Enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles: Via palladium-catalysed decarboxylative asymmetric allylic alkylation

Article abstract of DOI:10.1039/c7ob02161e

The highly enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl-β-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl-α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl-β-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl-α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.

Full text of DOI:10.1039/c7ob02161e

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Enantioselective synthesis of sterically hindered
α-allyl–α-aryl oxindoles via palladium-catalysed
decarboxylative asymmetric allylic alkylation†
Cite this: DOI: 10.1039/c7ob02161e
Mark Jackson,
Patrick J. Guiry
Calvin Quince O’Broin,
*
Helge Müller-Bunz and
The highly enantioselective synthesis of sterically hindered α-allyl–α-aryl oxindoles possessing an all-
carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the syn-
thetic route employed was a novel one-pot, two-step synthesis of α-aryl–β-amido allyl ester substituted
oxindoles in good yields of 41–75% (13 examples) by interception of an unstable allyl ester intermediate
through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkyl-
ation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of
chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective,
affording the corresponding α-allyl–α-aryl oxindole product in 96% yield and 99% ee. A substrate scope
of a further 12 α-aryl–β-amido allyl ester substituted oxindoles showed that products containing bulky di-
ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee’s (94–98%), whereas
those lacking this substitution pattern were formed in more moderate levels of enantioselectivities
(56–63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product
in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxy-
phenyl-substituted α-allyl–α-aryl oxindole product which enabled us to identify the absolute stereo-
chemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enan-
tioselection observed in these DAAA transformations is also proposed.
Received 29th August 2017,
Accepted 9th September 2017
DOI: 10.1039/c7ob02161e
rsc.li/obc
dearth of methods reported on the asymmetric synthesis of
oxindoles with sterically hindered aryl groups at the
Introduction
The oxindole moiety is a structural motif present in many 3-position.
naturally occurring and biologically active compounds.1–6
The Pd-catalyzed decarboxylative asymmetric allylic alkyl-
Typically such oxindoles contain substitution in the 3-position ation (DAAA) has been developed, primarily by the groups of
with the vast majority of these being spirocyclic. Due to their Trost, Stoltz and Tunge, into a powerful synthetic methodology
importance in nature and as lead pharmaceutical agents, a sig- in the toolkit of modern catalytic asymmetric reactions for the
nificant amount of work has been undertaken for the develop- formation of quaternary all-carbon stereocenters α- to a carbo-
ment of new methodologies for their synthesis.7 A selection of nyl group.16–26 Our contributions to this field have focused on
these approaches have employed Friedel–Crafts alkylation, developing approaches for the formation of tertiary and qua-
Heck cyclisations of ortho-halogenated anilides, oxidative ternary α-aryl compounds employing Pd-catalyzed decarboxyla-
rearrangement of indole derivatives, radical activated ring clo- tive asymmetric protonations and DAAA, respectively.27–32
sures and Cu-catalysed C–H activation as the key synthetic More specifically, we have applied the Pd-catalyzed DAAA to
transformations.8–15 The majority of these procedures enable the highly enantioselective synthesis of α-allyl–α-aryl-cyclopen-
the synthesis of alkyl-substituted oxindoles but there is a tanones,30 α-allyl–α-aryl-dihydrocoumarins and 3-isochroma-
nones31 and very recently to the highly enantioselective con-
struction of sterically hindered α-allyl–α-aryl-lactones with the
Centre for Synthesis and Chemical Biology, School of Chemistry, University College
(R,R)-ANDEN-phenyl Trost ligand being the optimal chiral
ligand.32 Applications of the DAAA for the preparation of
Dublin, Belfield, Dublin 4, Ireland. E-mail: p.guiry@ucd.ie
†Electronic supplementary information (ESI) available: Full analysis of all new
α-quaternary amides have been rare, with one recent example
from Stoltz and Marek for the asymmetric formation of acyclic
quaternary stereocenters.33 Of particular relevance to the
compounds including 1H and 13C NMR spectra, X-ray data and chromatographic
data (PDF). CCDC 1565411 (R-11a). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c7ob02161e
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current study, Taylor reported the application of the Pd-cata- α-aryl–β-amido-allyl ester 5 in only 12% yield using 1,10-phe-
lyzed DAAA for the asymmetric preparation of alkyl- and aryl- nanthroline as base. This low yield is in line with Pinhey’s
substituted oxindoles, with a substrate scope of four aryl observation that the synthesis of tertiary centres using aryllead
groups (ortho- and meta-methoxyphenyl, ortho-nitrophenyl and triacetates can be unpredictable.41 The subsequent cyclization
phenyl) affording products in high yields and ee’s between of 5 to afford the α-aryl–β-amido allyl ester-substituted oxi-
78–95%.34 A limitation of this study was the linear, three-step ndole 3a proceeded in 79% yield. Despite this successful cycli-
synthesis of the α-aryl–β-amido allyl ester-substituted oxindole zation, the low-yielding arylation step meant that this route
substrates (21–80% yield). Herein, we wish to report our was not viable and was therefore not further investigated.
studies on an alternative synthesis of
a
series of
We next proposed that α-aryl–β-amido-allyl esters 3 could be
α-aryl–β-amido allyl ester substituted oxindoles (12 new formed through a Pb-mediated arylation of the β-amido-allyl
examples) and their conversion into the corresponding ester 7, the proposed product of C-acylation of N-methyl oxi-
α-allyl–α-aryl oxindoles possessing an all-carbon quaternary ndole 6. However, the acylation of N-methyl oxindole 6 proved
stereocenter.
problematic, despite testing a range of bases (LiHMDS, LDA
and NaH) with diallylcarbonate or allyl chloroformate as the
electrophile. Both Taylor and Padwa had previously noted that
the β-amido-allyl ester 7 was unstable and could not be
isolated.35,42
Results and discussion
Liu had previously reported the synthesis of the β-amido-
Taylor’s approach to the α-aryl–β-amido allyl ester substituted
oxindoles 3 employed an amide bond formation from the aryl- ethyl ester 8 and, with this in mind, we investigated the aryla-
tion of β-amido-ethyl ester 8 and its subsequent conversion to
the required α-aryl β-amido-allyl esters 3 by transesterification
acetic acid 1, followed by allyloxycarbonylation to afford the
aryl-substituted linear precursor 2, Scheme 1(A).34 The
required oxindoles 3 were then accessed by a Cu(I)-mediated with allyl alcohol, Scheme 3.43 This acylation proceeded in
radical cyclization via a direct C–H, Ar–H coupling.12,13,35,36 As
71% yield and the product was stable, in contrast to its allyl
ester analogue 7. Subsequent arylation with 2,4,6-trimethoxy-
an alternative route we envisaged α-arylation of the β-amido-
allyl ester 4 by reaction with aryllead triacetates, a useful class phenyllead triacetate afforded the α-aryl–β-amido-ethyl ester 9
in 73% yield. However, transesterification using allyl alcohol
following a number of protocols was unsuccessful,44 poten-
of aryl cation equivalents in particular for their ability to intro-
duce sterically hindered aryl groups in high yields and are
superior to diaryliodionium salts,37–40 followed by the Cu-cata- tially due to the sterically hindered nature of the substrate.
We then returned to our previously unsuccessful route,
Scheme 2, and applied the identical reaction conditions to
lyzed double C–H activation ring closure, Scheme 1(B).
Choosing the 2,4,6-trimethoxyphenyl-containing oxindole 3a
as our model substrate for catalysis, we found that, despite those successfully employed in the synthesis of β-amido-ethyl
ester 8, changing from ethyl chloroformate to allyl chloro-
optimization attempts (change of base, temperature), arylation
formate. Again, we could not isolate any pure allyl ester 7 and
with 2,4,6-trimethoxyphenyllead triacetate afforded the
Scheme 1
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Scheme 2
Scheme 3
Scheme 4
Table 1 Synthesis of α-aryl–β-amido-allyl esters 3a–k
Entry
Ar
Yielda (%)
1
2
3
4
5
6
7
8
3a: 2,4,6-(MeO)3C6H2
3b: 2,6-(MeO)2C6H3
3c: 2,3,6-(MeO)3C6H2
3d: 2-BnOC10H6
67
75
62
66
67
69
75
73
67
66
41
3e: 2-MeOC10H6
Scheme 5 A novel one pot synthesis of 3a.
3f: 2,4-(MeO)2C6H3
3g: 2,3,4-(MeO)3C6H2
3h: (3,4)-OCH2O-C6H3
3i: 4-OMeC6H4
3j: 2-MeO-4,6-(Me)2C6H2
3k: 2,6-(Me)2C6H3
9
10
11
instead only isolated the diacylated oxindole 10 in a 5% yield,
Scheme 4.
We then decided to monitor the reaction and, after
18 hours, a H-NMR spectrum of the crude reaction material
a Isolated yield.
1
allowed us to identify the allyl peaks indicative of the desired
product 7. Thus, with confirmation that the desired allyloxy-
carbonylated product 7 was being formed prior to attempted
The α-phenyl- and α-para-CF3-phenyl-β-amido allyl ester-
purification we sought to perform the arylation step in situ by substituted oxindoles 3l and 3m were synthesized in situ
intercepting this intermediate. Thus, the acylation was carried without isolation of the corresponding aryllead triacetate
out at −78 °C to −55 °C over 12 h after which time 2,4,6-tri- reagent, Scheme 6. The α-phenyl–β-amido allyl ester-substi-
methoxyphenyllead triacetate, pyridine and CHCl3 were added tuted oxindole 3l was obtained in a 53% yield and the para-
and reacted at 40 °C for 18 h. To our delight a 67% yield of the CF3-phenyl-substituted analogue 3m was formed in 72% yield.
required α-aryl–β-amido allyl ester-substituted oxindole 3a was
For our catalysis investigations we chose the 2,4,6-tri-
achieved, Scheme 5.
methoxyphenyl-containing substrate 3a as our model sub-
With this novel one-pot synthesis, we set out to synthesise strate. To identify the optimal catalytic system we began by car-
the remaining substrates using this methodology. Good yields rying out a ligand screen. Firstly we employed the PHOX type
ranging between 41–75% (Table 1, entries 1–11) were observed. ligands, which have previously shown excellent ee’s in the
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Scheme 6 Synthesis of 3l and 3m through a one-pot, 3-step synthesis.
DAAA.17,24,45–51 Both t-Bu-PHOX L1 and the electron deficient
p-(CF3)3-t-Bu-PHOX L2 performed poorly, with ee’s of just 10%
and 7%, respectively, (Scheme 7). We then looked at applying
the Trost type ligands as they have also shown remarkable
selectivity in the DAAA.52 The (R,R)-DACH-phenyl Trost ligand
L3 showed a marked increase in ee with a moderate 58%.
Following this we applied the (R,R)-ANDEN-phenyl-Trost
ligand L4, which led to a significant increase in enantio-
selectivity to 99% ee.
Table 2 Solvent screen for the DAAA of oxindole 3a
With the optimal ligand in hand we aimed to optimize reac-
tion conditions beginning with a solvent screen. Excellent
enantioselectivity was observed for all six solvents screened
with toluene, THF and 2-Me-THF providing identical ee’s of
99% (Table 2, entries 1–3). From this we decided to continue
our investigation employing toluene as our optimal solvent
due to the knowledge that the reaction is sensitive to water
Entry
Solvent
Temp. (°C)
Conv.a (%)
eeb (%)
1
2
3
4
5
6
7
8
9
Toluene
THF
2-Me-THF
MTBE
rt
rt
rt
rt
rt
rt
40
0
100
100
100
100
100
100
100
100
60
99
97
97
91
96
95.5
94
96
93
93
Et2O
1,4-Dioxane
Toluene
Toluene
Toluene
Toluene
−20
−40
10
70
a Determined by 1H NMR spectroscopy. b Determined by chiral SFC.
and, while all three solvents are purchased anhydrous, toluene
is the least hygroscopic. We then looked at evaluating the ideal
reaction temperature by performing the reaction between
−40 °C to 40 °C (entries 1 & 7–10). However, this did lead to
longer reaction times and in some cases incomplete conver-
sion to the desired product.
Our optimized conditions (Table 2, entry 1) were then
applied to the other 12 α-aryl-containing substrates 3b–m,
Scheme 8. We observed that ortho-substitution is essential for
obtaining high levels of enantioselectivity. Di-ortho-methoxy-
substituted products 11a–c and both naphthyl-derived pro-
ducts 11d and 11e were prepared with excellent levels of
enantioselectivity ranging between 94–98%. Mono-ortho-sub-
stituted products were also formed with excellent levels of
Scheme 7 Ligand screen in the DAAA of 3a.
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Scheme 8 Substrate scope and enantioselectivity of Pd-catalyzed DAAA.
enantioselectivity 11f (98% ee) and 11g (92% ee). The removal
of ortho-substitution results in a decrease in enantioselectivity
seen with 11h (62% ee), 11i (58% ee), 11l (63% ee) and 11m
(56% ee). Interestingly, we observed a similar decrease to 60%
ee for the 2-methoxy-4,6-dimethyl product 11j. Although this
contains di-ortho-substitution we believe the increase in steric
bulk caused by the methyl group in the ortho-position has a
detrimental effect on the ee. Surprisingly the di-ortho-substi-
tuted substrate 3k failed to afford the expected C-allylated
product with the O-allylated compound being isolated in a
96% yield. We postulate this is a result of the greater steric hin-
drance of the 2,6-dimethyl group leading to a higher energy
C-allylation intermediate allowing for O-allylation to occur.
A crystal structure of the 2,4,6-trimethoxyphenyl-substituted
product 11a was successfully obtained (Fig. 1). From this we
were able to deduce the absolute stereochemistry of the
product formed. The (R)-isomer obtained is consistent with
the absolute stereochemistry reported previously by Taylor who
also used the (R,R)-ANDEN-phenyl Trost ligand L4.34
Fig. 1 Identification of absolute stereochemistry.
The stereochemical outcome of this Pd-catalyzed DAAA with
oxindoles is consistent with our transition-state model
described previously for the highly enantioselective synthesis
of α-allyl–α-aryl-cyclopentanones30 and α-allyl–α-aryl-lactones32
and is inspired by the mechanistic studies by Lloyd-Jones,
Norrby and co-workers on Trost-type ligands.53 In this model,
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optimised for the 2,4,6-(MeO)3C6H2-substituted oxindole
leading to a 99% ee with (R,R)-ANDEN phenyl Trost ligand.
Our substrate screen with 12 other aryl-containing substrates
revealed that the substituents on the aromatic ring had a sig-
nificant effect on enantioselectivity with ortho-substitution
proving essential for obtaining very high levels of enantio-
selectivity. A trend was observed that substrates with di-ortho-
substituted aryl groups led to greater ee’s (94–99%) than mono-
ortho-substituted analogues (92–97%), which in turn were far
higher than substrates with no ortho-substituents on the aryl
ring (56–63%). This trend however only applies to substrates
with methoxy groups in the ortho-position. The presence of a
methyl group in the ortho-position led to a significant decrease
in ee to 56% while the 2,6-dimethyl substrate 3k was too steri-
cally hindered to afford the desired product and the
O-allylated product was obtained instead. The crystal structure
obtained for the 2,4,6-trimethoxyphenyl-substituted product
enabled us to identify the absolute stereochemistry and hence
propose a plausible explanation to rationalise the sense of
enantioselection observed. Overall, the ability to generate all-
carbon quaternary stereocentres with such high levels of
enantioselectivity is noteworthy. We are currently exploiting
the Pd-catalyzed DAAA and DAP of a series of α-aryl-containing
substrates and the results of these investigations will form the
basis of future reports from these laboratories.
Fig. 2 Rationalizing the stereochemical outcome.
the amide proton directs the enolate carbon to the allyl unit
through H-bonding and there are two possible approaches,
pathway A or B, Fig. 2. In pathway A, the enolate orients itself
such that the aryl group is pointing away from the backbone of
the ligand leading to the formation of the preferred (R)-enan-
tiomer of 11 by attack on the Pd-allyl. In pathway B, the aryl
group experiences a significant steric clash with the ANDEN
framework of L4, much more so than the DACH-phenyl Trost
ligand L3, so that this approach leading to the formation of
(S)-11 is disfavoured.
We believe the aryl group to be non-coplanar so that the
steric clashes are maximised when there are two ortho-substi-
tuents. When there is just one ortho-substituent, the steric
clashes can be minimised as the aryl group rotates to offer its
least substituted (and sterically less demanding) side. This will
decrease the energy difference between the two-diastereomeric
transitions states leading to a lowering of enantioselectvity.
The high level of steric hindrance occurring in the 2,6-di-
methylphenyl substrate 3k instead leads to addition of the
allyl group to the enolate oxygen as the lowest energy pathway.
Experimental section
General information
Unless otherwise noted, reactions were performed with rigor-
ous exclusion of air and moisture, under an inert atmosphere
of nitrogen in flame-dried glassware with magnetic stirring.
N2-Flushed stainless steel cannulas or plastic syringes were
used to transfer air- and moisture-sensitive reagents. All
reagents were obtained from commercial sources and
used without further purification unless otherwise
stated. Anhydrous tetrahydrofuran (THF), diethyl ether (Et2O)
and dichloromethane (CH2Cl2) were obtained from a dry
solvent dispenser. Tris(dibenzylideneacetone)dipalladium(0)
chloroform adduct was prepared via the method of Zalesskiy.54
Allyl 3-(methyl(phenyl)amino)-3-oxopropanoate (4) and
N-methyloxindole (6) were prepared according to literature pro-
cedures.34 Aryllead triacetates used in the preparation of α-aryl
β-amido allyl esters 3a–m were also prepared according to the
literature.27
Allyl
3-(methyl(phenyl)amino)-3-oxo-2-(2,4,6-trimethoxy-
phenyl)propanoate (5). To a stirred solution of β-amido allyl
ester 4 (400 mg, 1.7 mmol) and 2,4,6-trimethoxyphenyllead
triacetate (1.04 g, 1.89 mmol) in CHCl3 (20 mL) was added
Conclusion
In conclusion,
a novel, one-pot, two-step synthesis of 1,10-phenanthroline (1.02 g, 5.66 mmol) dropwise. The result-
α-aryl–β-amido allyl ester substituted oxindoles in good yields ing mixture was heated to 40 °C and was allowed to stir for
of 41–75% (13 examples) has been developed by interception 18 h. The reaction was quenched with 6% H2SO4 and diluted
of an unstable allyl ester intermediate through reaction with with CHCl3 (20 mL). The aqueous phase was extracted with
aryllead triacetate reagents. Reaction conditions for the cata- CHCl3 (2 × 15 mL) and the combined organic extracts were
lytic asymmetric synthesis of α-aryl-substituted oxindoles were washed with water (2 × 20 mL) and dried over anhydrous
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magnesium sulfate. The resulting solution was concentrated dropwise over 5 min and the reaction was allowed to stir for
in vacuo and the crude brown oil was purified via flash column 18 h. To the solution was added 6% H2SO4 (20 mL) and the
chromatography to give allyl 3-(methyl(phenyl)amino)-3-oxo-2- aqueous phase was extracted with CHCl3 (2 × 30 mL). The com-
(2,4,6-trimethoxyphenyl)propanoate as a yellow oil (80 mg, bined organic extracts were washed with water (2 × 20 mL),
12%). Rf = 0.40 (1 : 1 pentane : EtOAc); IR (film) νmax 2938, dried over MgSO4, reduced in vacuo and purified by
1736, 1668, 1595, 1497 cm−1
δ 7.40–7.22 (m, 3H), 7.20–7.17 (m, 2H), 6.05 (s, 2H), 5.85 (ddt, product was isolated as a colorless solid (680 mg, 73%);
J = 17.3, 10.5, 5.6 Hz, 1H), 5.21–5.15 (m, 2H), 4.95 (s, 1H), 4.56 m.p. 119–122 °C; IR (film) νmax 1720, 1608, 1493 cm−1 1H
;
1H NMR (400 MHz, CDCl3): flash column chromatography (pentane : EtOAc 50 : 50). The
;
(dt, J = 5.6, 1.5 Hz, 2H), 3.74 (s, 3H), 3.67 (s, 6H), 3.26 (s, 3H); NMR (400 MHz, CDCl3) δ 7.20–7.25 (m, 4H), 6.96 (td, J = 7.6,
13C NMR (101 MHz, CDCl3) δ 169.8, 168.1, 160.8, 158.8, 143.7, 1.0 Hz, 1H), 6.80 (dt, J = 7.7, 0.8 Hz, 1H), 6.19 (s, 1H), 6.03 (s,
132.3, 129.1, 127.6, 127.5, 117.9, 105.3, 91.0, 65.6, 55.8, 55.3, 1H), 4.14–4.27 (m, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.54 (s, 3H),
46.1, 37.8, 29.7; HRMS: (ESI-TOF) calculated for C22H25NO6Na 3.26 (s, 3H), 1.22 (t, J = 7.1, Hz, 3H); 13C NMR (101 MHz,
[M + Na]+ 422.1580, found 422.1579.
Allyl
CDCl3): δ 173.1, 169.0, 160.7, 143.4, 129.7, 129.5, 128.1, 125.1,
1-methyl-2-oxo-3-(2,4,6-trimethoxyphenyl)indoline-3- 122.5, 121.5, 107.4, 92.3, 61.9, 59.2, 56.2, 55.3, 26.8, 14.1;
carboxylate (3a). To a 25 mL round bottom flask was added HRMS: (ESI-TOF) calculated for C21H23NO6Na [M + Na]+
allyl 3-(methyl(phenyl)amino)-3-oxo-2-(2,4,6-trimethoxyphenyl) 408.1423, found 408.1426.
propanoate (60 mg, 0.15 mmol). To this was added anhydrous
Cu(OAc)2 (2.72 mg, 0.015 mmol) and toluene (8 mL). The
resulting mixture was refluxed for 15 h after which time the
solution was concentrated in vacuo and the crude residue was
General procedure for the synthesis of α-aryl–β-amido allyl
esters 3a–m
purified via flash column chromatography to yield the title To a flame dried Schlenk flask was added LDA (1.1 equiv.) in
compound as an off white solid (47 mg, 79%); Rf = 0.27 THF (20 mL g−1 of starting material) and the mixture was
(pentane/EtOAc = 1 : 1); m.p. 159–163 °C; IR (film) νmax 2940, cooled to −78 °C. N-Methyl-oxindole (1 equiv.) was added and
1722, 1610 cm−1 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 2H), the reaction was allowed to stir for 1 h. To the solution was
;
7.00 (td, J = 7.7, 1.0 Hz, 1H), 6.84 (dt, J = 7.7, 1.0 Hz, 1H), 6.22 added allyl chloroformate (1.1 equiv., 1.134 g mL−1) and the
(s, 1H), 6.08 (s, 1H), 5.91 (ddt, J = 16.4, 10.9, 5.3 Hz, 1H), reaction was warmed to −55 °C. After stirring for 12 h, chloro-
5.20–5.29 (m, 2H), 4.60–4.77 (m, 2H), 3.55–3.81 (m, 9H), 3.30 form (5 mL), pyridine (3.3 equiv.) and ArPb(OAc)3 (0.9 equiv.)
(s, 3H); 13C NMR (101 MHz, CDCl3): δ 173.0, 168.7, 160.8, were added and the reaction was brought to 40 °C for a further
159.1, 143.4, 132.1, 129.5, 128.2, 125.1, 122.5, 118.0, 108.7, 18 h. The reaction mixture was stirred in 6% H2SO4 (50 mL)
107.6, 92.3, 66.4, 59.7, 56.2, 55.3, 26.8; HRMS: (ESI-TOF) calcu- and the organic layer was separated. The aqueous layer was
lated for C22H23NO6Na [M + Na]+ 420.1423, found 420.1433.
extracted with EtOAc (3 × 50 mL) and the combined organic
Ethyl 1-methyl-2-oxoindoline-3-carboxylate (8). To a stirred layers were filtered through Celite. The organic layer was
solution of LDA (0.55 mL, 4.08 mmol) in dry THF (5 mL) was reduced in vacuo and the product was purified by silica gel
added N-methyloxindole (500 mg, 3.40 mmol) in dry THF flash column chromatography.
(15 mL) at −78 °C. After stirring for 1 h, ethyl chloroformate
Allyl
1-methyl-2-oxo-3-(2,4,6-trimethoxyphenyl)indoline-3-
(0.48 mL, 5.1 mmol) was added and the mixture was then carboxylate (3a). N-Methyl-oxindole (971 mg, 6.60 mmol), LDA
warmed slowly to −55 °C and stirred for 18 h at this tempera- (0.984 mL, 7.26 mmol), allyl chloroformate (0.772 mL,
ture. A saturated NH4Cl solution (20 mL) was added and the 7.26 mmol), 2,4,6-trimethoxyphenyllead triacetate (3.28 g,
mixture was extracted with Et2O (3 × 20 mL). The combined 5.94 mmol), pyridine (1.60 mL, 19.8 mmol) afforded 3a as an
organic layer was washed with
1 M hydrochloric acid off white solid (2.073 g, 67%), identical to a previously
(3 × 20 mL) and water (3 × 20 mL), and then dried over with prepared sample.
anhydrous sodium sulfate. The solvent was concentrated
Allyl 3-(2,6-dimethoxyphenyl)-1-methyl-2-oxoindoline-3-car-
in vacuo and the crude product was purified by flash column boxylate (3b). N-Methyl-oxindole (400 mg, 2.72 mmol), LDA
chromatography (pentane : EtOAc 70 : 30). The product was iso- (0.4 mL, 3.00 mmol), allyl chloroformate (0.32 mL, 3.00 mmol),
1
lated as a colorless solid (529 mg, 71%); H NMR (300 MHz, 2,6-dimethoxyphenyllead triacetate (1.30 g, 2.50 mmol), pyri-
CDCl3): δ 7.36–7.32 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H), 6.85 (d, J = dine (0.66 mL, 8.16 mmol) gave 3b as
a colorless
7.6 Hz, 1H), 4.42 (s, 1H), 4.28–4.21 (m, 2H), 3.24 (s, 3H), 1.29 solid (740 mg, 75%); Rf = 0.29 (pentane/EtOAc = 1 : 1);
(t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 170.6, 166.8, m.p. 132–135 °C; IR (film) νmax 2939, 1755, 1723, 1612 cm−1
;
144.5, 129.1, 124.3, 123.4, 122.7, 108.4, 62.0, 52.2, 26.4, 14.0. 1H NMR (300 MHz, CDCl3): δ 7.29 (dd, J = 7.7, 1.1 Hz, 1H)
All other physical and spectroscopic data were in complete 7.25 (m, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.98 (td, J = 7.7, 1.1 Hz,
agreement with those previously reported.55
1H), 6.83 (app. d, J = 7.7 Hz, 1H), 6.63 (d, J = 6.9 Hz, 1H), 6.49
Ethyl 1-methyl-2-oxo-3-(2,4,6-trimethoxyphenyl)indoline-3- (d, J = 6.9 Hz, 1H), 5.89 (ddt, J = 16.9, 10.6, 5.6 Hz, 1H), 5.24 (d,
carboxylate (9). To a flame dried Schlenk flask was added J = 16.9 Hz, 1H), 5.15 (d, J = 10.6 Hz, 1H), 4.76–4.53 (m, 2H),
2,4,6-trimethoxyphenyllead triacetate (1.59 g, 2.89 mmol), 3.86 (s, 3H), 3.59 (s, 3H), 3.29 (s, 3H); 13C NMR (101 MHz,
β-amido-ethyl ester 8 (529 mg, 2.42 mmol) in anhydrous CDCl3): δ 172.8, 168.6, 158.4, 157.5, 143.5, 132.0, 129.1, 129.0,
CHCl3 (20 mL). Pyridine (0.64 mL, 7.97 mmol) was added 128.4, 125.2, 122.5, 118.0, 116.1, 107.7, 106.1, 105.2, 66.4, 59.9,
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56.3, 56.1, 26.8; HRMS: (ESI-TOF) calculated for C21H22NO6 3.00 mmol), 2,4-dimethoxyphenyllead triacetate (1.29 g,
[M + H]+, 368.7498, found 368.1511.
2.50 mmol), pyridine (0.66 mL, 8.16 mmol) gave 3f as a
Allyl 1-methyl-2-oxo-3-(2,3,6-trimethoxyphenyl)indoline-3- viscous oil (689 mg, 69%); Rf = 0.39 (pentane/EtOAc = 1 : 1); IR
1
carboxylate (3c). N-Methyl-oxindole (400 mg, 2.72 mmol), LDA (film) νmax 2939, 1721, 1610 cm−1; H NMR (300 MHz, CDCl3):
(0.4 mL, 3.00 mmol), allyl chloroformate (0.32 mL, δ 7.4 (app. d, J = 7.6 Hz, 1H), 7.29 (td, J = 7.6, 1.1 Hz, 1H), 7.03
3.00 mmol), 2,4-dimethoxyphenyllead triacetate (989 mg, (td, J = 7.6, 1.1 Hz, 1H), 6.89–6.81 (m, 1H), 6.77 (d, J = 8.6 Hz,
2.50 mmol), pyridine (0.66 mL, 8.16 mmol) to yield 3c as a 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.33 (dd, J = 8.6, 2.5 Hz, 1H), 5.84
pale yellow solid (840 mg, 62%); Rf = 0.37 (pentane/EtOAc = (ddt, J = 17.4, 10.7, 5.5 Hz, 1H), 5.25–5.17 (m, 1H), 5.15–5.10
1 : 1); m.p. 116–120 °C; IR (film) νmax 2942, 1755, 1726, (m, 1H), 4.70–4.54 (m, 2H), 3.79 (s, 3H), 3.7 (s, 3H), 3.19 (s,
1
1611 cm−1; H NMR (300 MHz, CDCl3): δ 7.39 (dd, J = 7.7, 1.4 3H); 13C NMR (101 MHz, CDCl3): δ 172.6, 168.7, 160.8, 159.0,
Hz, 1H), 7.35 (td, J = 7.7, 0.9 Hz, 1H), 7.08 (td, J = 7.7, 0.9 Hz, 143.9, 131.8, 129.2, 128.7, 128.3, 125.6, 122.8, 118.9, 118.1,
1H), 6.87 (app. d, J = 7.7 Hz, 1H), 6.48 (s, 2H), 5.92–5.80 (m, 108.3, 104.6, 100.2, 66.2, 61.9, 56.1, 55.3, 26.6; HRMS:
1H), 5.26–5.18 (m, 1H), 5.18–5.12 (m, 1H), 4.66 (app. d, J = (ESI-TOF) calculated for C21H22NO5 [M + H]+, 368.1498, found
5.6 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.24 (s, 3H); 368.1509.
13C NMR (101 MHz, CDCl3): δ 172.80, 168.58, 154.10, 152.71,
Allyl
1-methyl-2-oxo-3-(2,3,4-trimethoxyphenyl)indoline-3-
144.20, 142.39, 131.73, 129.28, 128.01, 125.91, 123.50, 122.84, carboxylate (3g). N-Methyl-oxindole (400 mg, 2.72 mmol), LDA
122.41, 118.15, 108.18, 106.21, 66.31, 62.08, 61.06, 60.52, (0.41 mL, 3.00 mmol), allyl chloroformate (0.32 mL,
55.94, 26.64; HRMS: (ESI-TOF) calculated for C22H24NO6 3.00 mmol), 2,3,4-trimethoxyphenyllead triacetate (0.989 g,
[M + H]+, 398.1604, found 398.1619.
2.50 mmol), pyridine (0.66 mL, 8.16 mmol) yielded 3g as a
Allyl 3-(2-(benzyloxy)naphthalen-1-yl)-1-methyl-2-oxoindoline- viscous oil (1.02 mg, 75%); Rf = 0.42 (pentane/EtOAc = 1 : 1);
3-carboxylate (3d). N-Methyl-oxindole (400 mg, 2.72 mmol), m.p. 123–127 °C; IR (film) νmax 2945, 1733, 1612 cm−1 1H
;
LDA (0.4 mL, 3.00 mmol), allyl chloroformate (0.32 mL, NMR (300 MHz, CDCl3): δ 7.39 (dd, J = 7.7, 1.4 Hz, 1H), 7.35
3.00 mmol), 2,4-dimethoxyphenyllead triacetate (1.54 g, (td, J = 7.7, 0.9 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.48 (s, 2H),
2.50 mmol), pyridine (0.66 mL, 8.16 mmol) yielded 3d as a 5.94–5.79 (m, 1H), 5.25–5.18 (m, 1H), 5.18–5.13 (m, 1H), 4.66
colorless solid (805 mg, 66%); Rf = 0.66 (pentane/EtOAc = (app. d, J = 5.6 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H),
1 : 1); m.p. 136–142 °C; IR (film) νmax 3424, 1720, 1612 cm−1
;
3.24 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 173.1, 168.9, 154.4,
1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 9.0 Hz, 1H), 153.1, 144.6, 142.7, 132.1, 129.6, 128.4, 126.3, 123.9, 123.2,
7.91–7.85 (m, 1H), 7.60–7.44 (m, 1H), 7.44–7.22 (m, 8H), 7.18 122.8, 118.5, 108.5, 106.6, 66.7, 62.4, 61.4, 60.9, 56.3, 27.0;
(d, J = 7.6 Hz, 1H), 7.03 (dt, J = 12.7, 7.6 Hz, 1H), 6.98 (td, J = HRMS: (ESI-TOF) calculated for C22H24NO6 [M + H]+, 398.1604,
7.6, 1.1 Hz, 1H), 5.71–5.61 (m, 1H), 5.13 (s, 2H), 5.08–4.98 (m, found 398.1593.
2H), 4.56–4.23 (m, 2H), 3.18–2.92 (m, 3H); 13C NMR (126 MHz,
Allyl
3-(benzo[d][1,3]dioxol-5-yl)-1-methyl-2-oxoindoline-3-
DMSO-d6) δ 171.3, 168.9, 143.1, 136.1, 131.3, 129.8, 129.2, carboxylate (3h). N-Methyl-oxindole (400 mg, 2.72 mmol), LDA
128.5 (2C), 128.3 (2C), 128.0, 127.7, 127.3, 127.2, 125.7, 124.0, (0.4 mL, 3.00 mmol), allylchloroformate (0.32 mL, 3.00 mmol),
122.9, 122.8, 121.9, 118.6, 117.0, 115.3, 108.2, 71.0, 65.1, 61.7, 3,4-methylenedioxyphenyllead triacetate (1.26 mg, 2.50 mmol),
25.9; HRMS: (ESI-TOF) calculated for C30H26NO4 [M + H]+, pyridine (0.66 mL, 8.16 mmol) gave 3h as a colorless solid
464.1862, found 464.1883.
(700 mg, 73%); Rf
=
0.63 (pentane/EtOAc
=
1 : 1);
1H
Allyl 3-(2-methoxynaphthalen-1-yl)-1-methyl-2-oxoindoline-3- m.p. 116–121 °C; IR (film) νmax 2893, 1745, 1719 cm−1
;
carboxylate (3e). N-Methyl-oxindole (400 mg, 2.72 mmol), LDA NMR (300 MHz, CDCl3): δ 7.43 (dd, J = 7.6, 1.3 Hz, 1H), 7.38
(0.41 mL, 3.00 mmol), allyl chloroformate (0.32 mL, (td, J = 7.6, 1.3 Hz, 1H), 7.13 (td, J = 7.6, 1.3 Hz, 1H), 6.92 (d,
3.00 mmol), 2-methoxynaphthyllead triacetate (1.32 g, J = 1.9 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 8.2,
2.50 mmol), pyridine (0.66 mL, 8.16 mmol) afforded 3e as a 1.9 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 5.78 (ddt, J = 17.2, 10.7,
colorless solid (700 mg, 67%); Rf = 0.45 (pentane/EtOAc = 5.4 Hz, 1H), 5.19–5.09 (m, 2H), 4.68–4.54 (m, 2H), 3.19 (s, 3H);
1 : 1); m.p. 180–184 °C; IR (film) νmax 2039, 1719, 1610 cm−1
;
13C NMR (101 MHz, CDCl3): δ 172.7, 168.8, 147.8, 147.6, 144.3,
1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 9.0 Hz, 1H), 131.2, 129.8, 129.3, 126.9, 125.9, 123.0, 121.3, 118.4, 108.9,
7.90–7.85 (m, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.37–7.25 (m, 4H), 108.8, 108.0, 101.3, 66.4, 63.5, 26.7; HRMS: (ESI-TOF) calcu-
7.17 (dd, J = 7.7, 1.2 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.98 (td, lated for C20H18NO5 [M + H]+, 352.1185, found 352.1197.
J = 7.7, 1.2 Hz, 1H), 5.78 (ddt, J = 17.4, 10.7, 5.4 Hz, 1H),
Allyl 3-(4-methoxyphenyl)-1-methyl-2-oxoindoline-3-carboxy-
5.18–5.07 (m, 2H), 4.59 (qdt, J = 13.8, 5.4, 1.6 Hz, 2H), 3.80 (s, late (3i). N-Methyl-oxindole (600 mg, 4.08 mmol), LDA
3H), 3.32 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 172.4, 168.8, (0.61 mL, 4.49 mmol), allylchloroformate (0.48 mL,
156.2, 143.9, 132.4, 130.8, 130.2, 129.5, 129.3, 129.2, 126.6, 4.49 mmol), 4-methoxylphenyllead triacetate (1.80 g,
125.1, 123.7, 122.9, 119.8, 118.1, 115.8, 109.1, 66.2, 62.5, 57.5, 3.67 mmol), pyridine (0.99 mL, 12.24 mmol) afforded 3i as an
27.2; HRMS: (ESI-TOF) calculated for C24H21NO4 [M + H]+ off white solid (923 mg, 67%); Rf = 0.58 (pentane/EtOAc =
388.1549, found 388.1552.
Allyl
3-(2,4-dimethoxyphenyl)-1-methyl-2-oxoindoline-3- 1H NMR (300 MHz, CDCl3): δ 7.45 (ddd, J = 7.7, 1.3, 0.6 Hz,
1 : 1); m.p. 86–89 °C; IR (film) νmax 3058, 1741, 1608 cm−1
;
carboxylate (3f). N-Methyl-oxindole (400 mg, 2.72 mmol), LDA 1H), 7.40 (td, J = 7.7, 1.3 Hz, 1H), 7.32–7.26 (m, 2H), 7.16 (td,
(0.4 mL, 3.00 mmol), allyl chloroformate (0.32 mL, J = 7.7, 1.0 Hz, 1H), 6.92 (app. d, J = 7.7 Hz, 1H), 6.88–6.83 (m,
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2H), 5.80 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H), 5.21–5.13 (m, 2H), oil (196 mg, 73%); Rf = 0.70 (pentane/EtOAc = 3 : 2), H NMR
4.70–4.57 (m, 2H), 3.76 (s, 3H), 3.21 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 7.55–7.25 (m, 7H), 7.26–7.12 (m, 1H), 6.95
(101 MHz, CDCl3): δ 173.2, 169.2, 159.7, 144.6, 131.5, 129.8, (m, 1H), 5.83 (ddt, J = 17.2, 10.7, 5.4 Hz, 1H), 5.27–5.11 (m,
129.3, 127.9, 127.3, 126.1, 123.1, 118.6, 114.2, 108.9, 66.6, 2H), 4.77–4.57 (m, 2H), 3.24 (s, 3H). All other physical and
63.5, 55.5, 26.9; HRMS: (ESI-TOF) calculated for C20H19NO4Na spectroscopic data were in complete agreement with those pre-
[M + Na]+ 360.1212, found 360.1205.
viously reported.34
Allyl 3-(2-methoxy-4,6-dimethylphenyl)-1-methyl-2-oxoindo-
Allyl 1-methyl-2-oxo-3-(4-(trifluoromethyl)phenyl)indoline-3-
line-3-carboxylate (3j). N-Methyl-oxindole (400 mg, 2.72 mmol), carboxylate (3m). To a flame dried Schlenk tube was added
LDA (0.4 mL, 3.00 mmol), allylchloroformate (0.32 mL, para-trifluoromethylphenylboronic acid (1.42 g, 7.48 mmol),
3.00 mmol), 2-methoxy-4,6-dimethylphenyllead triacetate Hg(OAc)2 (238.4 mg, 748 μmol) and Pb(OAc)4 (3.320 g,
(909 mg, 2.50 mmol), pyridine (0.66 mL, 8.16 mmol) yielded 3j 7.48 mmol). The mixture dried in vacuo for 4 h, then dissolved
as a colorless solid (835 mg, 66%); Rf = 0.63 (pentane/EtOAc = in anhydrous CHCl3 (25 mL) and stirred for 2 h. In a separate
1 : 1); m.p. 98–101 °C; IR (film) νmax 2935, 1721, 1610 cm−1
;
flame dried vessel was added LDA (0.93 mL, 7.48 mmol) in
1H NMR (500 MHz, DMSO-d6) δ 7.31 (td, J = 7.6, 1.3 Hz, 1H), THF (5 mL) and the mixture was cooled to −78 °C. N-Methyl-
7.17 (d, J = 7.6 Hz, 1H), 7.06–6.94 (m, 2H), 6.74 (s, 1H), 6.54 (s, oxindole (1.00 g, 6.8 mmol) was added and the reaction was
1H), 5.80 (ddt, J = 17.4, 10.6, 5.3 Hz, 1H), 5.24–5.06 (m, 2H), allowed to stir for 1 h. To the solution was added allyl chloro-
4.54 (ddt, J = 13.6, 5.3, 1.5 Hz, 2H), 3.66 (s, 3H), 3.20 (s, 3H), formate (0.8 mL, 7.48 mmol) and the reaction was slowly
2.23 (s, 3H), 1.79 (s, 3H); 13C NMR (126 MHz, DMSO-d6) warmed to −55 °C. After stirring for 12 h, the solution was
δ 172.3, 168.5, 158.5, 143.9, 138.2, 137.3, 132.6, 129.4, 129.1, transferred to the other Schlenk flask and pyridine (1.8 mL,
125.7, 125.3, 123.2, 122.8, 117.9, 112.1, 108.9, 65.9, 62.4, 22.44 mmol, 3.3 equiv.) added. The resultant mixture was
56.6, 27.0, 21.0, 20.7; HRMS: (ESI-TOF) calculated for stirred at 40 °C for 18 h, then stirred in 6% H2SO4 (20 ml) and
C22H23NO6 [M + H]+ 366.1705, found 366.1708.
the organic layer was separated. The aqueous layer was
Allyl 3-(2,6-dimethylphenyl)-1-methyl-2-oxoindoline-3-carboxy- extracted with EtOAc (3 × 50 mL) and the combined organic
late (3k). N-Methyl-oxindole (206 mg, 1.4 mmol), LDA (0.21 mL, layers were filtered through Celite, reduced in vacuo and puri-
1.54 mmol), allylchloroformate (0.16 mL, 1.54 mmol), 2,4-di- fied by silica gel flash column chromatography to give 3m as a
methylphenyllead triacetate (620 mg, 1.26 mmol), pyridine pale yellow solid (196 mg, 73%); Rf = 0.60 (pentane/EtOAc =
(0.339 mL, 4.2 mmol) afforded 3k as a pale green semi-solid 3 : 2); m.p. 83–87 °C; IR (film) νmax 1717, 1610, 1439 cm−1
;
(196 mg, 41%); Rf = 0.66 (pentane/EtOAc = 1 : 1); IR (film) νmax 1H NMR (400 MHz, CDCl3) δ 7.59–7.48 (m, 5H), 7.44–7.38 (m,
2928, 1716, 1609 cm−1; 1H NMR (300 MHz, CDCl3): 7.39 (td, J = 2H), 7.15 (td, J = 7.7, 1.0 Hz, 1H), 6.94 (dt, J = 7.7, 1.0 Hz, 1H),
7.7, 1.3 Hz, 1H), 7.32 (ddd, J = 7.8, 1.3, 0.8 Hz, 1H), 7.16–7.11 5.83–5.70 (m, 1H), 5.17–5.09 (m, 2H), 4.67–4.56 (m, 2H), 3.19
(m, 1H), 7.10–7.02 (m, 2H), 6.90 (dt, J = 7.8, 0.8 Hz, 1H), (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.9, 168.2, 144.3,
6.87–6.81 (m, 1H), 5.79 (ddt, J = 17.1, 10.5, 5.6 Hz, 1H), 139.6, 130.9, 130.2 (q, J = 33 Hz, 1C), 130.1, 128.5, 126.1, 125.7,
5.20–5.11 (m, 2H), 4.61 (dq, J = 5.6, 1.3 Hz, 2H), 3.32 (s, 3H), 125.3 (q, J = 3.67 Hz, 1C), 124.5 (q, J = 270 Hz, 1C),
2.54 (s, 3H), 2.53 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 172.3, 123.1, 118.5, 109.0, 66.5, 63.7, 26.7; 19F NMR (376 MHz,
169.4, 143.8, 137.1, 133.7, 130.9, 130.3, 130.1, 129.3, 128.9, CDCl3)
δ
−62.70; HRMS: (ESI-TOF) calculated for
127.4, 125.8, 122.9, 118.7, 108.6, 66.7, 26.8, 22.2; HRMS: C20H16NO3F3Na [M + Na]+ 398.0980, found 398.0971.
(ESI-TOF) calculated for C21H22NO3 [M + H]+ 336.1600, found
General procedure A for the Racemic decarboxylative allylic
alkylation
336.1589.
Allyl 1-methyl-2-oxo-3-phenylindoline-3-carboxylate (3l). To a
flame dried Schlenk tube was added phenylboronic acid To a mixture of α-aryl–β-amido allyl ester-substituted oxindole
(573 mg, 4.7 mmol), Hg(OAc)2 (65 mg, 235 μmol) and Pb(OAc)4 (3a–m) (1 equiv.), tris(dibenzylideneacetone)dipalladium·CHCl3
(2.20 g, 4.7 mmol) and this mixture was dried in vacuo for 4 h, (2.5 mol%) and 1,2-bis(diphenylphosphino)ethane (DPPE)
then dissolved in anhydrous CHCl3 (25 mL) and allowed to stir (6.5 mol%) under N2 was added toluene (0.033 M). The
for 2 h. In a separate flame dried vessel was added LDA mixture was allowed to stir at room temperature for 24 h. The
(0.582 mL, 4.7 mmol) in THF and the mixture was cooled to solution was reduced in vacuo and purified by flash column
−78 °C. N-Methyl-oxindole (627 mg, 4.27 mmol) was added chromatography.
and the reaction was allowed to stir for 1 h. To the solution
3-Allyl-1-methyl-3-(2,4,6-trimethoxyphenyl)indolin-2-one (11a).
was added allyl chloroformate (0.5 mL, 4.7 mmol) and the α-Aryl–β-amido allyl ester-substituted oxindole 3a (50 mg,
reaction was warmed slowly to −55 °C. After stirring for 12 h, 126 μmol), Pd2(dba)3·CHCl3 (3.3 mg, 3.15 μmol, 2.5 mol%),
the solution was transferred to the other Schlenk flask and pyr- and DPPE (3.26 mg, 8.19 μmol, 6.5 mol%) gave 11a as a white
idine (3.3 equiv.) was added. The resultant mixture was stirred solid (42 mg, 96%); Rf = 0.43 (pentane/EtOAc = 1 : 1);
at 40 °C for 18 h and then stirred in 6% H2SO4 (15 ml) and the m.p. 153–158 °C; IR (film) νmax 2979, 1608 cm−1 1H NMR
;
organic layer was separated. The aqueous layer was extracted (300 MHz, CDCl3): δ 7.25–7.11 (m, 2H), 6.93 (td, J = 7.6, 1.0 Hz,
with EtOAc (3 × 50 mL) and the combined organic layers were 1H), 6.77 (dt, J = 7.6, 1.0 Hz, 1H), 6.12 (s, 2H), 5.52 (ddt, J =
filtered through Celite, reduced in vacuo and purified by silica 17.1, 10.1, 7.3 Hz, 1H), 4.98–4.67 (m, 2H), 3.76 (s, 3H), 3.67 (s,
gel flash column chromatography to yield 3l as a pale yellow 6H), 3.24 (s, 3H), 3.22 (app dq, J = 7.3, 1.3 Hz, 2H); 13C NMR
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(101 MHz, CDCl3): δ 180.1, 160.1, 158.3, 143.4, 134.1, 133.8, 7.44–7.22 (m, 5H), 6.99 (dd, J = 7.5, 1.1 Hz, 1H), 6.96–6.90 (m,
127.1, 123.0, 121.9, 117.3, 109.9, 106.8, 92.5, 55.9, 55.2, 54.0, 1H), 5.59 (ddt, J = 17.0, 10.1, 7.0 Hz, 1H), 5.02–4.86 (m, 2H),
41.6, 25.8; HRMS: (ESI-TOF) calculated for C21H23NO4Na 3.84 (s, 2H), 3.46–3.39 (m, 2H), 3.37 (s, 3H); 13C NMR
[M + Na]+ 376.1525, found 376.1524.
(101 MHz, CDCl3): δ 179.8, 156.7, 143.0, 133.6, 133.5, 133.0,
3-Allyl-3-(2,6-dimethoxyphenyl)-1-methylindolin-2-one (11b). 130.5, 130.2, 129.1, 127.7, 126.0, 124.4, 123.6, 123.2, 122.5,
α-Aryl–β-amido allyl ester-substituted oxindole 3b (50 mg, 121.3, 118.1, 115.1, 107.6, 56.8, 56.3, 43.6, 26.1; HRMS:
136 μmol, 1 equiv.), Pd2(dba)3·CHCl3 (3.52 mg, 3.4 μmol, (ESI-TOF) calculated for C23H22NO2 [M + H]+ 344.1651, found
2.5 mol%), and DPPE (3.52 mg, 8.84 μmol, 6.5 mol%) afforded 344.1653.
11b as a pale yellow solid (43 mg, 98%); Rf = 0.54 (pentane/
EtOAc = 1 : 1); m.p. 97–99 °C; IR (film) νmax 3438, 1715, α-Aryl–β-amido allyl ester-substituted oxindole 3f (50 mg,
1611 cm−1 1H NMR (300 MHz, CDCl3): δ 7.24–7.09 (m, 3H), 136 μmol, 1 equiv.), Pd2(dba)3·CHCl3 (3.52 mg, 3.4 μmol,
3-Allyl-3-(2,4-dimethoxyphenyl)-1-methylindolin-2-one (11f).
;
6.93 (td, J = 7.5, 1.0 Hz, 1H), 6.78 (dt, J = 7.5, 1.0 Hz, 1H), 2.5 mol%), and DPPE (3.51 mg, 8.8 μmol, 6.5 mol%) gave 11f
6.62–6.50 (m, 2H), 5.53 (ddt, J = 17.1, 10.1, 7.1 Hz, 1H), 4.91 as a pale yellow solid (41 mg, 93%); Rf = 0.51 (pentane/EtOAc =
(ddt, J = 17.1, 2.2, 1.2 Hz, 1H), 4.86 (ddt, J = 10.1, 2.2, 1.2 Hz, 1 : 1); m.p. 139–142 °C; IR (film) νmax 3433, 1716, 1610 cm−1
;
1H), 3.69 (s, 6H), 3.25 (s, 3H), 3.27–3.23 (m, 2H); 13C NMR 1H NMR (300 MHz, CDCl3): δ 7.46 (d, J = 8.6 Hz, 1H), 7.21 (td,
(101 MHz, CDCl3): δ 179.8, 159.4, 143.5, 133.8, 133.7, 128.4, J = 7.6, 1.4 Hz, 1H), 6.93 (td, J = 7.4, 1.0 Hz, 1H), 6.87 (ddd, J =
127.3, 123.2, 121.9, 117.4, 117.2, 106.9, 106.0, 56.0, 54.3, 41.6, 7.4, 1.4, 0.6 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.54 (dd, J = 8.6,
25.9; HRMS: (ESI-TOF) calculated for C20H22NO3 [M + H]+ 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 5.41–5.27 (m, 1H),
324.1600, found 324.1606.
5.02–4.95 (m, 1H), 4.88 (ddt, J = 10.1, 1.9, 0.9 Hz, 1H), 3.78 (s,
3-Allyl-1-methyl-3-(2,3,6-trimethoxyphenyl)indolin-2-one (11c). 3H), 3.39 (s, 3H), 3.25 (s, 3H), 2.96 (dt, J = 7.1, 1.2 Hz, 2H);
α-Aryl–β-amido allyl ester-substituted oxindole 3c (50 mg, 13C NMR (101 MHz, CDCl3): δ 179.4, 160.2, 158.0, 144.2, 133.5,
126 μmol), Pd2(dba)3·CHCl3 (3.26 mg, 3.18 μmol, 2.5 mol%), 131.7, 127.9, 127.3, 122.4, 122.1, 122.0, 118.9, 106.9, 104.4,
and DPPE (3.26 mg, 8.19 μmol, 6.5 mol%) yielded 11c as a 100.0, 55.8, 55.3, 53.3, 40.5, 26.1; HRMS: (ESI-TOF) calculated
pale yellow wax (43 mg, 97%); Rf = 0.46 (pentane/EtOAc = 1 : 1); for C20H22NO3 [M + H]+ 324.1600, found 324.1606.
IR (film) νmax 2942, 1715, 1611 cm−1
;
1H NMR (500 MHz,
3-Allyl-1-methyl-3-(2,3,4-trimethoxyphenyl)indolin-2-one (11g).
DMSO-d6) δ 7.18 (td, J = 7.7, 1.4 Hz, 1H), 7.03 (dd, J = 7.7, 1.4 α-Aryl–β-amido allyl ester-substituted oxindole 3g (50 mg,
Hz, 1H), 6.95–6.82 (m, 3H), 6.69 (d, J = 9.0 Hz, 1H), 5.34 (ddt, 126 μmol, 1 equiv.), Pd2(dba)3·CHCl3 (3.26 mg, 3.18 μmol,
J = 17.0, 10.2, 7.0 Hz, 1H), 4.85–4.71 (m, 2H), 3.71 (s, 3H), 3.61 2.5 mol%), and DPPE (3.26 mg, 8.19 μmol, 6.5 mol%) yielded
(s, 3H), 3.47 (s, 3H), 3.14 (s, 3H), 3.07–2.98 (m, 2H); 13C NMR 11g as a pale yellow solid (44 mg, 98%); Rf = 0.57 (pentane/
(126 MHz, DMSO-d6) δ 178.6, 153.6, 149.3, 147.7, 144.2, 133.9, EtOAc = 1 : 1); m.p. 123–127 °C; IR (film) νmax 3430, 1714,
127.8, 123.3, 123.2, 123.0, 122.0, 117.7, 113.4, 108.6, 107.7, 1614 cm−1
60.4, 56.9, 56.8, 54.7, 41.4, 26.0; HRMS: (ESI-TOF) calculated 6.94 (td, J = 7.5, 1.0 Hz, 1H), 6.90–6.80 (m, 2H), 6.69 (d, J =
for C21H24NO4 [M + H]+ 354.1705, found 354.1696.
8.8 Hz, 1H), 5.41–5.30 (m, 1H), 4.99 (ddt, J = 17.0, 1.9, 1.0 Hz,
;
1H NMR (300 MHz, CDCl3): δ 7.27–7.19 (m, 2H),
3-Allyl-3-(2-(benzyloxy)naphthalen-1-yl)-1-methylindolin-2-one 1H), 4.89 (ddt, J = 10.0, 1.9, 1.0 Hz, 1H), 3.85 (s, 3H), 3.72 (s,
(11d). α-Aryl–β-amido allyl ester-substituted oxindole 3d 3H), 3.27 (s, 3H), 3.18 (s, 3H), 3.00–2.88 (m, 2H); 13C NMR
(50 mg, 104 μmol), Pd2(dba)3·CHCl3 (2.7 mg, 2.6 μmol, (101 MHz, CDCl3): δ 179.1, 153.41, 151.5, 144.2, 142.3, 133.9,
2.5 mol%), and DPPE (2.71 mg, 6.8 μmol, 6.5 mol%) gave 11d 131.6, 127.5, 127.0, 122.7, 122.0, 121.7, 119.0, 107.2, 106.3,
as a pale yellow solid (41 mg, 97%); Rf = 0.74 (pentane/EtOAc = 60.5, 59.6, 55.9, 53.4, 40.7, 26.1; HRMS: (ESI-TOF) calculated
1
1 : 1); m.p. 96–98 °C; IR (film) νmax 3421, 1716, 1611 cm−1; H for C21H24NO4 [M + H]+ 354.1705, 354.1718 found.
NMR (300 MHz, CDCl3): δ 8.49–7.86 (m, 2H), 7.76 (d, J = 8.6,
3-Allyl-3-(benzo[d][1,3]dioxol-5-yl)-1-methylindolin-2-one (11h).
1H), 7.69 (d, J = 8.6, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.37–7.27 (m, α-Aryl–β-amido allyl ester-substituted oxindole 3h (50 mg,
5H), 7.27–7.15 (m, 3H), 6.95 (td, J = 7.5, 1.0 Hz, 1H), 6.69 (d, 143 μmol), Pd2(dba)3·CHCl3 (3.7 mg, 3.6 μmol, 2.5 mol%), and
J = 7.7 Hz, 1H), 5.52 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.03 (s, DPPE (3.73 mg, 9.36 μmol, 6.5 mol%) gave 11h as an off-white
2H), 4.93–4.80 (m, 2H), 3.38 (app. d, J = 7.5 Hz, 2H), 2.74 (br. s, wax (42 mg, 96%); Rf = 0.74 (pentane/EtOAc = 1 : 1); IR (film)
3H); 13C NMR (101 MHz, CDCl3): δ 179.4, 158.5, 157.1, 143.2, νmax 3442, 1713, 1611 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.33
136.6, 135.0, 133.8, 133.5, 133.2, 132.8, 130.5, 130.1, 129.1, (td, J = 7.6, 1.1 Hz, 1H), 7.24 (dd, J = 7.4, 1.1 Hz, 1H), 7.11 (td,
128.4, 127.9, 127.8, 127.5, 125.9, 124.6 (2H), 123.4, 123.1, J = 7.6, 1.1 Hz, 1H), 6.91 (app. d, J = 1.9 Hz, 1H), 6.88 (app. d,
122.2, 118.1, 115.3, 107.6, 71.4, 43.8, 25.2; HRMS: (ESI-TOF) J = 7.8 Hz, 1H), 6.80 (dd, J = 8.2, 1.9 Hz, 1H), 6.71 (d, J =
calculated for C29H26NO2 [M + H]+ 420.1964, found 420.1981.
8.2 Hz, 1H), 5.91 (d, J = 1.1 Hz, 1H), 5.89 (d, J = 1.1 Hz, 1H),
3-Allyl-3-(2-methoxynaphthalen-1-yl)-1-methylindolin-2-one 5.38 (dddd, J = 17.0, 10.1, 7.6, 6.7 Hz, 1H), 5.02 (ddt, J = 17.0,
(11e). α-Aryl–β-amido allyl ester-substituted oxindole 3e 1.9, 1.1 Hz, 1H), 4.92 (ddt, J = 10.1, 1.9, 1.1 Hz, 1H), 3.19 (s,
(50 mg, 129 μmol), Pd2(dba)3·CHCl3 (3.34 mg, 3.23 μmol, 3H), 2.95 (app. dq, J = 7.6, 1.1 Hz, 2H); 13C NMR (101 MHz,
2.5 mol%), and DPPE (3.34 mg, 8.39 μmol, 6.5 mol%) afforded CDCl3): δ 178.0, 147.8, 146.8, 143.7, 133.3, 132.3, 131.7, 128.2,
11e as a yellow solid (43 mg, 98%); Rf = 0.57 (pentane/EtOAc = 125.1, 122.5, 120.4, 119.2, 108.2, 108.0, 107.9, 101.1, 56.0, 42.0,
1 : 1); m.p. 123–127 °C; IR (film) νmax 2937, 1714, 1630 cm−1
;
26.3; HRMS: (ESI-TOF) calculated for C19H18NO3 [M + H]+
1H NMR (300 MHz, CDCl3): δ 7.96 (s, 1H), 7.82–7.76 (m, 2H), 308.1287, found 308.1298.
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3-Allyl-3-(4-methoxyphenyl)-1-methylindolin-2-one (11i). EtOAc = 4 : 1); IR (film) νmax 1710, 1610, 1493 cm−1; H NMR
α-Aryl–β-amido allyl ester-substituted oxindole 3i (50 mg, (400 MHz, CDCl3) δ 7.52 (m, 4H), 7.35 (td, J = 7.6, 1.3 Hz, 1H),
148 μmol, 1 equiv.), Pd2(dba)3·CHCl3 (3.83 mg, 3.7 μmol, 7.25 (ddd, J = 7.6, 1.3, 0.6 Hz, 1H), 7.13 (td, J = 7.6, 1.0 Hz, 1H),
2.5 mol%), and DPPE (3.83 mg, 9.62 μmol, 6.5 mol%) afforded 6.91 (dt, J = 7.6, 1.0 Hz, 1H), 5.37 (dddd, J = 16.9, 10.1, 7.6,
11i as a white waxy solid (42 mg, 97%); Rf = 0.71 (pentane/ 6.8 Hz, 1H), 5.04 (m, 1H), 4.93 (ddt, J = 10.1, 1.8, 1.0 Hz, 1H),
EtOAc = 1 : 1); IR (film) νmax 2949, 1613 cm−1 1H NMR 3.20 (s, 3H), 3.01 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 177.2,
;
(300 MHz, CDCl3): δ 7.41–7.23 (m, 4H), 7.13 (td, J = 7.5, 1.1 Hz, 143.8, 143.4, 131.8, 130.0, 129.7, 129.4, 128.6, 127.6, 125.4,
1H), 6.91 (d, J = 7.5 Hz, 1H) 6.88–6.81 (m, 2H), 5.42 (ddt, J = 125.1, 122.7, 119.6, 108.5, 56.3, 42.1, 26.4; 19F NMR (376 MHz,
17.2, 10.0, 7.5 Hz, 1H), 5.1–4.98 (m, 1H), 4.93 (ddd, J = 10.0, CDCl3)
δ
−62.66; HRMS: (ESI-TOF) calculated for
1.9, 1.1 Hz, 1H), 3.79 (s, 3H), 3.21 (s, 3H), 3.01 (app. d, J = C19H16NOF3Na [M + Na]+ 354.1082, found 354.1065.
7.5 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 178.2, 171.1, 158.7,
General procedure for the decarboxylative asymmetric allylic
alkylation
140.8, 132.5, 131.8, 131.5, 128.1, 128.1, 122.3, 119.0, 113.8,
108.1, 55.7, 55.2, 42.1, 26.2; HRMS: (ESI-TOF) calculated for
C19H19NO2Na [M + Na]+ 316.1313, found 316.1311.
To a mixture of α-aryl–β-amido allyl ester-substituted oxindole
3-Allyl-3-(2-methoxy-4,6-dimethylphenyl)-1-methylindolin-2-one (3a–m) (1 equiv.) Pd2(dba)3·CHCl3 (2.5 mol%) and chiral
(11j). α-Aryl–β-amido allyl ester-substituted oxindole 3j (50 mg, ligand (6.5 mol%) under N2 was added toluene (0.033 M). The
137 μmol), Pd2(dba)3·CHCl3 (3.54 mg, 3.43 μmol, 2.5 mol%), mixture was allowed to stir at room temperature for 24 h. The
and DPPE (3.55 mg, 8.92 μmol, 6.5 mol%) yielded 11j as a pale solution was reduced in vacuo and purified by flash column
yellow solid (43 mg, 98%); Rf = 0.68 (pentane/EtOAc = 1 : 1); chromatography.
m.p. 95–100 °C; IR (film) νmax 3435, 1717, 1611 cm−1; 1H NMR
(R)-3-Allyl-1-methyl-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(300 MHz, CDCl3): δ 7.22 (td, J = 7.6, 1.2 Hz, 1H), 7.13 (d, J = ((R)-11a). α-Aryl–β-amido allyl ester-substituted oxindole 3a
7.6 Hz, 1H), 6.95 (td, J = 7.6, 1.2 Hz, 1H), 6.80 (d, J = 7.6 Hz, (50 mg, 126 μmol), Pd2(dba)3·CHCl3 (3.3 mg, 3.15 μmol,
1H), 6.59 (s, 1H), 6.54 (s, 1H), 5.45 (ddt, J = 17.1, 10.1, 7.0 Hz, 2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (6.7 mg,
1H), 4.97–4.79 (m, 2H), 3.58 (s, 3H), 3.24 (s, 3H), 3.20 (app. d, 8.19 μmol, 6.5 mol%) yielded (R)-11a as a white solid (42 mg,
J = 7.0 Hz, 2H), 2.39 (s, 3H), 2.25 (s, 3H); 13C NMR (101 MHz, 96%); 97% ee; SFC (Chiralpak IA, CO2(l)/IPA, 99 : 1–70 : 30 3 mL
CDCl3): δ 179.8, 158.7, 143.5, 138.1, 137.6, 133.7, 133.0, 127.4, min−1) RT 3.275 (major), 5.621 (minor) min; [α]D20 = +56.06
127.0, 123.0, 122.2, 117.9, 111.9, 107.1, 107.0, 56.4, 56.0, 42.9, (c 0.5, CHCl3). All other physical and spectroscopic data were
29.7, 25.8, 21.0; HRMS: (ESI-TOF) calculated for C21H24NO2 identical to that of the racemic compound.
[M + H]+ 322.1806, found 322.1807.
Crystals of (R)-11a suitable for X-ray analysis were grown by
2-(Allyloxy)-3-(2,6-dimethylphenyl)-1-methyl-1H-indole (11k). the slow evaporation of the solvents at room temperature:
α-Aryl–β-amido allyl ester-substituted oxindole 3k (50 mg, C21H23NO4, M = 353.40, orthorhombic, a = 8.75356 (7) Å, b =
149 μmol), Pd2(dba)3·CHCl3 (3.86 mg, 3.73 μmol, 2.5 mol%), 8.85744 (5) Å, c = 24.7460 (2) Å, U = 1918.66 Å3, T = 100 K,
and DPPE (3.17 mg, 9.7 μmol, 6.5 mol%) yielded 11k as a space group P212121, Z = 4, 19 851 reflections measured, 3983
yellow solid (34 mg, 80%); Rf = 0.74 (pentane/EtOAc = 1 : 1); unique (Rint = 0.0309) which were used in all calculations. The
m.p. 101–105 °C; IR (film) νmax 3430, 1715, 1639 cm−1
NMR (300 MHz, CDCl3): δ 7.25–7.11 (m, 5H), 7.05–6.99 (m,
;
1H final wR(F2) was 0.0729 (all data).
(R)-3-Allyl-3-(2,6-dimethoxyphenyl)-1-methylindolin-2-one
2H), 5.83 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H), 5.22–5.10 (m, 2H), ((R)-11b). α-Aryl–β-amido allyl ester-substituted oxindole 3b
4.26 (dt, J = 5.6, 1.4 Hz, 2H), 3.67 (s, 3H), 2.14 (s, 6H); 13C NMR (50 mg, 136 μmol), Pd2(dba)3·CHCl3 (3.52 mg, 3.4 μmol,
(101 MHz, CDCl3): δ 147.3, 138.9, 133.0, 132.7, 131.9, 127.1, 2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (7.27 mg,
127.0, 126.6, 119.8, 119.3, 118.3, 117.8, 108.1, 94.0, 73.0, 27.9, 8.84 μmol, 6.5 mol%) afforded (R)-11b as a pale yellow solid
20.7; HRMS: (ESI-TOF) calculated for C20H22NO [M + H]+ (43 mg, 98%); 96% ee; SFC LC (Chiralpak IA, CO2(l)/MeOH,
292.1701, found 292.1713.
99 : 1 to 70 : 30, 3 mL min−1) RT 3.017 (minor), 3.288 (major)
3-Allyl-1-methyl-3-phenylindolin-2-one (11l). α-Phenyl–β- min; [α]2D0 = +232.66 (c 1.0, CHCl3). All other physical and spec-
amido allyl ester-substituted oxindole 3l (30 mg, 100 μmol), troscopic data were identical to that of the racemic compound.
Pd2(dba)3·CHCl3 (2.6 mg, 2.50 μmol, 2.5 mol%), and DPPE
(R)-3-Allyl-1-methyl-3-(2,3,6-trimethoxyphenyl)indolin-2-one
(2.57 mg, 6.5 μmol, 6.5 mol%) gave 11l as a yellow oil (24 mg, ((R)-11c). α-Aryl–β-amido allyl ester-substituted oxindole 3c
92%); Rf = 0.50 (pentane/EtOAc = 4 : 1); 1H NMR (300 MHz, (50 mg, 126 μmol), Pd2(dba)3·CHCl3 (3.26 mg, 3.18 μmol,
CDCl3) δ 7.31 (m, 7H), 7.11 (td, J = 7.5, 1.1 Hz, 1H), 6.89 (m, 2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (6.73 mg,
1H), 5.39 (ddt, J = 17.1, 10.0, 7.5 Hz, 1H), 4.98 (m, 2H), 3.20 (s, 8.19 μmol, 6.5 mol%) gave (R)-11c as a pale yellow waxy solid
3H), 3.03 (dt, J = 7.5, 1.1 Hz, 2H). All other physical and (43 mg, 97%); 94% ee; SFC LC (Chiralpak IC, CO2(l)/IPA, 99 : 1
spectroscopic data was identical to those previously reported.34 to 70 : 30, 3 mL min−1) RT 6.773 (minor), 7.258 (major) min;
3-Allyl-1-methyl-3-(4-(trifluoromethyl)phenyl)indolin-2-one [α]2D0 = +116.51 (c 2.2, CHCl3). All other physical and spectro-
(11m). α-Aryl–β-amido allyl ester-substituted oxindole 3m scopic data were identical to that of the racemic compound.
(50 mg, 133 μmol), Pd2(dba)3·CHCl3 (3.44 mg, 3.33 μmol,
(R)-3-Allyl-3-(2-(benzyloxy)naphthalen-1-yl)-1-methylindolin-
2.5 mol%), and DPPE (3.46 mg, 8.70 μmol, 6.5 mol%) afforded 2-one ((R)-11d). α-Aryl–β-amido allyl ester-substituted oxindole
11m as a pale yellow oil (38 mg, 86%); Rf = 0.40 (pentane/ 3d (50 mg, 104 μmol), Pd2(dba)3·CHCl3 (2.7 mg, 2.6 μmol,
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2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (5.56 mg, (43 mg, 98%); 60% ee; SFC LC (Chiralpak IC, CO2(l)/IPA, 99 : 1
6.8 μmol, 6.5 mol%) afforded (R)-11d as a pale yellow solid to 70 : 30, 3 mL min−1) RT 4.821 (major), 5.873 (minor) min;
(41 mg, 97%); 97% ee; SFC LC (Chiralpak IC, CO2(l)/IPA, 99 : 1 [α]2D0 = +123.94 (c 0.5, CHCl3). All other physical and spectro-
to 70 : 30, 3 mL min−1) RT 6.152 (minor), 8.469 (major) min; scopic data were identical to that of the racemic compound.
[α]2D0 = +539.53 (c 0.5, CHCl3). All other physical and spectro-
scopic data were identical to that of the racemic compound.
(R)-3-Allyl-1-methyl-3-phenylindolin-2-one ((R)-11l). α-Phenyl–β-
amido allyl ester-substituted oxindole 3l (30 mg, 100 μmol),
(R)-3-Allyl-3-(2-methoxynaphthalen-1-yl)-1-methylindolin-2-one Pd2(dba)3·CHCl3 (2.6 mg, 2.50 μmol, 2.5 mol%), and (R,R)-
((R)-11e). α-Aryl–β-amido allyl ester-substituted oxindole 3e ANDEN-Phenyl-Trost (5.3 mg, 6.5 μmol, 6.5 mol%) gave (R)-11l
(50 mg, 129 μmol), Pd2(dba)3·CHCl3 (3.34 mg, 3.23 μmol, as yellow oil (24 mg, 91%); 61% ee; SFC LC (Chiralpak IC,
2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (6.81 mg, CO2(l)/IPA, 99 : 1 to 70 : 30, 3 mL min−1) RT 2.470 (major), 2.848
8.39 μmol, 6.5 mol%) gave (R)-11e as a yellow waxy solid (minor) min; [α]2D0 = −32.72 (c 0.5, CHCl3). All other physical
(43 mg, 98%); 98% ee; SFC LC (Chiralpak IC, CO2(l)/IPA, 99 : 1 and spectroscopic data were identical to those previously
to 70 : 30, 3 mL min−1) RT 6.502 (minor), 7.487 (major) min; reported.34
[α]2D0 = +481.68 (c 0.5, CHCl3). All other physical and spectro-
(R)-3-Allyl-1-methyl-3-(4-(trifluoromethyl)phenyl)indolin-2-
scopic data were identical to that of the racemic compound.
one ((R)-11m). α-Phenyl–β-amido allyl ester-substituted oxi-
(R)-3-Allyl-3-(2,4-dimethoxyphenyl)-1-methylindolin-2-one one ndole 3m (50 mg, 133 μmol), Pd2(dba)3·CHCl3 (3.44 mg,
((R)-11f). α-Aryl–β-amido allyl ester-substituted oxindole 3f 3.33 μmol, 2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost
(50 mg, 136 μmol), Pd2(dba)3·CHCl3 (3.52 mg, 3.4 μmol, (7.07 mg, 8.7 μmol, 6.5 mol%) yielded (R)-11m as pale yellow
2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (7.26 mg, oil (42 mg, 96%); 56% ee; SFC LC (Chiralpak IC, CO2(l)/ACN,
8.8 μmol, 6.5 mol%) yielded (R)-11f as a pale yellow solid 99 : 1 to 70 : 30, 3 mL min−1) RT 1.720 (major), 1.961 (minor)
(41 mg, 93%); 97% ee; SFC LC (Chiralpak IC, CO2(l)/IPA, 99 : 1 min; [α]2D0 = −29.94 (c 0.5, CHCl3). All other physical and spec-
to 70 : 30, 3 mL min−1) RT 4.397 (major), 5.760 (minor) min; troscopic data were identical to that of the racemic compound.
[α]2D0 = +82.23 (c 0.5, CHCl3). All other physical and spectro-
scopic data were identical to that of the racemic compound.
(R)-3-Allyl-1-methyl-3-(2,3,4-trimethoxyphenyl)indolin-2-one Conflicts of interest
one ((R)-11g). α-Aryl–β-amido allyl ester-substituted oxindole
3g (50 mg, 126 μmol), Pd2(dba)3·CHCl3 (3.26 mg, 3.18 μmol,
There are no conflicts to declare.
2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (6.73 mg,
8.19 μmol, 6.5 mol%) afforded (R)-11g as a pale yellow solid
Acknowledgements
(44 mg, 98%); 92% ee; SFC LC (Chiralpak IB, CO2(l)/ACN, 99 : 1
to 70 : 30, 3 mL min−1) RT 4.514 (major), 5.522 (minor) min;
M. J. acknowledges the financial support for his PhD pro-
gramme received from Molecular Medicine Ireland as part of
the Clinical & Translational Research Scholars Programme
(CTRSP), funded under the Programme for Research in Third
Level Institutions (PRTLI) Cycle 5, and co-funded under the
European Regional Development Fund (ERDF). C. Q. O’B.
acknowledges financial support from the Irish Research
Council through the Enterprise Partnership Scheme for the
award of a Ph.D scholarship (EPSPG/2016/62) co-funded by
Leo Pharma. We acknowledge the facilities provided by the
Centre for Synthesis and Chemical Biology (CSCB), funded by
the Higher Education Authority’s Programme for Research in
Third-Level Institutions. We thank Dr Yannick Ortin and
Geraldine Fitzpatrick for NMR spectroscopy, Dr Jimmy
Muldoon, Adam Coburn and Kevin Conboy for mass
spectrometry, and Ms Jinju James for a critical reading of this
[α]2D0 = +50.06 (c 0.5, CHCl3). All other physical and spectro-
scopic data were identical to that of the racemic compound.
(R)-3-Allyl-3-(benzo[d][1,3]dioxol-5-yl)-1-methylindolin-2-one
((R)-11h). α-Aryl–β-amido allyl ester-substituted oxindole 3h
(50 mg, 143 μmol), Pd2(dba)3·CHCl3 (3.7 mg, 3.6 μmol,
2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (7.61 mg,
9.36 μmol, 6.5 mol%) gave (R)-11h as an off-white solid
(42 mg, 96%); 61% ee; SFC LC (Chiralpak IC, CO2(l)/MeOH,
99 : 1 to 70 : 30, 3 mL min−1) RT 3.596 (major), 4.253 (minor)
min; [α]2D0 = −115.01 (c 1.5, CHCl3). All other physical and spec-
troscopic data were identical to that of the racemic compound.
(R)-3-Allyl-3-(4-methoxyphenyl)-1-methylindolin-2-one one
((R)-11i). α-Aryl–β-amido allyl ester-substituted oxindole 3i
(50 mg, 148 μmol), Pd2(dba)3·CHCl3 (3.83 mg, 3.7 μmol,
2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand (7.82 mg,
9.62 μmol, 6.5 mol%) yielded (R)-11i as a white waxy solid
manuscript.
(42 mg, 97%); 58% ee; SFC (Chiralpak IC, CO2(l)/IPA, 99 : 1 to
70 : 30, 3 mL min−1) RT 4.104 (minor), 5.083 (major) min;
[α]2D0 = −33.89 (c 1.52, CHCl3). All other physical and spectro-
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8.92 μmol, 6.5 mol%) afforded (R)-11j as a pale yellow solid
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