Chiral squaramide catalyzed asymmetric conjugate additions of 3-substituted oxindoles to vinylphosphonates

Article abstract of DOI:10.1055/s-0032-1316919

An efficient organocatalytic enantioselective conjugate addition of 3-substituted oxindoles to activated vinylphosphonates has been described. This reaction allows the facile synthesis of a new family of organophosphorus derivatives bearing an oxindole motif in high chemical yields with good to excellent stereoselectivities. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0032-1316919

SPECIAL TOPIC
▌1647
sCpehciailrtoapilc Squaramide Catalyzed Asymmetric Conjugate Additions of
3-Substituted Oxindoles to Vinylphosphonates
Conjugate Additions of 3-Substituted Oxindoles to Vinylphosphonates
Shu-Wen Duan, Yi-Yin Liu, Wei Ding, Tian-Ren Li, De-Qing Shi, Jia-Rong Chen,* Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, P. R. of China
Fax +86(27)67862041; E-mail: jiarongchen2003@yahoo.com.cn; E-mail: wxiao@mail.ccnu.edu.cn
Received: 25.01.2013; Accepted after revision: 20.03.2013
doles.10 A new family of unnatural Cγ-tetrasubstituted α-
amino acid derivatives were synthesized in excellent
yields and stereoselectivities. As part of our ongoing re-
search interest in oxindole chemistry11 and inspired by the
Abstract: An efficient organocatalytic enantioselective conjugate
addition of 3-substituted oxindoles to activated vinylphosphonates
has been described. This reaction allows the facile synthesis of a
new family of organophosphorus derivatives bearing an oxindole
motif in high chemical yields with good to excellent stereoselectiv- promising biological activity of organophosphorus com-
ities.
pounds, we envisaged the possibility of organocatalytic
stereoselective conjugate addition of 3-substituted oxin-
doles to activated vinylphosphonates to give a new class
of oxindoles that have potential as candidates for drug dis-
covery and biological investigations. Recently, Shi, Zhao,
and co-workers reported a highly enantioselective cincho-
na alkaloid thiourea catalyzed conjugate addition of 3-
aryloxindoles to a vinylbisphosphonate;12 the correspond-
ing geminal bisphosphonates were obtained in good
yields and high enantioselectivities. Alternatively, we
herein reported a chiral squaramide-catalyzed asymmetric
conjugate addition reaction of 3-substituted oxindoles to
α-phosphonoacrylates, affording phosphorus analogues
of amino acids in excellent yields (90–97%) with good to
excellent diastereo- (up to 94:6) and enantioselectivities
(92% to >99% ee).
Key words: organophosphorus compounds, conjugate addition,
oxindole, organocatalysis, squaramide catalyst
In the recent past, the construction of skeletally diverse
chiral organophosphorus compounds has attracted consid-
erable attention1 because of their great prevalence in im-
portant natural products, pharmaceuticals, and
agrochemicals.2 Moreover, their unique reactivity in vari-
ous chemical transformations, such as Horner–Wad-
sworth–Emmons olefination,3 makes organophosphorus
compounds a valuable class of building blocks in the con-
struction of molecular complexity. In this context, conju-
gate addition4 of carbo- and heteronucleophiles to
vinylphosphonates has provided a practical and atom-eco-
nomic route to these chiral compounds with highly func-
tional group tolerance and stereoselective control.5
Consequently, extensive research efforts have been di-
rected toward the development of more efficient methods
for the synthesis of organophosphorus compounds in an
enantioselective manner. Pioneered by the first successful
example of organocatalytic conjugate addition of bisphos-
phonates by the Alexakis group,6 several elegant strate-
gies have been reported for asymmetric addition with
vinylphosphonates to afford chiral adducts in high yields
and enantioselectivities.7 Despite advances, the search for
novel and more practical methods for the synthesis of en-
antioenriched phosphorus compounds with various func-
tional groups for further manipulations is still highly
desirable.
Initially, a model reaction between tert-butyl 2-oxo-3-
phenylindoline-1-carboxylate (1a) and ethyl 2-(diethoxy-
phosphoryl)acrylate (2) was chosen to optimize the reac-
tion conditions (Table 1). Catalyst screening first focused
on commonly used bifunctional organocatalysts. It was
found that amine-H bonding catalysts could promote this
reaction using dichloromethane as the solvent at room
temperature. For example, bifunctional amine-thiourea
catalysts I–III (Figure 1) worked well for this reaction
with catalyst III giving higher enantioselectivity (entry 3).
Stimulated by our previous success in chiral squaramide
catalysis,11b we extended our efforts to this promising cat-
alyst category to improve further the diastereoselectivity.
To our delight, the use of quinine-derived squaramide IV
as catalyst does indeed increase the diastereoselectivity
while maintained the excellent enantioselectivity (dr
72:28, 97% ee). Subsequently, evaluation of the reaction
media revealed that chloroform was the best solvent in
terms of yield and stereoselectivity (entry 5).
On the other hand, oxindole derivatives play a significant
role in synthetic and medicinal chemistry,8 and thus con-
siderable efforts have been devoted in this topical area of
research over the past few decades.9 In this field, we have
also developed a cinchona-derived, thiourea-catalyzed
asymmetric conjugate addition/protonation cascade of
ethyl 2-phthalimidoacrylate and 3-substituted oxin-
Inspired by the high efficiency and catalytic activity of the
squaramide catalysts,13 we hypothesize that finely tuning
the electronic and steric properties of IV may increase di-
astereoselectivity. Remarkably, replacement of the 3,5-
bis(trifluoromethyl)phenyl moiety in catalyst IV with the
3,5-dimethylphenyl group significantly improved the dia-
stereoselectivity to 83:17 with great enantioselectivity
SYNTHESIS 2013, 45, 1647–1653
Advanced online publication: 16.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316919; Art ID: SS-2013-C0080-ST
© Georg Thieme Verlag Stuttgart · New York

1648
S.-W. Duan et al.
SPECIAL TOPIC
Table 1 Condition Optimizationa
CF3
O
P
N
H
N
H
Ph
catalyst
Ph
N
F3C
N
OEt
OEt
S
O
(10 mol%)
H
OEt
OEt
EtO2C
P
+
S
N
N
H
CF3
O
solvent, r.t.
CO2Et
N
H
O
N
CF3
Boc
Me
Me
Boc
3a
N
I
II
1a
2
Entry Catalyst Solvent
Time
(h)
Yieldb
(%)
drc
eec
(%)
H
H
H
S
Ph
R
N
N
N
Ph
N
N
H
OMe
1
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
Et2O
1
1
88
93
92
94
99
93
99
90
95
99
92
89
91
90
66:34
51:49
68:32
72:28
75:25
69:31
60:40
56:44
39:61
72:28
83:17
83:17
93:7
35
H
O
O
N
NHMes
Me
Me
R
2
II
75
N
III
IV R = CF3
V R = CH3
3
III
IV
IV
IV
IV
IV
IV
IV
V
1
95
4
1
97
5
1
94
N
H
N
H
N
H
6
1
95
OMe
O
O
7
1
93
N
VI
8
THF
1
89
Figure 1 Organocatalysts used in the study
9
MeCN
DMF
1
64
10
11
12d
13d,e
14e
0.5
1
2
To further extend the substrate scope of this transforma-
tion, we synthesized a series of 3-aryl- and alkyl-substitut-
ed oxindoles and applied them to this asymmetric
conjugate addition (Table 3). It was found that the corre-
sponding adducts 3j–o were afforded in good yields and
stereoselectivities. Notably, a benzyl group can also be
tolerated, giving the desired organophosphorus product in
almost quantitative yield and excellent enantioselectivity.
CHCl3
CHCl3
CHCl3
CHCl3
>99
>99
>99
–95f
V
8
V
8
VI
8
76:24
a Conditions 1a (0.20 mmol), catalyst I–VI (0.02 mmol), 2 (0.24
mmol), solvent (1 mL), stirring, r.t.
b Isolated yield.
In order to confirm the absolute configuration of the prod-
uct, the Boc group in compound 3n was removed to give
4. The structural assignment of the resultant crystal com-
pound 4 shows a (7R,18S) conformational outcome (Fig-
ure 2).14
c Determined by chiral HPLC analysis.
d CHCl3 (5 mL) was used.
e The reaction was conducted at –60 °C.
f Product was ent-3a.
(>99% ee) (Table 1, entry 11 vs. entry 5). Finally, optimal
results were obtained by treating 1a and 2 at –60 °C in the
presence of 10 mol% of V, resulting in the isolation of 3a
in 91% yield with dr 93:7 and >99% ee (entry 13). More
importantly, the enantiomer of 3a could also be obtained
by simply changing the quinine-derived squaramide to its
quinidine analogue, albeit with slightly decreased diaste-
reoselectivity (entry 14).
With the optimal reaction conditions identified, we then
examined the substrate scope of this asymmetric conju-
gate addition. As shown in Table 2, the reaction appeared
to be general with various oxindole nucleophiles. In the
case of either electron-rich (entries 4 and 5) or electron-
deficient substrates (entries 1–3 and 6–16), the desired
products was always obtained in excellent yields and good
stereoselectivities. Importantly, variation of the substitu-
ent position (C4–C7) of the oxindole component does not
affect the reaction efficiency.
Figure 2 X-ray crystal structure of compound 4
In order to demonstrate the synthetic utility of the current
methodology, we applied the product 3a to Horner–Wad-
sworth–Emmons olefination reaction (Scheme 1). Unfor-
tunately, the expected alkene 5 was racemic but with good
yield, probably because of the inevitable retro-Michael
addition.
Synthesis 2013, 45, 1647–1653
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Conjugate Additions of 3-Substituted Oxindoles to Vinylphosphonates
1649
Table 3 Scope of the Asymmetric Conjugate Addition Reaction
Table 2 Scope of the Asymmetric Conjugate Addition Reaction
with 3-Substituted Oxindoles to Vinylphosphonatesa
with 3-Phenyl-Substituted Oxindoles to Vinylphosphonatesa
O
O
4
R
5
Ph
V or VI
R
V or VI
Ph
OEt
OEt
OEt
OEt
O
P
O
P
P
R
6
P
R
(10 mol%)
(10 mol%)
*
*
OEt
OEt
OEt
OEt
EtO2C
EtO2C
+
+
*
*
O
CO2Et
CO2Et
CHCl3, –60 °C
CHCl3, –60 °C
O
N
O
O
N
N
7
N
Boc
Boc
Boc
Boc
1
2
3
1
2
3
Catalyst Time Yieldb
drc
eec
(%)
Entry R
Catalyst Time Yieldb
drc
eec
(%)
Entry R
(h)
(%)
(h)
(%)
1
2
3
4
5
6d
7
4-FC6H4
V
VI
V
V
V
V
V
6
3j
91 91:9
98
1
H
V
8
8
7
8
8
6
6
6
6
6
6
6
6
6
6
6
3a
91
93:7
>99
95
4-FC6H4
6
ent-3j 94 81:19 97
2
H
VI
V
ent-3a
3b
90
92
90
92
94
90
97
99
97
92
90
94
95
94
90
76:24
84:16
94:6
4-MeC6H4
4-MeOC6H4
2-naphthyl
3,5-Me2C6H3
Bn
8
3k
3l
92 85:15 98
97 88:12 99
96 85:15 >99
97 86:14 99
96 84:16 95
3
4-Cl
5-Me
92
8
4
V
3c
>99
98
8
3m
3n
3o
5
5-Me VI
ent-3c
3d
86:14
93:7
8
6
5-F
V
>99
97
10
7
5-F
VI
V
ent-3d
3e
81:19
89:11
75:25
90:10
91:9
a Conditions 1 (0.20 mmol), 2 (0.24 mmol), catalyst V or VI (0.02
mmol), CHCl3 (5 mL), stirring at –60 °C.
b Isolated yield.
8
5-Br
5-Br
5-OCF3
6-Cl
6-Cl
6-Br
6-Br
7-F
99
9
VI
V
ent-3e
3f
97
c Determined by chiral HPLC analysis.
10
11
12
13
14
15
16
99
d One Br atom is introduced into 5-position of the benzene ring.
V
3g
>99
98
VI
V
ent-3g
3h
70:30
90:10
71:29
84:16
82:18
99
1H NMR spectra were recorded on Varian Mercury 400/600
(400/600 MHz) spectrometers; solvent resonance as the internal
standard (CDCl3: δ = 7.26 ppm). 13C NMR spectra were recorded on
Varian Mercury 400/600 (100/150 MHz) with complete proton de-
coupling spectrometers (CDCl3: δ = 77.0 ppm). Mass spectra were
measured on API 2000 LC/MS/MS (ESI-MS). Enantiomeric ratios
were determined by chiral HPLC on Agilent 1100 series with chiral
columns with hexane and i-PrOH as the solvents. Optical rotations
were measured with Jasco P-1020 polarimeter.
VI
V
ent-3h
3i
97
97
7-F
VI
ent-3i
95
a Conditions: 1 (0.20 mmol), 2 (0.24 mmol), catalyst V or VI (0.02
mmol), CHCl3 (5 mL), stirring, –60 °C.
b Isolated yield.
c Determined by chiral HPLC analysis.
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-2-oxo-3-phenylindoline-1-carboxylate (3a); Typical
Procedure
To a soln of ethyl 2-(diethoxyphosphoryl)acrylate (2, 56.7 mg, 0.24
mmol) in CHCl3 (5 mL) at –60 °C, a mixture of tert-butyl 2-oxo-3-
phenylindoline-1-carboxylate (1a, 61.9 mg, 0.20 mmol) and
squaramide V (10.5 mg, 0.02 mmol) was added. The resulting soln
was stirred at a constant temperature until completion (TLC moni-
toring). The crude product was purified by chromatography (silica
gel, PE–EtOAc, 2:1) to give the corresponding conjugate adduct 3a
as a light yellow oil; yield: 98.1 mg (91%); dr 93:7; >99% ee;
[α]D18 +23.30 (c 1.00, CH2Cl2). The diastereoisomers cannot be
separated by chromatography, so some NMR data contain both iso-
mers.
O
P
(HCHO)n (5.0 equiv)
MgCl2·6H2O
OEt
OEt
(2.0 equiv)
CO2Et
CO2Et
O
O
DBU (2.0 equiv)
61%
N
N
Boc
Boc
3a >99% ee
5 2% ee
Scheme 1 Horner–Wadsworth–Emmons olefination of 3a
In conclusion, an efficient and practical asymmetric con-
jugate addition of 3-substituted oxindoles to vinylphos-
phonate catalyzed by easily accessible squaramide
catalysts has been disclosed. This transformation provides
a highly efficient method for incorporating the phospho-
nate unit into oxindole skeletons, affording a new class of
oxindole derivatives. Further expansion of the reaction
scope and biological evaluation of these products are cur-
rently underway in our laboratories.
HPLC (Chiralpak AD-H column; detected at 254 nm; hexane–
i-PrOH, 90:10; flow: 1 mL/min): tR: t1 = 8.84, t2 = 9.86, t3 = 10.94,
t4 = 14.38 min.
1H NMR (600 MHz, CDCl3): δ = 7.90 (d, J = 8.1 Hz, 1 H), 7.36–
7.26 (m, 6 H, major + minor), 7.20–7.17 (m, 2 H), 4.19–4.13 (m, 4
H, major + minor), 3.88–3.76 (m, 1 H), 3.59–3.55 (m, 1 H), 3.09–
2.96 (m, 2 H), 2.84–2.76 (m, 1 H), 1.63 (s, 9 H), 1.33 (t, J = 7.0 Hz,
6 H), 1.05 (t, J = 7.1 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1647–1653

1650
S.-W. Duan et al.
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): δ = 175.71, 175.02, 168.43, 168.38,
148.78, 140.08, 139.71, 138.75, 128.98, 128.76, 128.55, 128.51,
127.68, 127.09, 126.76, 126.10, 124.89, 124.36, 124.04, 115.38,
114.96, 84.44, 84.17, 63.25, 63.20, 63.04, 62.79, 62.63, 62.57,
61.53, 61.40, 56.39, 56.24, 42.64, 41.37, 34.94, 34.42, 27.87, 16.15,
13.72, 13.53.
31P NMR (162 MHz, CDCl3): δ = 20.44.
MS: m/z = 545.24 ([M]+).
13C NMR (100 MHz, CDCl3): δ = 175.35, 168.43, 168.37, 160.73,
158.30, 148.80, 138.23, 135.68, 130.82, 130.74, 127.97, 126.71,
116.43, 115.58, 115.36, 113.43, 113.19, 84.72, 63.34, 63.28, 62.95,
61.58, 56.65, 56.51, 42.66, 41.39, 34.27, 27.92, 16.20, 13.66.
31P NMR (162 MHz, CDCl3): δ = 20.17.
MS: m/z = 563.23 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39FN2O8P: 581.2428;
found: 581.2417.
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H40N2O8P: 563.2522;
found: 563.2511.
tert-Butyl (R)-5-Bromo-3-[(S)-2-(diethoxyphosphoryl)-3-eth-
oxy-3-oxopropyl]-2-oxo-3-phenylindoline-1-carboxylate (3e)
Light yellow oil; yield: 120.9 mg (97%); dr 89:11; 99% ee; [α]D
19
tert-Butyl (R)-4-Chloro-3-[(S)-2-(diethoxyphosphoryl)-3-eth-
oxy-3-oxopropyl]-2-oxo-3-phenylindoline-1-carboxylate (3b)
Light yellow oil; yield: 106.7 mg (92%); dr 84:16; 92% ee; [α]D
+29.60 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 7.32,
t2 = 10.78, t3 = 12.99, t4 = 19.48 min.
1H NMR (600 MHz, CDCl3): δ = 7.82 (d, J = 8.7 Hz, 1 H), 7.47 (d,
J = 8.7 Hz, 1 H), 7.33–7.28 (m, 6 H), 4.16–4.10 (m, 4 H, major +
minor), 3.96–3.91 (m, 1 H), 3.81–3.76 (m, 1 H), 3.06 (t, J = 14.7
Hz, 1 H), 2.97 (t, J = 12.5 Hz, 1 H), 2.75 (dd, J = 24.2, 10.4 Hz, 1
H), 1.62 (s, 9 H), 1.33 (t, J = 7.0 Hz, 6 H), 1.12 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.86, 168.29, 148.58, 138.74,
138.09, 131.73, 130.97, 128.75, 127.94, 126.61, 117.12, 116.71,
84.81, 63.21, 62.80, 61.67, 56.42, 56.27, 42.67, 41.40, 34.23, 27.83,
16.15, 13.64.
31P NMR (162 MHz, CDCl3): δ = 20.09.
MS: m/z = 623.13 ([M]+).
17
+41.14 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 10.62,
t2 = 11.71, t3 = 18.86, t4 = 63.48 min.
1H NMR (600 MHz, CDCl3): δ = 7.91 (d, J = 8.2 Hz, 1 H), 7.36–
7.26 (m, 4 H, major + minor), 7.22 (d, J = 7.8 Hz, 2 H), 7.11 (d,
J = 8.1 Hz, 1 H), 4.21–4.12 (m, 4 H), 3.85–3.79 (m, 1 H), 3.65–3.59
(m, 1 H), 3.39–3.31 (m, 1 H), 3.18 (t, J = 14.4 Hz, 1 H), 2.81 (dd,
J = 23.9, 10.7 Hz, 1 H), 1.61 (s, 9 H), 1.36 (t, J = 6.9 Hz, 6 H), 1.09
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): 174.59, 167.66, 167.61, 148.56,
141.88, 136.81, 132.15, 130.15, 128.57, 127.80, 126.69, 126.55,
125.67, 113.41, 84.90, 63.46, 63.39, 62.83, 62.76, 61.51, 57.14,
56.99, 42.69, 41.42, 30.51, 27.85, 16.22, 13.57.
31P NMR (162 MHz, CDCl3): δ = 20.18.
MS: m/z = 579.03 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39BrN2O8P: 641.1627;
found: 641.1618.
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39ClN2O8P: 597.2133;
found: 597.2125.
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-2-oxo-3-phenyl-5-(trifluoromethoxy)indoline-1-car-
boxylate (3f)
19
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
Light yellow oil; yield: 121.6 mg (97%); dr 90:10; 99% ee; [α]D
propyl]-5-methyl-2-oxo-3-phenylindoline-1-carboxylate (3c)
Light yellow oil; yield: 100.7 mg (90%); dr 94:6; >99% ee; [α]D
+29.07 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 5.20,
t2 = 7.58, t3 = 8.41, t4 = 13.29 min.
1H NMR (600 MHz, CDCl3): δ = 7.96 (d, J = 8.9 Hz, 1 H), 7.37–
7.28 (m, 5 H, major + minor), 7.22 (d, J = 8.6 Hz, 1 H), 7.08 (s, 1
H), 4.18–4.10 (m, 4 H, major + minor), 3.93–3.87 (m, 1 H), 3.71–
3.66 (m, 1 H), 3.07–2.96 (m, 2 H), 2.83 (dd, J = 24.3, 10.1 Hz, 1 H),
1.63 (s, 9 H), 1.35–1.32 (m, 6 H), 1.09 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.17, 168.34, 168.28, 148.71,
145.57, 138.20, 137.98, 130.78, 128.86, 128.07, 126.71, 121.52,
119.22, 116.21, 84.98, 63.30, 62.97, 62.90, 61.75, 61.48, 56.57,
56.43, 42.62, 41.35, 34.30, 27.92, 16.22, 13.65, 0.94.
31P NMR (162 MHz, CDCl3): δ = 20.06.
MS: m/z = 629.16 ([M]+).
17
+24.51 (c 1.01, CH2Cl2); HPLC (Chiralpak OD-H column; detected
at 254 nm; hexane–i-PrOH, 90:10; flow: 1 mL/min): tR: t1 = 5.91,
t2 = 6.77, t3 = 8.56, t4 = 13.74 min.
1H NMR (600 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 1 H), 7.35–
7.30 (m, 4 H), 7.28–7.25 (m, 1 H), 7.13 (d, J = 8.3 Hz, 1 H), 6.97 (s,
1 H), 4.18–4.10 (m, 4 H), 3.87–3.81 (m, 1 H), 3.63–3.58 (m, 1 H),
3.07–2.95 (m, 2 H), 2.79 (dd, J = 24.0, 10.5 Hz, 1 H), 2.33 (s, 3 H),
1.62 (s, 9 H), 1.33 (t, J = 6.8 Hz, 6 H), 1.06 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.96, 168.56, 148.91, 139.00,
137.37, 133.72, 129.32, 128.60, 127.66, 126.85, 126.54, 114.82,
84.31, 63.21, 62.81, 61.35, 56.51, 56.37, 42.70, 41.42, 34.38, 27.95,
20.95, 16.22, 13.61.
31P NMR (162 MHz, CDCl3): δ = 20.53.
MS: m/z = 559.16 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C29H39F3N2O9P: 647.2345;
found: 647.2334.
+
HRMS (EI+): m/z [M + NH4 ] calcd for C29H42N2O8P: 577.2679;
found: 577.2672.
tert-Butyl (R)-6-Chloro-3-[(S)-2-(diethoxyphosphoryl)-3-eth-
oxy-3-oxopropyl]-2-oxo-3-phenylindoline-1-carboxylate (3g)
Light yellow oil; yield: 106.6 mg (92%); dr 91:9; >99% ee; [α]D
19
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-5-fluoro-2-oxo-3-phenylindoline-1-carboxylate (3d)
Light yellow oil; yield: 99.5 mg (94%); dr 93:7; >99% ee; [α]D
+32.98 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 7.45,
t2 = 9.74, t3 = 11.25, t4 = 20.12 min.
1H NMR (600 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.32 (s, 4 H, major
+ minor), 7.30–7.28 (m, 1 H), 7.16 (d, J = 8.1 Hz, 1 H), 7.11 (d,
J = 8.1 Hz, 1 H), 4.16–4.09 (m, 4 H, major + minor), 3.89–3.84 (m,
1 H), 3.67–3.62 (m, 1 H), 3.04 (t, J = 14.5 Hz, 1 H), 2.96 (t, J = 12.5
Hz, 1 H), 2.77 (dd, J = 24.0, 10.5 Hz, 1 H), 1.63 (s, 9 H), 1.35–1.32
(m, 6 H), 1.09 (t, J = 7.1 Hz, 3 H).
18
+21.15 (c 1.01, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 6.95,
t2 = 10.07, t3 = 12.57, t4 = 20.12 min.
1H NMR (600 MHz, CDCl3): δ = 7.90 (dd, J = 8.9, 4.4 Hz, 1 H),
7.33 (s, 4 H), 7.29 (d, J = 4.2 Hz, 1 H), 7.05 (t, J = 8.8 Hz, 1 H), 6.91
(d, J = 7.7 Hz, 1 H), 4.18–4.10 (m, 4 H), 3.93–3.87 (m, 1 H), 3.76–
3.71 (m, 1 H), 3.08–2.95 (m, 2 H), 2.79 (dd, J = 24.1, 10.5 Hz, 1 H),
1.62 (s, 9 H), 1.34 (t, J = 7.0 Hz, 6 H), 1.10 (t, J = 7.1 Hz, 3 H).
Synthesis 2013, 45, 1647–1653
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Conjugate Additions of 3-Substituted Oxindoles to Vinylphosphonates
1651
13C NMR (100 MHz, CDCl3): δ = 175.23, 168.48, 148.60, 140.68,
138.25, 134.59, 128.73, 127.94, 127.04, 126.70, 124.18, 115.68,
85.04, 63.28, 62.85, 61.66, 56.22, 56.08, 42.64, 41.37, 34.46, 27.88,
16.21, 13.57.
31P NMR (162 MHz, CDCl3): δ = 20.08.
MS: m/z = 579.15 ([M]+).
31P NMR (162 MHz, CDCl3): δ = 20.27.
MS: m/z = 563.11 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39FN2O8P: 581.2428;
found: 581.2420.
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-2-oxo-3-(4-tolyl)indoline-1-carboxylate (3k)
Light yellow oil; yield: 103.5 mg (92%); dr 85:15; 98% ee;
[α]D18 +28.07 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; de-
tected at 254 nm; hexane–i-PrOH, 80:20; flow: 0.7 mL/min): tR:
t1 = 21.87, t2 = 24.04, t3 = 44.51, t4 = 64.68 min.
1H NMR (600 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 1 H), 7.33 (t,
J = 7.5 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 2 H, major + minor), 7.19–7.16
(m, 2 H), 7.11 (d, J = 7.7 Hz, 2 H), 4.17–4.08 (m, 4 H), 3.85–3.79
(m, 1 H), 3.59–3.54 (m, 1 H), 3.05–2.94 (m, 2 H), 2.80 (dd, J = 23.8,
10.4 Hz, 1 H), 2.30 (s, 3 H), 1.62 (s, 9 H), 1.33 (t, J = 7.0 Hz, 6 H,
major + minor), 1.04 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.83, 168.48, 168.43, 148.85,
139.72, 137.46, 135.87, 129.23, 128.71, 126.64, 126.06, 124.01,
114.93, 84.35, 63.25, 63.18, 62.82, 62.76, 61.39, 56.12, 55.97,
42.68, 41.40, 34.46, 27.89, 20.78, 16.17, 13.54.
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39ClN2O8P: 597.2133;
found: 597.2118.
tert-Butyl (R)-6-Bromo-3-[(S)-2-(diethoxyphosphoryl)-3-eth-
oxy-3-oxopropyl]-2-oxo-3-phenylindoline-1-carboxylate (3h)
Light yellow oil; yield: 117.4 mg (94%); dr 90:10; 99% ee; [α]D
19
+23.24 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 8.03,
t2 = 10.52, t3 = 12.17, t4 = 21.87 min.
1H NMR (600 MHz, CDCl3): δ = 8.14 (d, J = 1.5 Hz, 1 H), 7.37–
7.23 (m, 6 H, major + minor), 7.05 (d, J = 8.1 Hz, 1 H), 4.17–4.09
(m, 4 H), 3.89–3.84 (m, 1 H), 3.67–3.62 (m, 1 H), 3.06–2.93 (m, 2
H), 2.77 (m, 1 H), 1.63 (s, 9 H), 1.33 (t, J = 7.0 Hz, 6 H), 1.09 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.10, 168.52, 168.47, 148.58,
140.81, 138.15, 128.72, 127.93, 127.57, 127.42, 127.09, 126.68,
122.50, 118.44, 85.02, 63.25, 62.82, 61.67, 56.26, 56.12, 42.62,
41.34, 34.37, 27.86, 16.19, 13.59.
31P NMR (162 MHz, CDCl3): δ = 20.05.
MS: m/z = 623.13 ([M]+).
31P NMR (162 MHz, CDCl3): δ = 20.44.
MS: m/z = 559.07 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C29H42N2O8P: 577.2679;
found: 577.2663.
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-3-(4-methoxyphenyl)-2-oxoindoline-1-carboxylate (3l)
Light yellow oil; yield: 111.6 mg (97%); dr 88:12; 99% ee; [α]D
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39BrN2O8P: 641.1627;
found: 641.1618.
18
+31.53 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 80:20; flow: 1 mL/min): tR: t1 = 20.59,
t2 = 23.71, t3 = 35.89, t4 = 62.22 min.
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-7-fluoro-2-oxo-3-phenylindoline-1-carboxylate (3i)
Light yellow oil; yield: 105.9 mg (94%); dr 84:16; 97% ee; [α]D
18
+19.71 (c 1.00, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 70:30; flow: 1 mL/min): tR: t1 = 16.64,
t2 = 19.06, t3 = 25.84, t4 = 40.38 min.
1H NMR (600 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H), 7.12 (m, 2 H),
6.99 (d, J = 7.2 Hz, 1 H), 4.20–4.06 (m, 4 H, major + minor), 3.89–
3.84 (m, 1 H), 3.66–3.61 (m, 1 H), 3.07–2.98 (m, 2 H), 2.85–2.79
(m, 1 H), 1.61 (s, 9 H), 1.35–1.32 (m, 6 H), 1.07 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.29, 168.43, 149.65, 147.10,
138.08, 132.23, 128.72, 127.92, 126.95, 126.68, 125.06, 124.99,
121.88, 116.91, 116.71, 85.10, 63.29, 63.22, 62.90, 62.84, 61.47,
57.06, 56.92, 42.43, 41.16, 34.40, 27.49, 16.17, 13.59.
31P NMR (162 MHz, CDCl3): δ = 20.14.
MS: m/z = 563.20 ([M]+).
1H NMR (600 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 1 H), 7.33 (t,
J = 7.7 Hz, 1 H), 7.25 (d, J = 8.6 Hz, 2 H), 7.19–7.15 (m, 2 H), 6.83
(d, J = 8.6 Hz, 2 H), 4.17–4.08 (m, 4 H, major + minor), 3.84–3.80
(m, 1 H), 3.76 (s, 3 H), 3.60–3.56 (m, 1 H), 3.03–2.92 (m, 2 H),
2.82–2.77 (m, 1 H), 1.62 (s, 9 H), 1.33 (t, J = 7.0 Hz, 6 H, major +
minor), 1.04 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.92, 168.46, 168.41, 158.89,
148.84, 139.70, 130.71, 128.65, 127.99, 126.07, 124.00, 114.96,
113.80, 84.35, 63.23, 63.18, 62.82, 62.76, 61.38, 55.74, 55.59,
55.06, 42.67, 41.40, 34.58, 27.87, 16.15, 13.53.
31P NMR (162 MHz, CDCl3): δ = 20.45.
MS: m/z = 575.29 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C29H42N2O9P: 593.2628;
found: 593.2608.
+
HRMS (EI+): m/z [M + NH4 ] calcd for C28H39FN2O8P: 581.2428;
found: 581.2415.
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-3-(naphthalen-2-yl)-2-oxoindoline-1-carboxylate (3m)
Light yellow oil; yield: 124.1 mg (96%); dr 85:15; >99% ee; [α]D
tert-Butyl (R)-3-[(S)-2-(Diethoxyphosphoryl)-3-ethoxy-3-oxo-
propyl]-3-(4-fluorophenyl)-2-oxoindoline-1-carboxylate (3j)
Light yellow oil; yield: 102.5 mg (91%); dr 91:9; 98% ee; [α]D
18
+1.76 (c 0.99, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 80:20; flow: 0.7 mL/min): tR: t1 = 21.97,
t2 = 24.30, t3 = 42.79, t4 = 51.05 min.
1H NMR (600 MHz, CDCl3): δ = 7.94 (d, J = 8.2 Hz, 1 H), 7.79 (m,
4 H), 7.45–7.43 (m, 3 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.23 (d, J = 7.4
Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 4.20–4.13 (m, 4 H), 3.86–3.81
(m, 1 H), 3.61–3.56 (m, 1 H), 3.21–3.17 (m, 1 H), 3.12–3.08 (m, 1
H), 2.92–2.87 (m, 1 H), 1.63 (s, 9 H), 1.35 (t, J = 7.0 Hz, 6 H), 1.04
(t, J = 7.1 Hz, 3 H).
17
+47.42 (c 0.99, CH2Cl2); HPLC (Chiralpak AD-H column; detected
at 254 nm; hexane–i-PrOH, 90:10; flow: 1 mL/min): tR: t1 = 8.62,
t2 = 10.32, t3 = 11.33, t4 = 16.33 min.
1H NMR (600 MHz, CDCl3): δ = 7.90 (d, J = 8.3 Hz, 1 H), 7.38–
7.30 (m, 3 H), 7.18 (d, J = 3.5 Hz, 2 H), 7.00 (t, J = 8.6 Hz, 2 H),
4.20–4.07 (m, 4 H, major + minor), 3.86–3.80 (m, 1 H), 3.61–3.55
(m, 1 H), 3.03–2.93 (m, 2 H), 2.81–2.75 (m, 1 H), 1.63 (s, 9 H), 1.33
(t, J = 7.1 Hz, 6 H), 1.05 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.63, 168.40, 168.35, 163.31,
160.85, 148.75, 139.73, 134.47, 128.97, 128.77, 128.69, 128.25,
126.08, 124.17, 115.50, 115.29, 115.12, 84.61, 63.30, 63.24, 62.89,
62.83, 61.48, 55.83, 55.68, 42.65, 41.37, 34.74, 27.90, 16.18, 13.57.
13C NMR (100 MHz, CDCl3): δ = 175.72, 168.46, 168.41, 148.84,
139.73, 136.09, 132.83, 132.40, 128.83, 128.46, 128.06, 127.21,
126.28, 126.16, 126.06, 125.88, 124.57, 124.17, 115.03, 84.46,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1647–1653

1652
S.-W. Duan et al.
SPECIAL TOPIC
63.26, 63.20, 62.84, 62.78, 61.41, 56.55, 56.40, 42.64, 41.36, 34.20,
27.89, 16.19, 13.55.
31P NMR (162 MHz, CDCl3): δ = 20.45.
MS: m/z = 595.18 ([M]+).
13C NMR (101 MHz, CDCl3): δ = 176.28, 166.76, 149.02, 139.89,
139.47, 135.95, 128.67, 128.54, 127.96, 127.64, 127.06, 126.40,
123.84, 114.90, 84.24, 60.66, 57.37, 38.40, 27.97, 13.99.
MS: m/z = 421.08 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C32H42N2O8P: 613.2679;
found: 613.2659.
Organocatalysts V and VI
Prepared according to the literature procedure.13e
tert-Butyl (R)-5-Bromo-3-[(S)-2-(diethoxyphosphoryl)-3-eth-
oxy-3-oxopropyl]-3-(3,5-dimethylphenyl)-2-oxoindoline-1-car-
boxylate (3n)
Catalyst V
1H NMR (600 MHz, DMSO-d6): δ = 9.58 (s, 1 H), 8.83 (d, J = 18
Hz, 1 H), 8.01 (s, 1 H), 7.99 (d, J = 4.5 Hz, 1 H), 7.80 (s, 1 H), 7.67
(s, 1 H), 7.45–7.45 (m, 1 H), 6.96 (s, 2 H), 6.65 (s, 1 H), 6.01–5.96
(m, 2 H), 5.01–4.98 (m, 2 H), 3.96 (s, 3 H), 3.49–3.45 (m, 1 H),
3.22–3.18 (m, 1 H), 2.72–2.62 (m, 2 H), 2.23 (m, 1 H), 2.21 (s, 6 H),
1.52 (s, 3 H), 0.65 (s, 1 H).
17
Light yellow oil; yield: 126.6 mg (97%); dr 84:16; 99% ee; [α]D
+20.13 (c 1.01, CH2Cl2); HPLC (Chiralpak IC column; detected at
254 nm; hexane–i-PrOH, 90:10; flow: 1 mL/min): tR: t1 = 13.83,
t2 = 21.08, t3 = 36.29, t4 = 41.08 min.
1H NMR (600 MHz, CDCl3): δ = 7.81 (d, J = 8.7 Hz, 1 H), 7.46 (d,
J = 8.7 Hz, 1 H), 7.24 (s, 1 H), 6.92 (s, 1 H), 6.87 (s, 2 H), 4.17–4.11
(m, 4 H), 3.96–3.92 (m, 1 H), 3.82–3.77 (m, 1 H), 3.07–3.02 (m, 1
H), 2.97–2.93 (m, 1 H), 2.77–2.72 (m, 1 H), 2.28 (s, 6 H), 1.63 (s, 9
H), 1.34 (t, J = 7.1 Hz, 6 H), 1.13 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.13, 168.39, 148.69, 138.66,
138.32, 138.13, 131.64, 129.66, 128.62, 124.71, 124.28, 117.16,
116.65, 84.77, 63.29, 63.23, 62.81, 61.68, 56.36, 56.22, 42.62,
41.35, 33.92, 27.89, 21.32, 16.19, 13.69.
13C NMR (101 MHz, DMSO-d6): δ = 183.89, 179.89, 167.79,
163.66, 157.83, 147.76, 144.28, 143.25, 142.18, 138.42, 131.49,
127.47, 124.45, 121.87, 115.92, 114.26, 101.47, 58.76, 55.64,
27.30, 26.13, 21.00.
MS: m/z = 522.46 ([M]+).
Catalyst VI
1H NMR (600 MHz, DMSO-d6): δ = 9.55 (s, 1 H), 8.82 (d, J = 3.4
Hz, 1 H), 8.05 (s, 1 H), 7.97 (d, J = 9.1 Hz, 1 H), 7.78 (s, 1 H), 7.67
(d, J = 3.4 Hz, 1 H), 7.43 (d, J = 8.8 Hz, 1 H), 6.95 (s, 2 H), 6.61 (s,
1 H), 6.13 (s, 1 H), 5.91–5.76 (m, 1 H), 5.20 (d, J = 17.4 Hz, 1 H),
5.07 (d, J = 10.5 Hz, 1 H), 3.95 (s, 3 H), 3.48–3.39 (m, 1 H), 3.18
(s, 1 H), 2.94 (d, J = 10.2 Hz, 1 H), 2.89–2.71 (m, 2 H), 2.18 (s, 6
H), 1.53 (s, 2 H), 1.48 (s, 1 H), 1.07 (s, 1 H), 0.89 (s, 1 H).
31P NMR (162 MHz, CDCl3): δ = 20.25.
MS: m/z = 651.30 ([M]+).
+
HRMS (EI+): m/z [M + NH4 ] calcd for C30H43BrN2O8P: 669.1940;
found: 669.1923.
13C NMR (101 MHz, DMSO-d6): δ = 184.03, 179.84, 167.94,
163.53, 157.86, 147.73, 144.28, 143.46, 140.75, 138.42, 131.48,
127.48, 124.41, 122.07, 115.89, 114.36, 101.14, 59.71, 58.66,
55.58, 52.44, 48.95, 45.56, 38.49, 27.20, 26.15, 25.22, 21.00, 20.70.
tert-Butyl (S)-3-Benzyl-3-[(S)-2-(diethoxyphosphoryl)-3-eth-
oxy-3-oxopropyl]-2-oxoindoline-1-carboxylate (3o)
Light yellow oil; yield: 107.4 mg (96%); dr 84:16; 95% ee; [α]D
+5.29 (c 1.00, CH2Cl2); HPLC (Chiralpak AD-H column; detected
at 254 nm; hexane–i-PrOH, 90:10; flow: 1 mL/min): tR: t1 = 8.31,
t2 = 9.09, t3 = 11.86, t4 = 24.06 min.
19
MS: m/z = 522.29 ([M]+).
1H NMR (600 MHz, CDCl3): δ = 7.55–7.45 (m, 1 H), 7.19–7.14 (m,
2 H), 7.10–7.09 (m, 1 H), 7.07–7.03 (m, 1 H), 7.02–6.99 (m, 2 H),
6.76–6.72 (m, 2 H), 4.17–4.14 (m, 2 H), 4.13–4.03 (m, 2 H, major
+ minor), 3.75–3.72 (m, 1 H), 3.46–3.43 (m, 1 H), 3.18 (d, J = 12.9
Hz, 1 H), 3.01 (d, J = 13.0 Hz, 1 H), 2.80–2.60 (m, 3 H), 1.55 (s, 9
H), 1.37–1.32 (m, 6 H), 0.96 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.67, 168.51, 148.24, 139.82,
134.14, 129.51, 128.37, 127.44, 127.02, 126.62, 124.80, 123.49,
114.35, 83.84, 63.16, 63.10, 62.76, 61.24, 54.89, 54.74, 45.55,
42.66, 41.38, 33.46, 27.78, 16.15, 13.42.
Acknowledgment
We are grateful to the National Science Foundation of China (No.
21002036, 21072069, 21232003 and 21202053) and the National
Basic Research Program of China (2011CB808600) for support of
this research. This study was also financially supported in part by
self-determined research funds of CCNU from the college’s basic
research and operation of MOE.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
31P NMR (162 MHz, CDCl3): δ = 20.34.
MS: m/z = 559.02 ([M]+).
m
tgioSrantnugIifoop
r
itmnatr
+
HRMS (EI+): m/z [M + NH4 ] calcd for C29H42N2O8P: 577.2679;
found: 577.2662.
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tert-Butyl 3-[2-(Ethoxycarbonyl)allyl]-2-oxo-3-phenylindoline-
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To a stirred soln of 3a (109.1 mg, 0.2 mmol) in MeCN (4 mL) were
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and paraformaldehyde (30.3 mg, 1.0 mmol). The mixture was
stirred at r.t. When the reaction was complete (TLC monitoring), the
solvent was removed. The product was purified by flash chromatog-
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PrOH, 90:10; flow: 1 mL/min): tR: t1 = 6.51, t2 = 7.23 min.
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.2 Hz, 1 H), 7.36–
7.22 (m, 7 H), 7.08 (t, J = 7.5 Hz, 1 H), 5.92 (s, 1 H), 5.44 (s, 1 H),
3.83 (dd, J = 14.1, 7.0 Hz, 2 H), 3.41 (s, 2 H), 1.53 (s, 9 H), 1.03 (t,
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Synthesis 2013, 45, 1647–1653
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Conjugate Additions of 3-Substituted Oxindoles to Vinylphosphonates
1653
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(14) Please see Supporting Information for X-ray crystal
structure for compound 4 (CCDC 921101).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1647–1653