely consumed as indicated by TLC), then purified by column
chromatography (silica gel, EtOAc/PE = 1:1) to give pure 3.
134.7 Hz), 20.7, 16.4 (d, 3JP–O–C–C = 5.6 Hz).
31P NMR (162 MHz, CDCl3):  = 25.90 (s).
HRMS (ESI): m/z [M + H]+ calcd for C20H22N2O4P: 385.1312; found:
385.1310.
(±)-4-Ethoxy-8-ethyl-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]-
oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3c)
(±)-4-Ethoxy-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]oxaphos-
phinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3a)
Yield: 76.5 mg (96%); yellow oil.
Yield: 64.4 mg (87%); white oil.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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T. Huang et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 9.08 (s, 1 H), 7.20 (d, J = 2.2 Hz, 1 H),
13C NMR (100 MHz, CDCl3):  = 180.8, 147.4 (d, 2JP–O–C = 6.3 Hz), 139.4,
3
7.09–6.99 (m, 2 H), 6.95–6.83 (m, 2 H), 6.82–6.71 (m, 2 H), 5.06 (dd,
130.2, 129.6, 128.7 (d, JP–O–C–C = 3.1 Hz), 128.2, 126.8, 126.7, 123.2,
3
3
3
3JP–C–C–H = 14.4, JH–C–C–H = 7.8 Hz, 1 H), 4.29–4.03 (m, 2 H), 3.33–3.03
122.4, 119.9 (d, JP–O–C–C = 6.6 Hz), 109.0, 66.8 (d, JP–C–C–C = 11.3 Hz),
2
2
(m, 1 H), 2.75–2.20 (m, 5 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.11 (t, J = 7.6 Hz,
3 H).
61.8 (d, JP–O–C = 7.0 Hz), 59.6 (d, JP–C–C = 3.5 Hz), 36.6, 34.4 (d, JP–C
=
134.9 Hz), 15.4 (d, 3JP–O–C–C = 5.6 Hz).
13C NMR (100 MHz, CDCl3):  = 181.2, 146.9 (d, 2JP–O–C = 6.4 Hz), 139.8,
31P NMR (162 MHz, CDCl3):  = 25.07 (s).
HRMS (ESI): m/z [M + H]+ calcd for C19H19ClN2O4P: 405.0765; found:
3
139.6, 130.5, 129.0, 128.1 (d, JP–O–C–C = 5.1 Hz), 124.3, 124.2, 123.1,
3
3
122.1, 118.3 (d, JP–O–C–C = 6.5 Hz), 109.1, 66.9 (d, JP–C–C–C = 10.6 Hz),
405.0770.
2
2
61.5 (d, JP–O–C = 7.0 Hz), 60.3 (d, JP–C–C = 3.7 Hz), 36.6, 34.9 (d, JP–C
=
134.4 Hz), 27.1, 15.4 (d, 3JP–O–C–C = 5.7 Hz), 14.6.
(±)-4-Ethoxy-6,8-dimethyl-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]-
oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3g)
31P NMR (162 MHz, CDCl3):  = 25.74 (s).
HRMS (ESI): m/z [M + H]+ calcd for C21H24N2O4P: 399.1468; found:
Yield: 70.1 mg (88%); yellow oil.
399.1494.
1H NMR (400 MHz, CDCl3):  = 9.08 (d, J = 4.4 Hz, 1 H), 7.09–7.01 (m,
2 H), 6.97 (s, 1 H), 6.89 (s, 1 H), 6.82 (t, J = 6.9 Hz, 1 H), 6.75 (d, J =
7.1 Hz, 1 H), 5.05 (dd, 3JP–C–C–H = 16.6, 3JH–C–C–H = 7.6 Hz, 1 H), 4.26–4.15
(m, 1 H), 4.12–4.03 (m, 1 H), 3.21–3.09 (m, 1 H), 2.72 (s, 1 H), 2.63–
2.45 (m, 2 H), 2.20 (s, 3 H), 2.16 (s, 3 H), 1.22 (t, J = 6.2 Hz, 3 H).
(±)-4-Ethoxy-8-methoxy-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]-
oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3d)
Yield: 72.1 mg (90%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 9.06 (s, 1 H), 7.11 (t, J = 7.7 Hz, 1 H),
7.00–6.94 (m, 3 H), 6.88 (t, J = 7.5 Hz, 1 H), 6.85–6.77 (m, 2 H), 5.10
(dd, 3JP–C–C–H = 16.6, 3JH–C–C–H = 8.6 Hz, 1 H), 4.29–4.13 (m, 2 H), 3.73 (s,
3 H), 3.12–3.18 (m, 1 H), 2.70–2.55 (m, 2 H), 2.52–2.42 (m, 1 H), 1.28
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 181.2, 145.3 (d, 2JP–O–C = 6.8 Hz), 139.9,
132.5, 130.7, 130.2, 128.1, 127.5, 127.0 (d, 3JP–O–C–C = 5.7 Hz), 124.1 (d,
3JP–O–C–C = 11.6 Hz), 123.3, 122.1, 109.0, 66.7 (d, 3JP–C–C–C = 9.5 Hz), 61.3
2
2
(d, JP–O–C = 7.1 Hz), 60.3 (d, JP–C–C = 4.0 Hz), 36.5, 34.7 (d, JP–C
=
135.4 Hz), 19.6, 15.4 (d, 3JP–O–C–C = 5.6 Hz), 14.8.
13C NMR (100 MHz, CDCl3):  = 182.1, 156.2, 143.5 (d, 2JP–O–C = 6.4 Hz),
31P NMR (162 MHz, CDCl3):  = 26.73 (s).
HRMS (ESI): m/z [M + H]+ calcd for C21H24N2O4P: 399.1468; found:
3
140.8, 131.4, 129.1, 126.7 (d, JP–O–C–C = 11.2 Hz), 124.1, 123.1, 120.3
3
3
(d, JP–O–C–C = 6.4 Hz), 115.8, 114.7, 110.1, 67.9 (d, JP–C–C–C = 10.9 Hz),
399.1490.
2
2
62.5 (d, JP–O–C = 6.9 Hz), 61.3 (d, JP–C–C = 3.6 Hz), 55.7, 37.7, 35.6 (d,
JP–C = 135.1 Hz), 16.4 (d, 3JP–O–C–C = 5.6 Hz).
(±)-1′-Benzyl-4-ethoxy-8-methyl-1,3,3a,9b-tetrahydrospiro[benzo[5,6]-
[1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide
(3h)
31P NMR (162 MHz, CDCl3):  = 25.96 (s).
HRMS (ESI): m/z [M + H]+ calcd for C20H22N2O5P: 401.1261; found:
401.1280.
Yield: 83.5 mg (88%); white oil.
1H NMR (400 MHz, CDCl3):  = 7.28–7.20 (m, 6 H), 7.08–6.97 (m, 3 H),
3
(±)-4-Ethoxy-8-isopropyl-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]-
oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3e)
6.93–6.85 (m, 2 H), 6.60 (d, J = 7.8 Hz, 1 H), 5.12 (dd, JP–C–C–H = 14.9,
3JH–C–C–H = 7.9 Hz, 1 H), 4.96–4.85 (m, 1 H), 4.76–4.66 (m, 1 H), 4.27–
4.10 (m, 2 H), 3.29–3.16 (m, 1 H), 2.69–2.47 (m, 3 H), 2.24 (s, 3 H),
1.25 (t, J = 7.1 Hz, 3 H).
Yield: 79.2 mg (96%); light-yellow oil.
1H NMR (400 MHz, CDCl3):  = 9.01 (s, 1 H), 7.32 (d, J = 2.3 Hz, 1 H),
7.18–7.07 (m, 2 H), 7.00–6.96 (m, 1 H), 6.90–6.83 (m, 2 H), 6.82 (d, J =
7.9 Hz, 1 H), 5.13 (dd, 3JP–C–C–H = 14.1, 3JH–C–C–H = 7.7 Hz, 1 H), 4.34–4.17
(m, 2 H), 3.29–3.15 (m, 1 H), 2.91–2.80 (m, 1 H), 2.70–2.45 (m, 3 H),
1.31 (t, J = 7.1 Hz, 3 H), 1.20 (s, 3 H), 1.19 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 179.9, 147.8 (d, 2JP–O–C = 6.3 Hz), 142.4,
135.6, 134.1, 131.1, 130.9, 130.3, 129.1, 128.9 (2C), 127.7, 127.2 (2C),
125.2 (d, 3JP–O–C–C = 11.4 Hz), 123.9, 123.5, 119.3 (d, 3JP–O–C–C = 6.4 Hz),
3
2
109.1, 67.6 (d, JP–C–C–C = 10.4 Hz), 62.5 (d, JP–O–C = 7.0 Hz), 61.4 (d,
2JP–C–C = 3.8 Hz), 43.7, 37.9, 35.9 (d, JP–C = 134.6 Hz), 20.7, 16.4 (d,
3JP–O–C–C = 5.6 Hz).
13C NMR (100 MHz, CDCl3):  = 182.1, 147.9 (d, 2JP–O–C = 6.5 Hz), 145.2,
3
140.8, 131.7, 129.1, 128.7, 127.7, 125.1 (d, JP–O–C–C = 11.0 Hz), 124.2,
3
3
123.1, 119.3 (d, JP–O–C–C = 6.6 Hz), 110.0, 67.9 (d, JP–C–C–C = 10.7 Hz),
31P NMR (162 MHz, CDCl3):  = 25.55 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H28N2O4P: 475.1781; found:
2
2
62.5 (d, JP–O–C = 7.0 Hz), 61.4 (d, JP–C–C = 3.6 Hz), 37.7, 36.1 (d, JP–C
=
134.1 Hz), 33.6, 24.0, 24.0, 16.4 (d, 3JP–O–C–C = 5.5 Hz).
475.1793.
31P NMR (162 MHz, CDCl3):  = 25.56 (s).
HRMS (ESI): m/z [M + H]+ calcd for C22H26N2O4P: 413.1625; found:
413.1691.
(±)-1′-Benzyl-4-ethoxy-8-methoxy-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3i)
Yield: 70.6 mg (72%); white oil.
(±)-8-Chloro-4-ethoxy-1,3,3a,9b-tetrahydrospiro[benzo[5,6][1,2]-
1H NMR (400 MHz, CDCl3):  = 7.30–7.17 (m, 5 H), 7.08–7.00 (m, 2 H),
6.95–6.86 (m, 3 H), 6.79 (d, J = 8.3 Hz, 1 H), 6.61 (d, J = 7.4 Hz, 1 H),
5.11 (dd, JP–C–C–H = 14.5, JH–C–C–H = 7.4 Hz, 1 H), 4.93–4.89 (m, 1 H),
4.73–4.69 (m, 1 H), 4.28–4.10 (m, 2 H), 3.70 (s, 3 H), 3.33–3.19 (m,
1 H), 2.68–2.47 (m, 2 H), 2.14 (s, 1 H), 1.27–1.22 (m, 3 H).
oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-Oxide (3f)
Yield: 71.1 mg (88%); light-yellow oil.
3
3
1H NMR (400 MHz, CDCl3):  = 8.45 (s, 1 H), 7.41 (d, J = 2.6 Hz, 1 H),
7.24–7.17 (m, 1 H), 7.12–7.07 (m, 1 H), 6.99–6.84 (m, 3 H), 6.76 (d, J =
7.7 Hz, 1 H), 5.04 (dd, 3JP–C–C–H = 13.1, 3JH–C–C–H = 7.9 Hz, 1 H), 4.29–4.11
(m, 2 H), 3.30–3.14 (m, 1 H), 2.73–2.28 (m, 3 H), 1.25 (t, J = 7.0 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 178.9, 155.2, 142.7 (d, 2JP–O–C = 6.5 Hz),
141.4, 134.6, 129.9, 128.1, 127.9 (2C), 126.7, 126.2 (2C), 125.5 (d,
3
3JP–O–C–C = 11.2 Hz), 123.0, 122.5, 119.4 (d, JP–O–C–C = 6.3 Hz), 115.0,
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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T. Huang et al.
Paper
Synthesis
3
2
3
2
113.6, 108.1, 66.6 (d, JP–C–C–C = 10.7 Hz), 61.4 (d, JP–O–C = 7.0 Hz),
3JP–O–C–C = 6.5 Hz), 108.1, 66.6 (d, JP–C–C–C = 10.5 Hz), 61.5 (d, JP–O–C
=
2
2
60.5 (d, JP–C–C = 3.7 Hz), 54.7, 42.8, 37.0, 34.9 (d, JP–C = 135.0 Hz),
6.9 Hz), 60.7 (d, JP–C–C = 3.7 Hz), 42.7, 37.0, 35.2 (d, JP–C = 134.0 Hz),
15.4 (d, 3JP–O–C–C = 5.7 Hz).
33.4, 30.4 (3C), 15.4 (d, 3JP–O–C–C = 5.5 Hz).
31P NMR (162 MHz, CDCl3):  = 25.56 (s).
31P NMR (162 MHz, CDCl3):  = 25.37 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H28N2O5P: 491.1730; found:
HRMS (ESI): m/z [M + H]+ calcd for C30H34N2O4P: 517.2251; found:
491.1722.
517.2263.
(±)-1′-Benzyl-4-ethoxy-8-ethyl-1,3,3a,9b-tetrahydrospiro[benzo-
[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-
Oxide (3j)
(±)-1′-Benzyl-8-chloro-4-ethoxy-1,3,3a,9b-tetrahydrospiro[ben-
zo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-
Oxide (3m)
Yield: 90.9 mg (93%); yellow oil.
Yield: 93.0 mg (94%); white oil.
1H NMR (400 MHz, CDCl3):  = 7.27–7.19 (m, 6 H), 7.11–7.01 (m, 2 H),
6.99–6.89 (m, 2 H), 6.85 (t, J = 7.5 Hz, 1 H), 6.60 (d, J = 7.8 Hz, 1 H),
5.12 (dd, JP–C–C–H = 14.8, JH–C–C–H = 7.8 Hz, 1 H), 4.94–4.87 (m, 1 H),
4.73–4.67 (m, 1 H), 4.27–4.10 (m, 2 H), 3.27–3.15 (m, 1 H), 2.74–2.59
(m, 1 H), 2.59–2.59 (m, 4 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.13 (t, J = 7.6 Hz,
3 H).
1H NMR (400 MHz, CDCl3):  = 7.43 (d, J = 2.6 Hz, 1 H), 7.29–7.17 (m,
6 H), 7.10–7.04 (m, 1 H), 6.97–6.85 (m, 3 H), 6.62 (d, J = 7.8 Hz, 1 H),
5.10 (dd, JP–C–C–H = 13.1, JH–C–C–H = 7.9 Hz, 1 H), 4.94–4.85 (m, 1 H),
4.77–4.67 (m, 1 H), 4.34–4.09 (m, 2 H), 3.33–3.20 (m, 1 H), 2.78 (s,
1 H), 2.69–2.41 (m, 2 H), 1.26 (t, J = 7.1 Hz, 3 H).
3
3
3
3
13C NMR (100 MHz, CDCl3):  = 178.8, 147.4 (d, 2JP–O–C = 6.5 Hz), 141.3,
13C NMR (100 MHz, CDCl3):  = 179.9, 148.0 (d, 2JP–O–C = 6.4 Hz), 142.4,
140.5, 135.6, 131.1, 130.0, 129.2, 129.1, 128.9 (2C), 127.7, 127.2 (2C),
125.1 (d, 3JP–O–C–C = 11.3 Hz), 124.0, 123.5, 119.3 (d, 3JP–O–C–C = 6.5 Hz),
134.5, 129.6, 128.7, 128.2, 127.9 (2C), 126.8, 126.2 (2C), 122.7 (d,
3JP–O–C–C = 28.9 Hz), 119.9 (d, 3JP–O–C–C = 6.6 Hz), 108.2, 66.6 (d, 2JP–O–C
=
=
2
11.6 Hz), 61.8 (d, JP–C–C = 6.9 Hz), 59.8, 42.8, 36.9, 34.6 (d, JP–C
3
2
109.1, 67.6 (d, JP–C–C–C = 10.3 Hz), 62.5 (d, JP–O–C = 7.1 Hz), 61.5 (d,
2JP–C–C = 3.8 Hz), 43.8, 38.0, 36.1 (d, JP–C = 134.3 Hz), 28.2, 16.4 (d,
3JP–O–C–C = 5.6 Hz), 15.7.
134.9 Hz), 15.4 (d, 3JP–O–C–C = 5.7 Hz).
31P NMR (162 MHz, CDCl3):  = 24.74 (s).
HRMS (ESI): m/z [M + H]+ calcd for C26H25ClN2O4P: 495.1235; found:
31P NMR (162 MHz, CDCl3):  = 25.36 (s).
HRMS (ESI): m/z [M + K]+ calcd for C28H29N2KO4P: 522.1497; found:
495.1251.
522.1510.
(±)-1′-Benzyl-4-ethoxy-6,8-dimethyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3n)
(±)-1′-Benzyl-4-ethoxy-8-isopropyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3k)
Yield: 88.9 mg (91%); white oil.
1H NMR (400 MHz, CDCl3):  = 7.35–7.25 (m, 5 H), 7.19 (d, J = 7.3 Hz,
1 H), 7.14–7.08 (m, 2 H), 7.02–6.92 (m, 2 H), 6.67 (d, J = 7.9 Hz, 1 H),
Yield: 86.4 mg (86%); light-yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.30–7.16 (m, 6 H), 7.09 (dd, J = 8.4,
2.2 Hz, 1 H), 7.08–6.99 (m, 1 H), 6.97–6.86 (m, 2 H), 6.82 (t, J = 7.5 Hz,
3
3
5.20 (dd, JP–C–C–H = 16.6, JH–C–C–H = 7.6 Hz, 1 H), 5.00–4.93 (m, 1 H),
4.82–4.74 (m, 1 H), 4.37–4.23 (m, 1 H), 4.24–4.11 (m, 1 H), 3.35–3.22
(m, 1 H), 2.91–2.60 (m, 3 H), 2.30 (s, 3 H), 2.26 (s, 3 H), 1.31 (t, J =
7.1 Hz, 3 H).
3
3
1 H), 6.59 (d, J = 7.8 Hz, 1 H), 5.12 (dd, JP–C–C–H = 14.4, JH–C–C–H
=
7.7 Hz, 1 H), 4.94–4.87 (m, 1 H), 4.74–7.65 (m, 1 H), 4.30–4.09 (m,
2 H), 3.26–3.14 (m, 1 H), 2.87–2.74 (m, 2 H), 2.71–2.37 (m, 2 H), 1.27–
1.13 (m, 9 H).
13C NMR (100 MHz, CDCl3):  = 179.9, 148.0 (d, 2JP–O–C = 6.5 Hz), 145.2,
13C NMR (100 MHz, CDCl3):  = 180.0, 146.4 (d, 2JP–O–C = 6.8 Hz), 142.4,
135.7, 133.5, 131.8, 130.8, 129.1, 128.9 (2C), 128.6, 128.1 (d, 3JP–O–C–C
=
3
5.6 Hz), 127.7, 127.2 (2C), 125.0 (d, JP–O–C–C = 11.5 Hz), 124.1, 123.5,
3
2
142.3, 135.6, 131.2, 129.1, 128.9 (2C), 128.7, 127.8, 127.2 (2C), 125.0,
109.1, 67.4 (d, JP–C–C–C = 9.5 Hz), 62.3 (d, JP–O–C = 6.9 Hz), 61.5 (d,
2JP–C–C = 4.1 Hz), 43.7, 37.9, 35.9 (d, JP–C = 135.3 Hz), 20.6, 16.4 (d,
3JP–O–C–C = 5.7 Hz), 15.9.
124.9, 124.0, 123.4, 119.3 (d, 3JP–O–C–C = 6.6 Hz), 109.1, 67.6 (d, 3JP–C–C–C
=
2
2
10.6 Hz), 62.5 (d, JP–O–C = 6.9 Hz), 61.6 (d, JP–C–C = 3.7 Hz), 43.8, 38.0,
36.2 (d, JP–C = 134.0 Hz), 33.6, 24.1, 16.5 (d, 3JP–O–C–C = 5.7 Hz), 14.2.
31P NMR (162 MHz, CDCl3):  = 26.41 (s).
HRMS (ESI): m/z [M + H]+ calcd for C28H30N2O4P: 489.1938; found:
31P NMR (162 MHz, CDCl3):  = 25.24 (s).
HRMS (ESI): m/z [M + H]+ calcd for C29H32N2O4P: 503.2094; found:
489.1959.
503.2099.
(±)-1′-Benzyl-4-ethoxy-6-methoxy-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-oxide (3o)
(±)-1′-Benzyl-8-(tert-butyl)-4-ethoxy-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3l)
Yield: 88.3 mg (90%); yellow oil.
Yield: 91.9 mg (89%); light-yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.43–7.23 (m, 6 H), 7.19–7.03 (m, 3 H),
1H NMR (400 MHz, CDCl3):  = 7.43 (d, J = 2.4 Hz, 1 H), 7.31–7.15 (m,
6 H), 7.13–6.98 (m, 1 H), 7.01–6.88 (m, 2 H), 6.83 (t, J = 7.5 Hz, 1 H),
6.94 (q, J = 7.6 Hz, 2 H), 6.67 (d, J = 7.8 Hz, 1 H), 5.23 (dd, JP–C–C–H
=
3
3
16.7, JH–C–C–H = 7.9 Hz, 1 H), 5.00–4.92 (m, 1 H), 4.83–4.74 (m, 1 H),
4.40–4.11 (m, 2 H), 3.90 (s, 3 H), 3.50–3.16 (m, 1 H), 2.87–2.52 (m,
3 H), 1.40–1.26 (m, 3 H).
3
3
6.60 (d, J = 7.8 Hz, 1 H), 5.13 (dd, JP–C–C–H = 14.6, JH–C–C–H = 7.6 Hz,
1 H), 4.96–4.88 (m, 1 H), 4.77–4.63 (m, 1 H), 4.37–4.03 (m, 2 H), 3.34–
3.09 (m, 1 H), 2.76–2.40 (m, 2 H), 2.10 (s, 1 H), 1.22 (s, 12 H).
13C NMR (100 MHz, CDCl3):  = 180.0, 149.7 (d, 2JP–O–C = 5.4 Hz), 142.4,
13C NMR (100 MHz, CDCl3):  = 179.0, 146.7 (d, 2JP–O–C = 6.3 Hz), 146.4,
141.3, 134.6, 130.2, 128.0, 127.9 (2C), 126.7 (d, JP–O–C–C = 5.0 Hz),
139.7 (d, JP–O–C–C = 6.3 Hz), 135.6, 130.8, 129.1, 128.9 (2C), 127.7,
3
3
3
127.2 (2C), 127.1, 127.0, 124.2 (d, JP–O–C–C = 23.4 Hz), 123.5, 121.9,
126.2 (2C), 125.8, 125.5, 123.5 (d, J = 11.1 Hz), 123.1, 122.4, 117.9 (d,
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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T. Huang et al.
Paper
Synthesis
3
2
112.2, 109.1, 67.4 (d, JP–C–C–C = 9.6 Hz), 62.6 (d, JP–O–C = 7.0 Hz), 61.5
13C NMR (100 MHz, CDCl3):  = 179.8, 148.0 (d, 2JP–O–C = 6.4 Hz), 140.5,
140.0, 135.7, 133.0, 131.1, 130.1, 129.3, 129.1, 128.8 (2C), 127.7, 127.2
2
(d, JP–C–C = 4.3 Hz), 56.2, 43.7, 37.8, 36.0 (d, JP–C = 135.7 Hz), 16.3 (d,
3JP–O–C–C = 5.7 Hz).
(2C), 125.3 (d, JP–O–C–C = 11.2 Hz), 124.7, 119.3 (d, JP–O–C–C = 6.5 Hz),
3
3
3
2
108.9, 67.8 (d, JP–C–C–C = 10.9 Hz), 62.5 (d, JP–O–C = 7.0 Hz), 61.4 (d,
2JP–C–C = 3.6 Hz), 43.8, 38.0, 36.1 (d, JP–C = 134.2 Hz), 28.2, 21.0, 16.4 (d,
3JP–O–C–C = 5.6 Hz), 15.7.
31P NMR (162 MHz, CDCl3):  = 26.13 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H28N2O5P: 491.1730; found:
491.1744.
31P NMR (162 MHz, CDCl3):  = 25.46 (s).
HRMS (ESI): m/z [M + H]+ calcd for C29H32N2O4P: 503.2094; found:
503.2089.
(±)-1′-Benzyl-4-ethoxy-5′-methyl-1,3,3a,9b-tetrahydrospiro[ben-
zo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-
Oxide (3p)
(±)-1′-Benzyl-8-chloro-4-ethoxy-5′-methyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3s)
Yield: 90.2 mg (95%); white oil.
1H NMR (400 MHz, CDCl3):  = 7.40 (d, J = 7.7 Hz, 1 H), 7.30–7.16 (m,
6 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 6.83 (d, J = 7.9 Hz,
1 H), 6.70 (s, 1 H), 6.48 (d, J = 7.9 Hz, 1 H), 5.16 (dd, 3JP–C–C–H = 14.3,
3JH–C–C–H = 8.0 Hz, 1 H), 4.91–4.84 (m, 1 H), 4.72–4.64 (m, 1 H), 4.32–
4.08 (m, 2 H), 3.32–3.19 (m, 1 H), 2.77–2.44 (m, 3 H), 2.09 (s, 3 H),
1.24 (t, J = 7.1 Hz, 3 H).
Yield: 96.7 mg (95%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.48–7.39 (m, 1 H), 7.29–7.16 (m, 6 H),
6.96 (d, J = 8.7 Hz, 1 H), 6.86 (d, J = 8.1 Hz, 1 H), 6.71 (s, 1 H), 6.50 (d,
J = 8.0 Hz, 1 H), 5.11 (dd, 3JP–C–C–H = 12.9, 3JH–C–C–H = 8.0 Hz, 1 H), 4.92–
4.83 (m, 1 H), 4.75–4.67 (m, 1 H), 4.25–4.13 (m, 2 H), 3.33–3.20 (m,
1 H), 2.69–2.37 (m, 2 H), 2.12 (s, 3 H), 1.84 (s, 1 H), 1.26 (t, J = 7.1 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 179.7, 148.5 (d, 2JP–O–C = 6.3 Hz), 139.9,
135.6, 133.2, 130.7, 130.6, 129.7, 129.6, 129.4, 128.9 (2C), 127.7,
127.2 (2C), 124.7, 120.1, 120.9, 109.0, 67.7 (d, 3JP–C–C–C = 11.6 Hz), 62.8
(d, 2JP–O–C = 7.0 Hz), 60.7, 43.8, 37.8, 35.6 (d, JP–C = 134.7 Hz), 21.0, 16.4
(d, 3JP–O–C–C = 5.9 Hz).
13C NMR (100 MHz, CDCl3):  = 179.8, 150.1 (d, 2JP–O–C = 6.2 Hz), 139.9,
135.7, 133.1, 130.9, 130.8, 129.7, 129.3, 128.9 (2C), 127.7, 127.2 (2C),
125.9 (d, 3JP–O–C–C = 11.5 Hz), 124.7, 124.5, 119.6 (d, 3JP–O–C–C = 6.4 Hz),
3
2
108.9, 67.7 (d, JP–C–C–C = 10.8 Hz), 62.5 (d, JP–O–C = 7.0 Hz), 61.2 (d,
2JP–C–C = 3.8 Hz), 43.7, 37.9, 35.9 (d, JP–C = 134.7 Hz), 21.0, 16.4 (d,
3JP–O–C–C = 5.6 Hz).
31P NMR (162 MHz, CDCl3):  = 25.49 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H28N2O4P: 475.1781; found:
31P NMR (162 MHz, CDCl3):  = 25.01 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H27ClN2O4P: 509.1391; found:
475.1793.
509.1384.
(±)-1′-Benzyl-4-ethoxy-5′,8-dimethyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3q)
(±)-1′-Benzyl-4-ethoxy-5′,6,8-trimethyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3t)
Yield: 76.2 mg (78%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.25–7.16 (m, 6 H), 7.04 (d, J = 8.3 Hz,
1 H), 6.90 (d, J = 8.3 Hz, 1 H), 6.83 (d, J = 7.3 Hz, 1 H), 6.72 (d, J = 1.7 Hz,
1 H), 6.47 (d, J = 7.9 Hz, 1 H), 5.12 (dd, 3JP–C–C–H = 14.6, 3JH–C–C–H = 8.0 Hz,
1 H), 4.92–4.83 (m, 1 H), 4.73–4.64 (m, 1 H), 4.31–4.07 (m, 2 H), 3.30–
3.16 (m, 1 H), 2.69–2.41 (m, 3 H), 2.23 (s, 3 H), 2.09 (s, 3 H), 1.24 (t, J =
7.1 Hz, 3 H).
Yield: 92.5 mg (92%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.30–7.16 (m, 5 H), 7.00 (s, 1 H), 6.90
(d, J = 7.5 Hz, 2 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.46 (d, J = 8.1 Hz, 1 H),
3
3
5.13 (dd, JP–C–C–H = 16.8, JH–C–C–H = 8.1 Hz, 1 H), 4.90–4.82 (m, 1 H),
4.70–4.63 (m, 1 H), 4.27–4.05 (m, 2 H), 3.26–3.14 (m, 1 H), 2.68–2.49
(m, 3 H), 2.22 (s, 3 H), 2.18 (s, 3 H), 2.11 (s, 3 H), 1.22 (t, J = 7.1 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 179.8, 147.9 (d, 2JP–O–C = 6.4 Hz), 140.0,
135.7, 134.1, 133.0, 131.2, 130.9, 130.3, 129.3, 128.8 (2C), 127.7, 127.2
3
3
(2C), 125.4 (d, JP–O–C–C = 11.6 Hz), 124.7, 119.3 (d, JP–O–C–C = 6.3 Hz),
13C NMR (100 MHz, CDCl3):  = 179.9, 146.4 (d, 2JP–O–C = 6.9 Hz), 140.0,
3
2
108.9, 67.7 (d, JP–C–C–C = 10.6 Hz), 62.4 (d, JP–O–C = 7.0 Hz), 61.3 (d,
2JP–C–C = 3.8 Hz), 43.7, 37.9, 35.9 (d, JP–C = 134.5 Hz), 21.0, 20.7, 16.4 (d,
3JP–O–C–C = 5.6 Hz).
135.8, 133.5, 133.0, 131.7, 130.6, 129.3, 128.8 (2C), 128.6, 128.1 (d,
3
3JP–O–C–C = 5.7 Hz), 127.7, 127.2 (2C), 125.1 (d, JP–O–C–C = 11.7 Hz),
3
2
124.8, 108.9, 67.5 (d, JP–C–C–C = 9.6 Hz), 62.2 (d, JP–O–C = 7.0 Hz), 61.4
(d, 2JP–C–C = 4.1 Hz), 43.7, 37.8, 35.8 (d, JP–C = 135.3 Hz), 21.0, 20.6, 16.4
(d, 3JP–O–C–C = 5.7 Hz), 15.9.
31P NMR (162 MHz, CDCl3):  = 25.78 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C28H29N2NaO4P: 511.1757; found:
31P NMR (162 MHz, CDCl3):  = 26.68 (s).
HRMS (ESI): m/z [M + H]+ calcd for C29H32N2O4P: 503.2049; found:
511.1764.
503.2104.
(±)-1′-Benzyl-4-ethoxy-8-ethyl-5′-methyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3r)
(±)-1′-Benzyl-4-ethoxy-6-methoxy-5′-methyl-1,3,3a,9b-tetrahy-
drospiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indo-
lin]-2′-one 4-Oxide (3u)
Yield: 96.4 mg (96%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.30–7.15 (m, 6 H), 7.06 (dd, J = 8.3,
2.3 Hz, 1 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.82 (dd, J = 8.0, 1.8 Hz, 1 H), 6.67
Yield: 96.9 mg (96%); yellow oil.
3
3
(s, 1 H), 6.47 (d, J = 7.9 Hz, 1 H), 5.12 (dd, JP–C–C–H = 13.9, JH–C–C–H
=
1H NMR (400 MHz, CDCl3):  = 7.18 (s, 5 H), 7.02–6.92 (m, 2 H), 6.87
(s, 1 H), 6.82 (s, 2 H), 6.46 (d, J = 6.2 Hz, 1 H), 5.19–5.10 (m, 1 H), 4.87–
4.79 (m, 1 H), 4.70–4.60 (m, 1 H), 4.28–4.06 (m, 2 H), 3.79 (s, 3 H),
3.32–3.05 (m, 1 H), 2.68–2.44 (m, 3 H), 2.08 (s, 3 H), 1.20 (t, J = 6.3 Hz,
3 H).
7.9 Hz, 1 H), 4.91–4.81 (m, 1 H), 4.70–4.63 (m, 1 H), 4.31–4.05 (m,
2 H), 3.28–3.13 (m, 1 H), 2.67–2.40 (m, 5 H), 2.07 (s, 3 H), 1.23 (t, J =
7.1 Hz, 3 H), 1.12 (t, J = 7.6 Hz, 3 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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T. Huang et al.
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Synthesis
13C NMR (100 MHz, CDCl3):  = 179.9, 149.7 (d, 2JP–O–C = 5.2 Hz), 140.0,
139.8, 139.7, 135.8, 133.0, 130.6, 129.3, 128.8 (2C), 127.6, 127.2 (2C),
124.8, 124.3, 122.0, 112.2, 108.9, 67.5 (d, 3JP–C–C–C = 9.7 Hz), 62.5 (d,
13C NMR (100 MHz, CDCl3):  = 178.9, 155.2, 142.6 (d, 2JP–O–C = 6.3 Hz),
141.3, 134.6, 129.9, 128.1, 127.8 (2C), 126.7, 126.2 (2C), 125.6 (d,
3
3JP–O–C–C = 11.2 Hz), 122.9, 122.4, 119.3 (d, JP–O–C–C = 6.3 Hz), 114.9,
2JP–O–C = 7.0 Hz), 61.3 (d, 2JP–C–C = 4.4 Hz), 56.2, 43.7, 37.8, 35.8 (d, JP–C
135.7 Hz), 21.0, 16.3 (d, 3JP–O–C–C = 5.7 Hz).
=
113.7, 108.1, 66.6 (d, 3JP–C–C–C = 10.7 Hz), 61.4 (d, 2JP–O–C = 7.0 Hz), 60.4
2
(d, JP–C–C = 3.7 Hz), 54.7, 42.7, 37.0, 34.8 (d, JP–C = 135.0 Hz), 15.4 (d,
3JP–O–C–C = 5.5 Hz).
31P NMR (162 MHz, CDCl3):  = 26.59 (s).
HRMS (ESI): m/z [M + H]+ calcd for C28H30N2O5P: 505.1887; found:
31P NMR (162 MHz, CDCl3):  = 25.62 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H27BrN2O5P: 569.0835; found:
505.1891.
569.0844.
(±)-1′-Benzyl-5′-bromo-4-ethoxy-8-methyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3v)
(±)-1′-Benzyl-5′-bromo-8-chloro-4-ethoxy-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-Oxide (3y)
Yield: 102.9 mg (93%); white oil.
Yield: 97.5 mg (85%); yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.29–7.16 (m, 5 H), 7.08–6.93 (m, 3 H),
3
6.93–6.82 (m, 2 H), 6.59 (d, J = 7.8 Hz, 1 H), 5.11 (dd, JP–C–C–H = 15.0,
1H NMR (400 MHz, CDCl3):  = 7.40 (s, 1 H), 7.24–7.16 (m, 5 H), 7.03
(t, J = 7.8 Hz, 1 H), 6.97–6.90 (m, 2 H), 6.85 (t, J = 7.6 Hz, 1 H), 6.59 (d,
J = 7.7 Hz, 1 H), 5.07 (dd, 3JP–C–C–H = 12.2, 3JH–C–C–H = 8.4 Hz, 1 H), 4.91–
4.83 (m, 1 H), 4.73–4.65 (m, 1 H), 4.26–4.07 (m, 2 H), 3.31–3.18 (m,
1 H), 2.80 (s, 1 H), 2.64–2.54 (m, 1 H), 2.49– 2.39 (m, 1 H), 1.23 (t, J =
7.1 Hz, 3 H).
3JH–C–C–H = 7.8 Hz, 1 H), 4.92–4.83 (m, 1 H), 4.74–4.66 (m, 1 H), 4.28–
4.06 (m, 2 H), 3.29–3.16 (m, 1 H), 2.73–2.43 (m, 3 H), 2.23 (s, 3 H),
1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 180.0, 148.0 (d, 2JP–O–C = 6.5 Hz), 142.5,
135.7, 134.2, 131.2, 131.0, 130.4, 129.2, 129.0 (2C), 127.8, 127.3 (2C),
125.3 (d, 3JP–O–C–C = 11.5 Hz), 124.0, 123.6, 119.4 (d, 3JP–O–C–C = 6.6 Hz),
13C NMR (100 MHz, CDCl3):  = 179.8, 148.5 (d, 2JP–O–C = 6.2 Hz), 142.3,
135.6, 130.8, 130.7, 129.7, 129.2, 128.9 (2C), 127.9, 127.8, 127.2 (2C),
109.2, 67.7 (d, 3JP–C–C–C = 10.3 Hz), 62.6 (d, 2JP–O–C = 7.0 Hz), 61.5 (d, 2JP–C–C
3.8 Hz), 43.8, 38.0, 36.1 (d, JP–C = 134.4 Hz), 20.8, 16.5 (d, JP–O–C–C
=
=
3
3
123.9, 123.6, 120.9, 120.9, 109.2, 67.6 (d, JP–C–C–C = 11.1 Hz), 62.8 (d,
2
5.7 Hz).
2JP–O–C = 7.0 Hz), 60.8 (d, JP–C–C = 3.6 Hz), 43.8, 37.9, 35.6 (d, JP–C
=
134.7 Hz), 16.4 (d, 3JP–O–C–C = 5.5 Hz).
31P NMR (162 MHz, CDCl3):  = 25.57 (s).
HRMS (ESI): m/z [M + H]+ calcd for C27H27BrN2O4P: 553.0886; found:
31P NMR (162 MHz, CDCl3):  = 24.84 (s).
HRMS (ESI): m/z [M + H]+ calcd for C26H24BrClN2O4P: 573.0340;
533.0879.
found: 573.0364.
(±)-1′-Benzyl-5′-bromo-4-ethoxy-8-ethyl-1,3,3a,9b-tetrahydro-
spiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-
2′-one 4-oxide (3w)
(±)-4-Ethoxy-5′-fluoro-8-methyl-1,3,3a,9b-tetrahydrospiro[ben-
zo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-
Oxide (3z)
Yield: 104.4 mg (92%); light-yellow oil.
Yield: 76.4 mg (95%); light-yellow oil.
1H NMR (400 MHz, CDCl3):  = 7.26–7.17 (m, 5 H), 7.09–6.99 (m, 2 H),
6.97–6.88 (m, 2 H), 6.83 (t, J = 7.5 Hz, 1 H), 6.59 (d, J = 7.8 Hz, 1 H),
5.12 (dd, JP–C–C–H = 14.7, JH–C–C–H = 7.8 Hz, 1 H), 4.93–4.86 (m, 1 H),
4.72–4.66 (m, 1 H), 4.29–4.01 (m, 2 H), 3.27–3.15 (m, 1 H), 2.74–2.40
(m, 5 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.12 (t, J = 7.6 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.91–8.82 (m, 1 H), 7.26 (s, 1 H), 7.12
(d, J = 8.3 Hz, 1 H), 6.96 (d, J = 8.3 Hz, 1 H), 6.89–6.80 (m, 1 H), 6.73–
3
3
3
3
6.68 (m, 1 H), 5.11 (dd, JP–C–C–H = 14.2, JH–C–C–H = 7.7 Hz, 1 H), 4.41–
4.18 (m, 2 H), 3.21–3.08 (m, 1 H), 2.86 (s, 1 H), 2.77–2.59 (m, 1 H),
2.58–2.42 (m, 1 H), 2.31 (s, 3 H), 2.11 (s, 1 H), 1.32 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 179.9, 148.0 (d, 2JP–O–C = 6.3 Hz), 142.4,
140.5, 135.6, 131.1, 130.0, 129.2, 129.1, 128.9 (2C), 127.7, 127.2 (2C),
125.2 (d, 3JP–O–C–C = 11.1 Hz), 124.0, 123.5, 119.3 (d, 3JP–O–C–C = 6.5 Hz),
13C NMR (100 MHz, CDCl3):  = 182.1, 159.4 (d, JF–C = 241.7 Hz), 147.7
2
3
(d, JP–O–C = 6.5 Hz), 136.4, 134.3, 133.4 (d, JF–C–C–C = 7.9 Hz), 131.1,
3
3
109.1, 67.6 (d, 3JP–C–C–C = 10.5 Hz), 62.5 (d, 2JP–O–C = 7.0 Hz), 61.5 (d, 2JP–C–C
3.7 Hz), 43.8, 38.0, 36.1 (d, JP–C = 134.4 Hz), 28.2, 16.4 (d, JP–O–C–C
=
=
130.5, 125.0 (d, JP–O–C–C = 11.0 Hz), 119.3 (d, JP–O–C–C = 6.6 Hz), 115.5
3
2
2
3
(d, JF–C–C = 23.7 Hz), 112.3 (d, JF–C–C = 25.2 Hz), 110.7 (d, JF–C–C–C =
3
2
5.5 Hz), 15.7.
31P NMR (162 MHz, CDCl3):  = 25.40 (s).
HRMS (ESI): m/z [M + H]+ calcd for C28H29BrN2O4P: 567.1043; found:
567.1053.
7.8 Hz), 68.2 (d, JP–C–C–C = 11.9 Hz), 62.6 (d, JP–O–C = 6.9 Hz), 61.3 (d,
2JP–C–C = 3.8 Hz), 37.8, 35.9 (d, JP–C = 134.6 Hz), 20.7, 16.4 (d, 3JP–O–C–C
=
5.6 Hz).
31P NMR (162 MHz, CDCl3):  = 25.19 (s).
19F NMR (377 MHz, CDCl3):  = –119.21 (s).
HRMS (ESI): m/z [M + Na]+ calcd for C20H20FN2NaO4P: 425.1037;
found: 425.1058.
(±)-1′-Benzyl-5′-bromo-4-ethoxy-8-methoxy-1,3,3a,9b-tetrahy-
drospiro[benzo[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indo-
lin]-2′-one 4-Oxide (3x)
Yield: 76.3 mg (67%); yellow oil.
(±)-4-Ethoxy-8-ethyl-5′-fluoro-1,3,3a,9b-tetrahydrospiro[benzo-
[5,6][1,2]oxaphosphinino[4,3-b]pyrrole-2,3′-indolin]-2′-one 4-
Oxide (3z1)
1H NMR (400 MHz, CDCl3):  = 7.20 (s, 4 H), 7.05–6.97 (m, 2 H), 6.90
(s, 2 H), 6.85 (s, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 6.59 (d, J = 6.5 Hz, 1 H),
5.15–5.02 (m, 1 H), 4.91–4.82 (m, 1 H), 4.73–4.64 (m, 4.0 Hz, 1 H),
4.25–4.07 (m, 2 H), 3.66 (s, 3 H), 3.28–3.14 (m, 1 H), 2.74–2.40 (m,
3 H), 1.23 (t, J = 6.1 Hz, 3 H).
Yield: 79.9 mg (96%); white oil.
1H NMR (400 MHz, CDCl3):  = 8.85–8.77 (m, 1 H), 7.36–7.15 (m, 1 H),
7.08 (dd, J = 8.2, 2.3 Hz, 1 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.79–6.68 (m,
3
1 H), 6.54 (dd, J = 8.1, 2.6 Hz, 1 H), 5.04 (dd, JP–C–C–H = 13.4, JH–C–C–H
=
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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T. Huang et al.
Paper
Synthesis
7.6 Hz, 1 H), 4.43–4.10 (m, 2 H), 3.21–3.07 (m, 1 H), 2.81 (s, 1 H),
2.60–2.50 (m, 3 H), 2.46–2.35 (m, 1 H), 2.07 (s, 1 H), 1.25 (t, J = 7.1 Hz,
3 H), 1.13 (t, J = 7.6 Hz, 3 H).
Song, H.; Liu, Y.; Gu, Y.; Wang, L.; Wang, Q. J. Agric. Food Chem.
2016, 64, 6508. (e) Ma, Y.; Fan, C.; Jia, B.; Cheng, P.; Liu, J.; Ma,
Y.; Qiao, K. Chirality 2017, 29, 737.
(3) (a) Kumar, A.; Gupta, G.; Bishnoi, A. K.; Saxena, R.; Saini, K. S.;
Konwar, R.; Kumar, S.; Dwivedi, A. Bioorg. Med. Chem. 2015, 23,
839. (b) Yu, B.; Sun, X. N.; Shi, X. J.; Qi, P. P.; Zheng, Y. C.; Yu, D.
Q.; Liu, H. M. Steroids 2015, 102, 92.
(4) (a) Bhaskar, G.; Arun, Y.; Balachandran, C.; Saikumar, C.;
Perumal, P. T. Eur. J. Med. Chem. 2012, 51, 79. (b) Singh, S. B.;
Tiwari, K.; Verma, P. K.; Srivastava, M.; Tiwari, K. P.; Singh, J.
Supramol. Chem. 2013, 25, 255. (c) Kumar, R. S.; Antonisamy, P.;
Almansour, A. I.; Arumugam, N.; Periyasami, G.; Altaf, M.; Kim,
H.-R.; Kwon, K.-B. Eur. J. Med. Chem. 2018, 152, 417.
13C NMR (100 MHz, CDCl3):  = 181.0, 158.4 (d, JF–C = 241.7 Hz), 146.8
2
3
(d, JP–O–C = 6.3 Hz), 139.7, 135.4 (d, JF–C–C–C = 2.2 Hz), 132.6 (d, J =
7.9 Hz), 129.0, 128.3, 123.9 (d, 3JP–O–C–C = 10.9 Hz), 118.3 (d, 3JP–O–C–C
=
6.7 Hz), 114.4 (d, 2JF–C–C = 23.7 Hz), 111.3 (d, 2JF–C–C = 25.1 Hz), 109.6 (d,
3JF–C–C–C = 7.9 Hz), 67.2 (d, 3JP–C–C–C = 11.1 Hz), 61.6 (d, 2JP–O–C = 7.0 Hz),
60.4 (d, 2JP–C–C = 3.6 Hz), 36.8, 35.0 (d, JP–C = 134.1 Hz), 27.1, 15.4 (d,
3JP–O–C–C = 5.5 Hz), 14.6.
31P NMR (162 MHz, CDCl3):  = 24.90 (s).
19F NMR (377 MHz, CDCl3):  = –119.30 (s).
HRMS (ESI): m/z [M + H]+ calcd for C21H23FN2O4P: 417.1374; found:
417.1385.
(5) (a) Gollner, A.; Rudolph, D.; Arnhof, H.; Bauer, M.; Blake, S. M.;
Boehmelt, G.; Cockroft, X. L.; Dahmann, G.; Ettmayer, P.;
Gerstberger, T.; Karolyi-Oezguer, J.; Kessler, D.; Kofink, C.;
Ramharter, J.; Rinnenthal, J.; Savchenko, A.; Schnitzer, R.;
Weinstabl, H.; Weyer-Czernilofsky, U.; Wunberg, T.; McConnell,
D. B. J. Med. Chem. 2016, 59, 10147. (b) Gao, X.; Wei, M.; Shan,
W.; Liu, Q.; Gao, J.; Liu, Y.; Zhu, S.; Yao, H. Pharmacol. Res. 2019,
148, 104400.
(6) (a) Weber, G. F.; Waxman, D. J. Biochem. Pharmacol. 1993, 45,
1685. (b) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem. Rev.
2005, 105, 899. (c) Stoianova, D. S.; Whitehead, A.; Hanson, P. R.
J. Org. Chem. 2005, 70, 5880.
(7) (a) Borch, R. F.; Canute, G. W. J. Med. Chem. 1991, 34, 3044.
(b) Clarion, L.; Jacquard, C.; Sainte-Catherine, O.; Loiseau, S.;
Filippini, D.; Hirlemann, M.-H.; Volle, J.-N.; Virieux, D.;
Lecouvey, M.; Pirat, J.-L.; Bakalara, N. J. Med. Chem. 2012, 55,
2196. (c) Dayde, B.; Pierra, C.; Gosselin, G.; Surleraux, D.;
Ilagouma, A. T.; Laborde, C.; Volle, J.-N.; Virieux, D.; Pirat, J.-L.
Eur. J. Org. Chem. 2014, 1333.
(±)-1-Benzyl-4′-ethoxy-1′,3′,3a′,11c′-tetrahydrospiro[indoline-
3,2′-naphtho[1′,2′:5,6][1,2]oxaphosphinino[4,3-b]pyrrol]-2-one
4′-Oxide (3z2)
Yield: 91.9 mg (90%); white oil.
1H NMR (400 MHz, CDCl3):  = 7.42 (dd, J = 7.7, 1.7 Hz, 1 H), 7.28–7.19
(m, 8 H), 7.13–7.01 (m, 3 H), 6.94 (d, J = 6.2 Hz, 1 H), 6.85 (t, J = 7.0 Hz,
1 H), 6.60 (d, J = 7.8 Hz, 1 H), 5.15 (dd, 3JP–C–C–H = 14.3, JH–C–C–H = 7.8 Hz,
1 H), 4.94–4.87 (m, 1 H), 4.75–4.68 (m, 1 H), 4.29–4.10 (m, 2 H), 3.78–
3.47 (m, 1 H), 2.77–2.48 (m, 3 H), 1.25 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 178.9, 149.0, 149.0, 141.3, 134.6,
130.0, 129.9, 128.7, 128.1, 127.9 (2C), 126.7, 126.4, 126.2 (2C), 124.8,
3
124.7, 123.5, 122.9, 122.5, 118.6, 118.5, 108.1, 66.6 (d, JP–C–C–C
=
2
2
10.7 Hz), 61.5 (d, JP–O–C = 7.2 Hz), 60.3 (d, JP–C–C = 3.7 Hz), 42.7, 37.0,
35.0 (d, JP–C = 134.5 Hz), 15.4 (d, 3JP–O–C–C = 5.6 Hz).
31P NMR (162 MHz, CDCl3):  = 25.14 (s).
HRMS (ESI): m/z [M + H]+ calcd for C30H28N2O4P: 511.1781; found:
(8) Li, X.; Zhang, D.; Pang, H.; Shen, F.; Fu, H.; Jiang, Y.; Zhao, Y. Org.
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(9) Li, Z.; Han, J.; Jiang, Y.; Browne, P.; Knox, R. J.; Hu, L. Bioorg. Med.
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511.1773.
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2015, 71, 5765. (b) Zheng, P. F.; Ouyang, Q.; Niu, S. L.; Shuai, L.;
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137, 9390. (c) Tian, Y. M.; Tian, L. M.; He, X.; Li, C. J.; Jia, X. S.; Li,
J. Org. Lett. 2015, 17, 4874. (d) Wang, S. Z.; Jiang, Y.; Wu, S. C.;
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2016, 18, 1028. (e) Zhu, L. Y.; Chen, Q. L.; Shen, D.; Zhang, W. H.;
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(f) Zhao, K.; Zhi, Y.; Li, X. Y.; Puttreddy, R.; Rissanen, K.; Enders,
D. Chem. Commun. 2016, 52, 2249. (g) Luo, M. P.; Yuan, R. J.; Liu,
X. S.; Yu, L. Q.; Wei, W. H. Chem. Eur. J. 2016, 22, 9797.
(h) Chaudhari, P. D.; Hong, B. C.; Lee, G. H. Org. Lett. 2017, 19,
6112. (i) Jiang, S.; Guo, H. M.; Yao, S.; Shi, D. Q.; Xiao, W. J. J. Org.
Chem. 2017, 82, 10433. (j) Jiang, Y.; Yu, S. W.; Yang, Y.; Liu, Y. L.;
Xu, X. Y.; Zhang, X. M.; Yuan, W. C. Org. Biomol. Chem. 2018, 16,
6647. (k) Yan, J.; Shi, K. X.; Zhao, C. T.; Ding, L. Y.; Jiang, S. S.;
Yang, L. M.; Zhong, G. F. Chem. Commun. 2018, 54, 1567. (l) Liu,
T.; Feng, J. J.; Chen, C.; Deng, Z. J.; Kotagiri, R.; Zhou, G. X.; Zhang,
X. H.; Cai, Q. Org. Lett. 2019, 21, 4505. (m) Qiu, B.; Xu, D. Q.; Sun,
Q. S.; Lin, J.; Sun, W. Org. Lett. 2019, 21, 618.
Funding Information
We gratefully acknowledge the financial support from Program of
Natural Science Foundation of Hainan Province (2019RC215) and
Graduate Innovative Research Project of Hainan Normal University
(Hsyx2018-25).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691597.
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