Low-Temperature, Transition-Metal-Free Cross-Dehydrogenative Coupling Protocol for the Synthesis of 3,3-Disubstituted Oxindoles

Article abstract of DOI:10.1021/acs.joc.7b02085

A new low-temperature procedure for the synthesis of 3,3-disubstituted 2-oxindoles via cross-dehydrogenative coupling (CDC) is reported. The use of a strong, nonreversible base in these reactions has been found to effect a dramatic drop in reaction temperature (to room temperature) relative to the current state-of-the-art (>100 °C) procedure. When employing iodine as an oxidant , new evidence suggests that this transformation may occur via a transiently stable iodinated intermediate rather than by direct single-electron oxidation.

Full text of DOI:10.1021/acs.joc.7b02085

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Note
A Low-Temperature, Transition Metal-Free Cross Dehydrogenative
Coupling Protocol for the Synthesis of 3,3-Disubstituted Oxindoles.
James R. Donald, Richard John Kenneth Taylor, and Wade F. Petersen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02085 • Publication Date (Web): 19 Sep 2017
Downloaded from http://pubs.acs.org on September 20, 2017
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The Journal of Organic Chemistry
A Low–Temperature, Transition Metal–Free Cross Dehydrogenative Coupling Protocol
for the Synthesis of 3,3–Disubstituted Oxindoles
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James R. Donald, Richard J. K. Taylor* and Wade F. Petersen*
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Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
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Abstract
R4
R3
R4 R3
i) KHMDS, THF, -78 ℃
X
X
R1
R1
O
ii) I2 to rt
N
O
N
R2
14 examples
up to 75% yield
R2
A new low–temperature procedure for the synthesis of 3,3-disubstituted 2-oxindoles via cross
dehydrogenative coupling (CDC) is reported. The use of a strong, non-reversible base in
these reactions has been found to effect a dramatic drop in reaction temperature (to room
temperature) relative to the current state-of-the-art (>100 °C). When employing iodine as an
‘oxidant’, new evidence suggests that this transformation may occur via a transiently stable
iodinated intermediate rather than by direct single–electron oxidation.
The remarkable biological properties of oxindoles, particularly 3,3-disubstituted 2-oxindoles,
has made this class of small molecules very attractive targets for synthesis and medicinal
chemistry research programs.1 These heterocyclic scaffolds also feature in many structurally
complex natural products2,3 and therefore inspire the development of new, creative and
mechanistically interesting methods for their construction.
Of the methods available for their synthesis, which include functionalization of mono-
substituted 3-oxindoles4 and isatin derivatives,5 transition metal catalyzed arylations,6 radical
additions to N-acrylamides,7 reactions of indoles8 and oxidation of indolenines,9 one of the
most versatile and straightforward approaches is through the use of oxidative cross
dehydrogenative coupling (CDC) reactions.10-16 This approach, which proceeds via a key
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intramolecular homolytic aromatic substitution of an amidyl radical 1, was pioneered
independently by Kündig et al.10 as well as our own group11 and utilizes easily prepared
acyclic starting materials, offering a broad functional group scope and avoiding the need for
expensive catalysts and ligands (Scheme 1). Bisai later extended this to a metal free variant
by employing DDQ, iodine, NIS or ICl as oxidants, again at elevated temperatures.13
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Scheme 1. Independent reports from the Kündig and Taylor groups of the CDC approach to oxindoles.
Kündig
R3
CuCl2 (2.2 eq.)
NaOtBu (5.0 eq.)
Ar
R3
Ar
R1
R1
O
via
R3 R4
N
N
O
DMF, 110 ℃
R2
R2
R1
N
R2
O
Taylor
R3
EWG
R3
EWG
1
Cu(OAc)2.H2O (5 mol%)
R1
R1
O
N
N
R2
O
Mesitylene, 165 ℃
air
R2
EWG = CO2R, CN, P(O)(OEt)2
Despite the many methods to choose from for the synthesis of the 2-oxindole framework,
including those in Scheme 1, the overwhelming majority of these methods require high
reaction temperatures. This therefore precludes thermally–sensitive substrates and/or
products and makes developing asymmetric variants of these reactions particularly
challenging. Furthermore, these temperatures are often well above the flash points, but
perhaps more worryingly, also above the fire points of the solvents they are carried out in.17
Therefore, particularly when carrying out these reactions in the presence of air/oxygen, there
is a pressing urgency to develop safer, lower temperature protocols. In a notable recent
example, Wu and Xu reported the synthesis of a variety of heat-sensitive C3-fluorinated
oxindoles using a CDC approach under electrochemical conditions at operational
temperatures between –30 °C and 0 °C.18 While this is an enormous step forward in offering a
safer alternative, it requires specialized equipment and has only been demonstrated in the
synthesis of C3-fluorinated products. Herein we report low–temperature conditions for the
synthesis of a diverse range of 3,3-disubstituted oxindoles via cross dehydrogenative
coupling as a complementary and safer addition to the current literature.
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The Journal of Organic Chemistry
The oxidative generation of α-carbonyl radicals using a strong base and a suitable oxidant at
low temperature is well documented (particularly in applications to the synthesis of 1,4-
diketones)19 and we proposed that these conditions might similarly generate the requisite α-
carbonyl amidyl radical intermediate 1 (Scheme 1), which could subsequently cyclize to
afford 3,3-disubstituted 2-oxindoles at safer operating temperatures. Traditionally, the
oxidative generation of α-carbonyl radicals utilizes a lithium amide base and a copper(II) salt
and this was used as a basis for the reaction design, with room temperature envisaged as the
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upper reaction temperature limit. In the event, model anilide 2a was subjected to various
conditions, the results of which are summarized in Table 1.
Table 1. Optimization of low temperature CDC of anilide 2a.a
Me
Me
N
CO2Et
O
CO2Et
O
O
O
i) Base (1.2 eq.), THF, -78 ℃
N
OEt
ii) oxidant (2.2 eq.), temp.
N
MeCl
Me
Me
Me
(±)-3a
2a
4
Entry
Base
Temperatureb (°C)
Oxidant
CuCl2
Yield (%)c
1
2
3
LiHMDS
LiHMDS
KHMDS
−78
rt
15d
48e
54f
Cu(II) 2-ethylhexanoate
CuCl2
−78
4
5
KHMDS
KHMDS
KHMDS
KHMDS
LiHMDS
LDA
−78 to rt
rt
Cu(II) 2-ethylhexanoate
Cu(OTf)2
30g,h
23e,g
0e,g
16
6
rt
Cu(OAc)2
7
−78
DDQ
h
8
−78 to rt
−78 to rt
−78 to rt
I2
52
h
9
I2
56
h
10
KHMDS
I2
70
aReactions were stopped after complete conversion of the starting material (by TLC) unless otherwise
b
d
stated (typically 2 – 8 hours). Temperature after addition of the oxidant. cIsolated yield. 55% of C-
Chlorination. Reaction left overnight. 34% yield of C-chlorinated product. g All starting material
e
f
recovered. h1.2 eq. of I2.
Treating 2a with LiHMDS and CuCl2 at −78 °C afforded 3a in 15% yield with the α-
chlorinated anilide (4) isolated as the major product in 55% yield after 2 h at −78 °C (entry
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1). It was suspected that poor the solubility of CuCl2 in THF was negatively affecting the
reaction but unfortunately no conversion was observed at −78 °C using the more soluble
Cu(II) 2-ethylhexanoate. On carrying out the reaction at room temperature, however,
oxindole 3a was formed in 48% yield (entry 2). Switching to KHMDS, CuCl2 afforded the
desired oxindole in an improved yield of 54% after 2 h along with the undesired C-
chlorinated product (4) in 34% yield (entry 3), whereas Cu(II) 2-ethylhexanoate gave 3a in a
disappointing 30% yield (entry 4). Neither copper(II) trifluoromethanesulfonate nor
Cu(OAc)2 was able to effect the reaction at room temperature (entries 5 and 6) while the
organic oxidant DDQ gave 3a in a poor yield of 16% (entry 7). A breakthrough was achieved
when iodine was employed as the oxidant. Introducing iodine (1.2 eq.) to the enolate at −78
°C and subsequently warming to room temperature afforded 3a in 52% and 56% yields when
using LiHMDS and LDA (entries 8 and 9), respectively, while KHMDS provided optimal
conditions, affording 3a in 70% yield (entry 10). The use of N-iodosuccinimide as well as
other solvents, including diethyl ether, DMSO, CH3CN and DMF were also tested but I2 and
THF was found to be the best combination for this transformation. This optimized low
temperature protocol was then applied to the synthesis of a range of 3,3-disubstituted 2-
oxindoles in order to explore the substrate scope (Scheme 2).
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Scheme 2. Substrate scope.
R4
R3
R4 R3
X
X
i) KHMDS, THF, -78 ℃
R1
O
R1
ii) I2 to rt
O
N
N
R2
(±)-3
R2
2
Me
CO2Et
O
Ph
Me
CO2Et
O
CO2R
O
CO2Et
O
N
N
N
N
Bn
Me
Me
R = Et: 3a, 70%
R = Me: 3b, 69%
Me
3c, 75%
3e, 62%
3d, 60%
X
O
Me
Me
Me
R
CO2Et
CO2Et
CO2Et
Cl
O
N
O
O
N
O
N
N
N
Me
Me
3g, 68%
Me
Me
Ph
3f, 45%; dr: 1.7:1
R = H, X = NBoc: 3i, 40%
R = Me, X = O: 3j, 23%
3h, 61%
R
CO2Et
F
BocNMe
CO2Et
CO2Et
RO
CO2Et
MeO
O
O
N
O
N
O
N
N
Me
Me
Me
R = Piv (3l), 62%
= Ac (3m), 0%
Me
3k, 54%
R = F (3n), 57%
= Cl (3o), 0%
= Br (3p), 0%
3q, 53%
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The Journal of Organic Chemistry
Variation of the ester group had little effect on the efficiency of the reaction and changes to
the alkyl group at the methylene position were also well tolerated and afforded oxindole
products 3b − 3d in 60 – 75% yields. Variation of the protecting group on nitrogen is
possible, for example N-benzyl oxindole 3e was produced in 62% yield. A key drawback of
the typical high temperature CDC methods to access 2-oxindoles is in applications for
stereoselective synthesis and we were interested to investigate the potential of a
diastereoselective cyclization under the new room temperature conditions. Unfortunately,
when the process was performed on anilide 2f, oxindole 3f was produced in 45% yield with a
dr of 1.7:1. A similar dr was obtained using CuCl2, even at −78 °C and investigations to
develop stereoselective applications are currently ongoing. Substitution on the aromatic ring
as well as variation to a pyridine ring was also possible giving 3g and 3h in 68% and 61%
yields, respectively. Spirocyclic oxindoles have gained considerable interest due to their
promising therapeutic potential as anticancer and antiviral agents1b,1c and these new
conditions were found to be appropriate for the construction of these frameworks, affording
nitrogen containing spiro-oxindole 3i in 40% yield and the oxygen containing variant 3j in
23% yield, both under the standard conditions. It should be noted that these low temperature
conditions cannot be used to prepare 3-aryl oxindoles and anilides with a free N-H also did
not provide oxindole formation (however these are easily accessed by deprotection of 3e).
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Oxindoles bearing heteroatoms at the 3-position are highly sought–after targets and we were
interested to see whether the low temperature conditions would be amenable to their
synthesis. In the event, we were delighted that oxindoles 3k – 3q, bearing nitrogen, oxygen as
well as fluorine at the 3-position could be also be synthesized at room temperature in 53 –
62% yield. For 3-hydroxy-oxindoles synthesis, O–protection with a non-enolizable group
was essential; thus, the OPiv substituted 3k was obtained in 62% yield whereas the acetate
protected analog was not suitable for the cyclization reaction. Interestingly, fluorine was the
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only halogen compatible with the methodology affording 3-fluoro-oxindoles 3n and 3q in
57% and 53% yield, respectively, while neither chloride, bromide nor iodide variants were
found to be suitable for this transformation. The utility of this low temperature procedure is
perhaps best highlighted with respect to compounds 3n and 3q. 3–Fluoro-oxindoles have
very encouraging therapeutic properties but their exploration has been limited due to
challenges in their synthesis as they are susceptible to base–mediated decomposition above
temperatures as low as –30 °C,18 which therefore makes most CDC approaches challenging.
The current method however offers a viable alternative for their synthesis without the need
for specialized electrochemistry equipment18 or transition metal catalysts.20
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Mechanistically, these new reaction conditions raised interesting questions, since in a related
protocol, Bisai’s group reported that when using KOtBu and I2 the reaction required heating
to 110 °C in order to obtain high yields and when performed at room temperature the desired
oxindole was produced in 30 – 39% yields only when using NIS or ICl.13 The mechanism
proposed by Bisai features a single–electron oxidation of the enolate by I2 (or iodine source)
to form the α-carbonyl radical, followed by a cyclization, and it was therefore somewhat
surprising that variation of the base could have such a dramatic difference in the yield at
room temperature. In monitoring our reaction, it was found that when iodine was introduced
to the preformed enolate at –78 °C, complete formation of the C-iodinated anilide (A) was
observed (1H-NMR and HRMS evidence) and upon warming to room temperature, this
intermediate slowly decomposed to the desired oxindole (Scheme 3).
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The Journal of Organic Chemistry
1
Scheme 3. Proposed mechanism for the low temperature metal–free CDC protocol.
Me
2
3
4
5
6
7
8
9
CO2Et
Me
CO2Et
i) KHMDS, THF, -78 ℃
O
ii) I2 to rt
N
O
N
Me
Me
i) KHMDS,
-78 ℃
ii) I2, -78 ℃
Me
CO2Et
SET pathway
-H / -H+, -e-
Me
N
CO2Et
O
I
homolysis
rt
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N
O
Me
I
Me
A
B
In Bisai’s report it was suggested that their high reaction temperatures (110 °C) may have
prevented the observation of this transient iodide, which we can now confirm, but do not rule
out the proposed direct iodine single-electron transfer oxidation mechanism at elevated
temperatures. In fact, reconciling with Bisai’s mechanism, it is possible that at low
temperature the enolate is indeed oxidized to radical B but is quickly intercepted by the
Ÿ
iodine atom (I ) to form A rather than undergoing cyclization (as shown by the dotted SET
pathway in Scheme 4). On warming to rt, the iodide slowly undergoes thermal homolysis
(since exclusion of light did not inhibit product formation) back to the α-carbonyl radical B,
presumably facilitated by halogen-bond activation with the solvent and/or HMDS,21 and
cyclizes to afford the oxindole.
To probe the homolysis, we thought that it might be possible to trap radical B with O2, by
exposing the iodinated intermediate formed in situ, to air. In the event, alcohol 5 was
obtained in 79% (over 2 steps) following work-up with Na2S2O3 and therefore affords
evidence in support of the proposed radical intermediate (Scheme 4).
Scheme 4. Radical trapping with O2 to form tertiary alcohol 5.
Me
N
CO2Et
i) KHMDS, THF,
O
O
O
O
I
N
OEt
-78 ℃
air
O
Me
N
OEt
OH
Me
5
79% (over 2 steps)
Me
Me
2a
ii) I2, -78 ℃
Me
A
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Similar homolyses have been proposed by Miao and Yang22 as well as the Itoh groupin their
iodine–catalyzed CDC of thiophenes23 with carbonyl compounds and our mechanistic studies
and analytical data are in agreement with this report.
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In summary, we have developed a mild, low–temperature and scalable set of conditions for
the synthesis of a diverse range of 3,3-disubstituted 2-oxindoles via cross dehydrogenative
coupling, in yields up to 75%. The significantly lower reaction temperatures described,
compared to existing methods, offer conditions more appropriate for stereoselective synthesis
and asymmetric CDC routes to 2-oxindoles, and these are currently being investigated. New
mechanistic insight into the iodine mediated CDC reaction suggests that at temperatures
below or up to rt, this process proceeds via the formation and subsequent homolysis of a
transiently stable tertiary-iodide intermediate. This work, together with the report from the
Itoh group,23 highlights the scope for application of these tertiary iodides as masked radical
synthons that can be activated under very mild and metal–free conditions and is currently
being explored in our group.
Experimental Section
General information
Except where stated, all reagents were purchased from commercial sources and used without
further purification. THF was freshly distilled from sodium-benzphenone ketyl and all other
solvents were dried on an Innovative Technology Inc. PureSolv Solvent Purification System.
1H NMR and 13C NMR spectra were recorded on a JEOL ECX400 or JEOL ECS400
spectrometer, operating at 400 MHz and 100 MHz, respectively. All spectral data was
acquired at 295 K. Chemical shifts are reported in parts per million (ppm, δ), downfield from
tetramethylsilane (TMS, δ = 0.00 ppm) and are referenced to residual solvent (CDCl3, δ =
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The Journal of Organic Chemistry
7.26 ppm (1H) and 77.16 ppm (13C)). Coupling constants (J) are reported in Hertz (Hz). The
multiplicity abbreviations used are: br broad, s singlet, d doublet, t triplet, q quartet, m
multiplet, app. apparent. Signal assignment was achieved by analysis of DEPT, COSY,
HMBC and HSQC experiments where required. Infrared (IR) spectra were recorded on a
PerkinElmer UATR 2 spectrometer, either as a compressed solid or a thin film dispersed
from CH2Cl2 or CDCl3. High-resolution mass-spectra were obtained by the University of
York Mass Spectrometry Service, using electrospray ionisation (ESI) on a Bruker Daltonics,
Micro-tof spectrometer. Melting points were determined using Gallenkamp apparatus. Thin
layer chromatography was carried out on Merck silica gel 60F254 pre-coated aluminium foil
sheets and visualized using UV light (254 nm) and stained with basic aqueous potassium
permanganate.
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Synthesis of novel anilides (2):24
Ethyl 2-methyl-3-(methyl(pyridin-4-yl)amino)-3-oxopropanoate (2h). To a solution of 4-
(methylamino)pyridine (0.379 g, 3.51 mmol), 3-ethoxy-2-methyl-3-oxopropanoic acid (0.466
g, 3.19 mmol) and DIPEA (1.67 mL, 9.57 mmol) in DCM (30 mL) at 0 °C was added
dropwise T3P (50 % w/w in EtOAc, 2.64 g, 4.15 mmol) and the solution allowed to warm to
rt. After 3 h sat. aq. NaHCO3 (50 mL) was added and the aqueous phase extracted with DCM
(2 x 30 mL). The combined organic extracts were dried with MgSO4, filtered and the solvent
removed in vacuo. The crude material was purified by flash chromatography (3% MeOH in
DCM) to afford 2i as a yellow oil (0.752 g, quant.). Rf 0.24 (5% MeOH/DCM); IR (film,
1
νmax/cm-1) 2984, 1838, 1662, 1585, 1497, 1400, 1191; H-NMR (400 MHz, CDCl3) δ (ppm)
8.63 (app. d, J = 6.2 Hz, 2H), 7.19 (app. d, J = 6.2 Hz, 2H), 4.14-4.01 (m, 2H), 3.47 (q, J =
13
7.0 Hz, 1H), 3.28 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); C-NMR (100
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MHz, CDCl3) δ (ppm) 170.2, 169.6, 151.6, 151.0, 121.7, 61.5, 43.8, 37.2, 14.2, 14.1; HRMS
(ESI+) m/z calcd. for C12H16N2NaO3 [M+Na+] 259.1053, found 259.1046.
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N-Methyl-2-oxo-N-(p-tolyl)tetrahydrofuran-3-carboxamide (2j). To a solution of N-methyl-
p-toluidine (0.695 g, 5.73 mmol), 2-oxotetrahydrofuran-3-carboxylic acid25 (0.626 g, 4.81
mmol), 2-chloro-1-methylpyridinium iodide (1.59 g, 6.21 mmol) in DCM (50 mL) at 0 °C
was added NEt3 (2.0 mL, 14.3 mmol) and the reaction warmed to rt and left to stir for 18 h. A
solution of HCl in water (10%, 30 mL) and after the layers were separated, the aqueous phase
extracted two more times with DCM (2 x 30 mL). The combined DCM extracts were washed
with sat. aq. NaHCO3 (60 mL), dried with MgSO4, filtered and the solvent removed in vacuo.
Purification of the crude material by flash silica gel chromatography (1:5->1:1
EtOAc:hexanes) afforded the title compound as a white solid (0.615 g, 55%). Rf 0.21 (2:3
EtOAc:hexanes); M.P. 74−76 °C; IR (film, νmax/cm-1) 2921, 1762, 1650, 1512, 1374, 1156,
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1121; H-NMR (400 MHz, CDCl3) δ (ppm) 7.22 (s, 4H), 4.46 (td, J = 8.5 Hz, 4.4 Hz, 1H),
4.13 (q, J = 8.5 Hz, 1H), 3.53 (t, J = 8.6 Hz, 1H), 3.28 (s, 3H), 2.69 (dq, J = 12.7 Hz, 8.6 Hz,
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1H), 2.36 (s, 3H), 2.28-2.17 (m, 1H); C-NMR (100 MHz, CDCl3) δ (ppm) 174.1, 167.9,
140.6, 138.5, 130.6, 127.2, 67.4, 43.4, 37.9, 27.4, 21.1; HRMS (ESI+) m/z calcd. for
C13H15NNaO3 [M+Na+] 256.0944, found 256.0947.
Ethyl 2-(benzyl(methyl)amino)-3-(methyl(phenyl)amino)-3-oxopropanoate. A mixture of
ethyl 2-bromo-3-(methyl(phenyl)amino)-3-oxopropanoate26 (0.467 g, 1.56 mmol), N-
benzylmethylamine (0.60 mL, 4.7 mmol) and DIPEA (0.81 mL, 4.67 mmol) in CH3CN (30
mL) was heated overnight at 70 °C under an Ar atmosphere. The solvent was removed in
vacuo and the crude material purified by flash silca gel chromatography eluting with 1:9
EtOAc:hexanes to afford the title compound as a yellow oil (0.337 g, 64%). Rf 0.36 (1:9
1
EtOAc:hexanes); IR (film, νmax/cm-1) 2979, 1745, 1659, 1595, 1495, 1184; H-NMR (400
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MHz, CDCl3) δ (ppm) 7.38-7.30 (m, 3H), 7.37-7.15 (m, 7H), 4.27-4.10 (m, 3H), 3.84 (d, J =
13.7 Hz, 1H), 3.73 (d, J = 13.7 Hz, 1H), 3.31 (s, 3H), 2.35 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H);
13C-NMR (100 MHz, CDCl3) δ (ppm) 168.9, 167.7, 143.4, 139.6, 129.8, 128.9, 128.3, 128.1,
127.4, 127.0, 66.5, 61.1, 58.5, 38.9, 37.7, 14.4; HRMS (ESI+) m/z calcd. for C20H24N2NaO3
[M+Na+] 363.1679, found 363.1666.
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Ethyl 2-((tert-butoxycarbonyl)(methyl)amino)-3-(methyl(phenyl)amino)-3-oxopropanoate
(2k). A slurry of 10 % Pd/C (0.094 g, 0.09 mmol) and ethyl 2-(benzyl(methyl)amino)-3-
(methyl(phenyl)amino)-3-oxopropanoate (0.300 g, 0.88 mmol) in EtOAc (25 mL) pre-purged
with N2 was equipped with a H2 balloon and stirred at rt for 3 h. The mixture was then filtered
through Celite®, washing with EtOAc (3 x 30 mL) and the solvent removed in vacuo. The
crude material was then dissolved in THF (20 mL) and sat. aq. NaHCO3 (20 mL) and
(Boc)2O (0.269 g, 1.23 mmol) added and the mixture stirred overnight. The reaction mixture
was then extracted with EtOAc (3 x 20 mL), dried with MgSO4 and the solvent removed in
vacuo. Flash silica gel chromatography of the crude material afforded anilide 2m as colorless
oil (0.224 g, 73%, over 2 steps). Rf 0.51 (1:3 EtOAc:hexanes); IR (film, νmax/cm-1) 2977,
1
1753, 1695, 1664, 1366, 1312, 1144; H-NMR (400 MHz, CDCl3) δ (ppm) (rotamers) 7.45-
7.29 (m, 3H), 7.25-7.19 (m, 2H), 5.51-5.22 (2 x s, 1H), 4.29-4.06 (m, 2H), 3.29 (s, 3H), 2.93-
2.89 (2 x s, 3H), 1.33 (s, 5H), 1.28-1.20 (2 x t, J = 7.1 Hz, 3H), 1.16 (s, 4H); 13C-NMR (100
MHz, CDCl3) δ (ppm) (rotamers) 168.1, 168.0, 166.7, 165.9, 142.8, 142.4, 130.1, 130.0,
128.6, 128.5, 127.3, 127.1, 80.5, 80.3, 61.7, 61.6, 61.0, 59.8, 38.0, 32.2, 31.6, 28.3, 28.1,
14.3, 14.2; HRMS (ESI+) m/z calcd. for C18H26N2NaO5 [M+Na+] 373.1734, found 373.1736.
Ethyl 3-(methyl(phenyl)amino)-3-oxo-2-(pivaloyloxy)propanoate (2l). Cesium hydroxide
hydrate (0.587 g, 3.50 mmol) was added to a solution of pivalic acid (0.357 g, 0.402 mL, 3.50
mmol) in DMF (1.2 mL) and stirred at rt for 5 min. The resulting solution was then added to
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ethyl 2-bromo-3-(methyl(phenyl)amino)-3-oxopropanoate26 (0.350 g, 1.17 mmol), and the
reaction stirred at rt for 16 h. The reaction was then diluted with water (10 mL), extracted
with EtOAc (3 x 20 mL) and the combined organic extracts dried with MgSO4, filtered and
the solvent removed in vacuo. Purification of the crude material by flash silica gel
chromatography (3:7 EtOAc:hexanes) afforded the title compound as a colorless oil (0.372 g,
99%). Rf 0.43 (2:3 EtOAc:hexanes); IR (film, νmax/cm-1) 2924, 1668, 1595, 1478, 1373, 1303,
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1291, 1138, 1080; H-NMR (400 MHz, CDCl3) δ (ppm) 7.43-7.27 (m, 5H), 5.44 (s, 1H),
4.16 (q, J = 7.1 Hz, 2H), 3.30 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.19 (s, 9 H); 13C-NMR (100
MHz, CDCl3) δ (ppm) 177.0, 165.5, 164.4, 142.3, 129.9, 128.7, 127.6, 69.9, 62.1, 38.7, 38.1,
27.0, 14.0; HRMS (ESI+) m/z calcd. for C17H23NNaO5 [M+Na+] 344.1468, found 344.1465.
Ethyl 2-fluoro-3-(methyl(phenyl)amino)-3-oxopropanoate (2n). Prepared according to the
literature procedure18 using ethyl 3-(methyl(phenyl)amino)-3-oxopropanoate (0.300 g, 1.36
mmol), NaOtBu (0.287 g, 2.98 mmol), ZnCl2 solution in diethyl ether (1 M, 2.98 mL, 2.98
mmol) and Selectfluor® (0.720 g, 2.03 mmol) to afford the title compound as a clear,
colorless oil (0.285 g, 88%). Rf 0.23 (3:7 EtOAc:hexanes); IR (film, νmax/cm-1) 2985, 1766,
1
1742, 1595, 1496, 1211, 1093; H-NMR (400 MHz, CDCl3) δ (ppm) 7.48-3.37 (m, 3H),
7.32-7.27 (m, 2H), 5.21 (d, JH-F = 48.1 Hz, 1H), 4.28-4.19 (m, 2H), 3.34 (s, 3H), 1.28 (t, J =
7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 165.3 (d, JC-F = 24.2 Hz), 163.7 (d, JC-F
=
20.9 Hz), 141.9, 130.1, 128.9, 127.6, 83.5 (d, JC-F = 189.9 Hz), 62.4, 38.1, 14.1; HRMS
(ESI+) m/z calcd. for C12H14FNNaO3 [M+Na+] 262.0850, found 262.0854.
Ethyl 3-fluoro-5-methoxy-1-methyl-2-oxoindoline-3-carboxylate (2q). Prepared according
to the literature procedure18 using ethyl 3-((4-methoxyphenyl)(methyl)amino)-3-
oxopropanoate (0.688 g, 2.74 mmol), NaOtBu (0.579 g, 6.02 mmol), ZnCl2 solution in diethyl
ether (1 M, 6.02 mL, 6.02 mmol) and Selectfluor® (1.45 g, 4.11 mmol) to afford the title
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compound as a clear, colorless oil (0.435 g, 59%). Rf 0.35 (2:3 EtOAc:hexanes); IR (film,
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νmax/cm-1) 2983, 1766, 1742, 1668, 1510, 1247, 1025; H-NMR (400 MHz, CDCl3) δ (ppm)
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7.22-7.17 (m, 2H), 6.95-6.90 (m, 2H), 5.22 (d, JH-F = 48.2 Hz, 1H), 4.28-4.18 (m, 2H), 3.81
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(m, 3H), 3.29 (app s, 3H), 1.28 (t, J = 7.2 Hz, 3H); C-NMR (100 MHz, CDCl3) δ (ppm)
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165.4 (d, JC-F = 24.2 Hz), 163.9 (d, JC-F = 21.0 Hz), 159.7, 134.5, 128.8, 115.1, 83.5 (d, JC-F
=
189.5 Hz), 62.4, 55.6, 38.2, 14.1; HRMS (ESI+) m/z calcd. for C13H16FNNaO4 [M+Na+]
292.0956, found 292.0967.
Synthesis of 3,3-disubstituted 2-oxindoles (3) via I2 mediated CDC:
General procedure:
KHMDS (1.0 M, 1.2 eq.) was added dropwise to a solution of anilide 2 (1.0 eq.) in THF
(approx. 20 mL / 0.150 g) under an Ar atmosphere, cooled to –78 °C and the reaction mixture
stirred at this temperature for 15 min. A solution of iodine (1.2 eq.) in THF (3 – 5 mL) was
added and the reaction held at this temperature until complete formation of the C-iodinated
intermediate was observed by TLC (approx. 15 min). The reaction was then removed from
the cooling bath and stirred for the specified amount of time. Once the reaction was complete
(by TLC), sat. aq. Na2S2O3 (25 mL) was added and once the mixture was decolorised it was
extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried with MgSO4,
filtered and the solvent removed in vacuo. The crude material was purified by flash silica gel
chromatography eluting with 1:9->1:4 EtOAc/hexanes (unless otherwise stated) to afford
oxindole 3.
Ethyl 1,3-dimethyl-2-oxoindoline-3-carboxylate (3a).11b Using anilide 2a11b (0.200 g, 0.85
mmol) in THF (25 mL), KHMDS (1.02 mL, 1.02 mmol) and I2 (0.261 g) in THF (4 mL) to
1
afford title compound as a colourless oil (0.140 g, 70%). Rf 0.32 (1:9 EtOAc:hexanes); H-
NMR (400 MHz, CDCl3) δ (ppm) 7.30 (td, J = 7.8 Hz, 1.2 Hz, 1H), 7.25-7.21 (m, 1H), 7.07-
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7.01 (m, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.17-4.03 (m, 2H), 3.23 (s, 3H), 1.63 (s, 3H), 1.12 (t,
J = 7.1 Hz, 3H). All recorded data were in accordance with those previously reported.
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Methyl 1,3-dimethyl-2-oxoindoline-3-carboxylate (3b).13a Using anilide 2b13a (0.167 g, 0.75
mmol) in THF (20 mL), KHMDS (0.91 mL, 0.91 mmol) and I2 (0.232 g, 0.91 mmol) in THF
(3 mL) to afford the title compound as a colorless solid (0.114 g, 69%). Rf 0.42 (2:3
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EtOAc:hexanes); H-NMR (400 MHz, CDCl3) δ (ppm) 7.32 (td, J = 7.7 Hz, 1.2 Hz, 1H),
7.27-7.23 (m, 1H), 7.07 (td, J = 7.7 Hz, 0.9 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 3.65 (s, 3H),
3.25 (s, 3H), 1.66 (s, 3H). All recorded data were in accordance with those previously
reported.
Ethyl 3-allyl-1-methyl-2-oxoindoline-3-carboxylate (3c).13a Using anilide 2c13a (0.357 g, 1.37
mmol) in THF (30 mL), KHMDS (1.64 mL, 1.64 mmol) and I2 (0.419 g, 1.64 mmol) in THF
(5 mL) to afford the title compound as a light yellow solid (0.267 g, 75%). Rf 0.41 (3:7
1
EtOAc:hexanes); H-NMR (400 MHz, CDCl3) δ (ppm) 7.29 (td, J = 7.7 Hz, 1.2 Hz, 1H),
7.26-7.23 (m, 1H), 7.04 (td, 7.7 Hz, 1.0 Hz, 1H), 6.82 (d, 7.7 Hz, 1H), 5.41-5.28 (m, 1H),
5.00 (dq, J = 17.0 Hz, 1.3 Hz, 1H), 4.91-4.87 (m, 1H), 4.18-4.04 (m, 2H), 3.20 (s, 3H), 2.98
(dd, J = 13.8 Hz, 6.7 Hz, 1H), 2.91 (dd, J = 13.8 Hz, 7.8 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H). All
recorded data were in accordance with those previously reported.
Ethyl 3-benzyl-1-methyl-2-oxoindoline-3-carboxylate (3d).11b Using anilide 2d11b (0.424 g,
1.36 mmol) in THF (35 mL), KHMDS (1.63 mL, 1.63 mmol) and I2 (0.418 g, 1.63 mmol) in
THF (5 mL) to afford the title compound as a colorless solid (0.254 g, 60%). Rf 0.31 (3:7
1
EtOAc:hexanes); H-NMR (400 MHz, CDCl3) δ (ppm) 7.32 (ddd, J = 7.6 Hz, 1.2 Hz, 0.5
Hz, 1H), 7.21 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.05 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.04-6.97 (m,
3H), 6.86-6.81 (m, 2H), 6.56 (d, J = 7.6 Hz, 1H), 4.26-4.09 (m, 2H), 3.56 (d, J = 13.7 Hz,
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1H), 3.52 (d, J = 13.7 Hz, 1H), 2.93 (s, 3H), 1.19 (s, 3H). All recorded data were in
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accordance with those previously reported.
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Ethyl 1-benzyl-3-methyl-2-oxoindoline-3-carboxylate (3e).11b Using anilide 2e11b (0.148 g,
0.48 mmol) in THF (15 mL), KHMDS (0.57 mL, 0.57 mmol) and I2 (0.146 g, 0.57 mmol) in
THF (3 mL) to afford the title compound as a colourless solid (0.91 g, 62%). Rf 0.31 (3:7
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EtOAc:hexanes); H-NMR (400 MHz, CDCl3) δ (ppm) 7.35-7.22 (m, 6H), 7.18 (td, J = 7.8
Hz, 1.3 Hz, 1H), 7.02 (td, J = 7.8 Hz, 1.0 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.19 (d, J = 15.8
Hz, 1H), 4,73 (d, J = 15.8 Hz, 1H), 4.24-4.04 (m, 2H), 1.72 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).
All recorded data were in accordance with those previously reported.
Ethyl 3-methyl-2-oxo-1-((S)-1-phenylethyl)indoline-3-carboxylate (3f).11d Using anilide 2f11d
(0.180 g, 0.55 mmol) in THF (15 mL), KHMDS (0.66 mL, 0.66 mmol) and I2 (0.170 g, 0.66
mmol) in THF (3 mL) to afford the title compound as a colorless oil (0.080 g, 45%) in a 1.7:1
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mixture of inseparable diastereomers. Rf 0.28 (1:4 EtOAc:hexanes); H-NMR (400 MHz,
CDCl3) δ (ppm) 7.42-7.39 (m, 1H), 7.37-7.22 (m, 5H), 7.09-7.01 (m, 1H), 7.00-6.94 (m, 1H),
6.53-6.44 (2 x ddd, J = 7.8 Hz, 1.1 Hz, 0.6 Hz, 1H), 5.97-5.81 (2 x q, J = 7.2 Hz, 1H), 4.26-
4.02 (m, 2H), 1.88-1.81 (2 x d, J = 7.2 Hz, 3H), 1.74-1.71 (2 x s, 3H), 1.23-1.14 (2 x t, J =
7.1 Hz, 3H). All recorded data were in accordance with those previously reported.
Ethyl 5-chloro-1,3-dimethyl-2-oxoindoline-3-carboxylate (3g).16 Using anilide 2g16 (0.225 g,
0.83 mmol) in THF (20 mL), KHMDS (1.0 mL, 1.00 mmol) and I2 (0.256 g, 1.00 mmol) in
THF (5 mL) to afford the title compound as a colorless oil (0.151 g, 68%). Rf 0.43 (3:7
1
EtOAc:hexanes); H-NMR (400 MHz, CDCl3) δ (ppm) 7.28 (dd, J = 8.3 Hz, 2.1 Hz, 1H),
7.22 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.20-4.05 (m, 2H), 3.22 (s, 3H), 1.64 (s,
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3H), 1.16 (d, J = 7.2 Hz, 3H). All recorded data were in accordance with those previously
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reported.
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Ethyl 1,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylate (3h). Using
anilide 2h (0.171 g, 0.72 mmol) in THF (20 mL), KHMDS (0.87 mL, 0.87 mmol) and I2
(0.222 g, 0.87 mmol) in THF (5 mL). Purification by flash chromatography using alumina gel
eluting with 1:20->1:4 EtOAc:hexanes afforded the title compound as a colorless oil (0.106
g, 61%). Rf 0.27 (2:3 hexanes/EtOAc); IR (film, νmax/cm-1) 2985, 1722, 1603, 1496, 1340,
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1236, 1218, 1123; H-NMR (400 MHz, CDCl3) δ (ppm) 8.49 (d, J = 5.3 Hz, 1H), 8.35 (s,
1H), 6.82 (d, J = 5.3 Hz, 1H), 4.20-4.05 (m, 2H), 3.23 (s, 3H), 1.68 (s, 3H), 1.15 (t, J = 7.1
13
Hz, 3H); C-NMR (100 MHz, CDCl3) δ (ppm) 174.9, 168.8, 151.0, 150.8, 143.3, 126.1,
104.3, 62.4, 53.7, 26.7, 20.0,14.0; HRMS (ESI+) m/z calcd. for C12H15N2O3 [M+H+]
235.1077, found 235.1067.
Tert-butyl 1-methyl-2,2'-dioxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (3i).11f Using
anilide 2i11d (0.200 g, 0.628 mmol) in THF (20 mL), KHMDS (0.754 mL, 0.754 mmol) and I2
(0.191 g, 0.754 mmol) in THF (3 mL). Purification of the crude material by flash silica gel
chromatography (3:7 EtOAc:hexanes) afforded the title compound as a colorless solid (0.079
g, 40%). Rf 0.34 (1:1 hexanes/EtOAc); 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.33 (t, J = 7.7
Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 4.19
(ddd, J = 10.8, 8.0, 7.0 Hz, 1H), 3.98 (ddd, J = 10.8, 8.4, 4.6 Hz, 1H), 3.22 (s, 3H), 2.63 (ddd,
J = 13.0, 8.0, 4.6 Hz, 1H), 2.37 (ddd, J = 13.0, 8.4, 7.0 Hz, 1H), 1.54 (s, 9H); HRMS (ESI+)
m/z calcd. for C17H20N2NaO4 [M+Na+] 339.1315, found 339.1311. All recorded data were in
accordance with those previously reported.
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1',5'-Dimethyl-4,5-dihydro-2H-spiro[furan-3,3'-indoline]-2,2'-dione (3j). Using anilide 2j
(0.200 g, 0.86 mmol) in THF (25 mL), KHMDS (1.03 mL, 1.03 mmol) and I2 (0.263 g, 1.03
mmol) in THF (5 mL) to afford the title compound as a colorless solid (0.046 g, 23%). Rf
0.49 (9:11 hexanes/EtOAc); M.P. 162−164 °C; IR (film, νmax/cm-1) 2921, 1767, 1702, 1621,
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1603, 1500, 1358, 1161, 1022; H-NMR (400 MHz, CDCl3) δ (ppm) 7.15 (app. d, J = 8.0
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Hz, 1H), 7.04 (app. s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.80 (dt, J = 8.8 Hz, 7.6 Hz, 1H), 4.60
(ddd, J = 8.8 Hz, 8.2 Hz, 5.0 H), 3.21 (s, 3H), 2.92-2.83 (m, 1H), 2.70-2.59 (m, 1H), 2.33 (s,
13
3H); C-NMR (100 MHz, CDCl3) δ (ppm) 173.3, 173.3 142.0, 133.3, 130.0, 127.8, 123.9,
108.8, 66.9, 55.7, 33.6, 26.8, 21.2; HRMS (ESI+) m/z calcd. for C13H13NNaO3 [M+Na+]
254.0788, found 254.0789.
Ethyl 3-((tert-butoxycarbonyl)(methyl)amino)-1-methyl-2-oxoindoline-3-carboxylate (3k).
Using anilide 2k (0.181 g, 0.52 mmol) in THF (20 mL), KHMDS (0.62 mL, 0.62 mmol) and
I2 (0.159 g, 0.62 mmol) in THF (4 mL) to afford the title compound as a yellow oil (0.095 g,
61%). Rf 0.38 (3:7 hexanes/EtOAc); IR (film, νmax/cm-1) 2979, 1747, 1726, 1698, 1608, 1472,
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1365, 1341, 1239, 1151, 1089; H-NMR (400 MHz, CDCl3) δ (ppm) 7.47 (d, J = 7.7 Hz,
1H), 7.34 (td, J = 7.7 Hz, 1.3 Hz, 1H), 7.08 (td, J = 7.7 Hz, 1.0 Hz, 1H), 6.82 (d, J = 7.7 Hz,
1H), 4.23-4.15 (m, 2H), 3.21 (s, 3H), 2.71 (s, 3H), 1.43 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H); 13C-
NMR (100 MHz, CDCl3) δ (ppm) (rotamers) 171.3, 166.7, 156.0, 144.0, 130.4, 130.1 126.8,
125.8, 125.4, 123.2, 108.7, 81.7, 71.5, 62.3, 32.9, 28.2, 26.7, 13.9; HRMS (ESI+) m/z calcd.
for C18H24N2NaO5 [M+Na+] 371.1577, found 371.1579.
Ethyl 1-methyl-2-oxo-3-(pivaloyloxy)indoline-3-carboxylate (3l). Using anilide 2l (0.199 g,
0.62 mmol) in THF (20 mL), KHMDS (0.74 mL, 0.74 mmol) and I2 (0.190 g, 0.74 mmol) in
THF (4 mL) to afford the title compound as a yellow oil (0.095 g, 61%). Rf 0.55 (3:7
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hexanes/EtOAc); IR (film, νmax/cm-1) 2973, 1739, 1611, 1471, 1347, 1236, 1135, 1068; H-
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NMR (400 MHz, CDCl3) δ (ppm) 7.36 (td, J = 7.7 Hz, 1.2 Hz, 1H), 7.31-7.28 (m, 1H), 7.03
(td, J = 7.7 Hz, 1.0 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 4.27-4.10 (m, 2H), 3.26 (s, 3H), 1.23 (s,
9H), 1.17 (t, J = 7.1 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) (rotamers) 176.4, 170.2,
165.1, 164.4, 145.1, 131.0, 129.9, 128.7, 127.6, 124.7, 123.6, 123.2, 108.9, 79.9, 70.0, 62.7,
62.1, 38.9, 38.1, 26.9, 13.9; HRMS (ESI+) m/z calcd. for C17H21NNaO5 [M+Na+] 342.1312,
found 342.1308.
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Ethyl 3-fluoro-1-methyl-2-oxoindoline-3-carboxylate (3n).20 Using anilide 2n (0.221 g, 0.92
mmol) in THF (25 mL), KHMDS (1.11 mL, 1.11 mmol) and I2 (0.236 g, 1.11 mmol) in THF
(5 mL) to afford the title compound as a colourless solid (0.124 g, 57%). Rf 0.26 (1:3
hexanes/EtOAc); M.P. 79−81 °C; IR (film, νmax/cm-1) 2985, 1763, 1729, 1613, 1471, 1494,
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1252, 1226, 1071; H-NMR (400 MHz, CDCl3) δ (ppm) 7.46-7.41 (m, 1H), 7.40-7.36 (m,
1H), 7.13-7.08 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.33-4.18 (m, 2H), 3.23 (s, 3H), 1.21 (t, J =
7.1 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 168.7 (d, JC-F = 21.2 Hz), 165.4 (d, JC-F
=
31.0 Hz), 145.3 (d, JC-F = 5.1 Hz), 132.5 (d, JC-F = 3.1 Hz), 124.8 (d, JC-F = 1.2 Hz), 123.7 (d,
JC-F = 2.7 Hz), 123.1 (d, JC-F = 19.0 Hz), 109.4 (d, JC-F = 1.4 Hz), 90.2 (d, JC-F = 200.5 Hz),
62.9, 26.7, 14.0; HRMS (ESI+) m/z calcd. for C12H12FNNaO3 [M+Na+] 260.0693, found
260.0693.
Ethyl 3-fluoro-5-methoxy-1-methyl-2-oxoindoline-3-carboxylate (3q). Using anilide 2q
(0.340 g, 1.26 mmol) in THF (30 mL), KHMDS (1.52 mL, 1.52 mmol) and I2 (0.388 g, 1.52
mmol) in THF (5 mL) to afford the title compound as a colorless solid (0.178 g, 53%). Rf
0.34 (3:7 hexanes/EtOAc); M.P. 101−103 °C; IR (film, νmax/cm-1) 2941, 1761, 1725, 1605,
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1497, 1471, 1287, 1233, 1070, 1028; H-NMR (400 MHz, CDCl3) δ (ppm) 7.00-6.97 (m,
1H), 6.96-6.92 (m, 1H), 6.79 (dd, J = 8.5 Hz, 1.1 Hz, 1H), 4.33-4.17 (m, 2H), 3.77 (s, 3H),
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3.20 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); C-NMR (100 MHz, CDCl3) δ (ppm) 168.4 (d, J =
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21.3 Hz), 165.4 (d, J = 30.9 Hz), 156.6 (d, J = 2.9 Hz,), 138.4 (d, J = 5.2 Hz), 124.0 (d, J =
18.7 Hz), 117.0 (d, J = 3.0 Hz), 111.6 (d, J = 1.1 Hz), 110.0 (d, J = 1.4 Hz), 90.4 (d, J =
200.9 Hz), 63.0, 56.0, 26.8, 14.0; HRMS (ESI+) m/z calcd. for C13H14FNNaO4 [M+Na+]
290.0799, found 290.0809.
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Ethyl 2-iodo-2-methyl-3-(methyl(phenyl)amino)-3-oxopropanoate (A). Modified from the
general procedure. Using 2a (0.100 g, 0.43 mmol), KHMDS (0.51 mL, 0.51 mmol) and I2
(0.130 g, 0.51 mmol). After formation of the iodide (by TLC), aq. NH4Cl was added (20 mL)
and extracted with EtOAc (2 x 20 mL), dried with MgSO4 and the solvent removed in vacuo.
The crude material was then subjected to flash chromatography (1:9 EtOAc:hexanes) and
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quickly transferred for H-NMR and HRMS analysis. H-NMR (400 MHz, CDCl3) δ (ppm)
7.52-7.14 (m, 5H), 4.25-3.67 (m, 2H), 3.27 (s, 3H), 2.30 (s, 3H), 1.28-1.16 (m, 3H); HRMS
(ESI+) m/z calcd. for C13H16INNaO3 [M+Na+] 384.0067, found 384.0067.
Ethyl 2-hydroxy-2-methyl-3-(methyl(phenyl)amino)-3-oxopropanoate (5). Modified from
the general procedure. Using 2a (0.127 g, 0.54 mmol), KHMDS (0.65 mL, 0.65 mmol) and I2
(0.166 g, 0.65 mmol). After formation of the iodide (by TLC), the reaction flask was opened
to the air and stirred at rt for 18 hr. The reaction was worked–up as per the general procedure
to afford 6 as a colorless oil (0.107 g, 79%). IR (film, νmax/cm-1) 3386, 2986, 2939, 1732,
1643, 1595, 1247, 1104; 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.41-7.33 (m, 3H), 7.21-7.14
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(m, 2H), 4.31-3.88 (m, 3H), 3.29 (s, 3H), 1.39 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H); C-NMR
(100 MHz, CDCl3) δ (ppm) 171.9, 170.1, 141.8, 138.6, 129.5, 128.9, 76.0, 62.2, 40.3, 24.1,
13.9; HRMS (ESI+) m/z calcd. for C13H18NO4 [M+H+] 252.1230, found 252.1239.
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Supporting Information
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The supporting information is available free of charge on the ACS publication website at
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DOI:.
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NMR spectra of products and new anilides (PDF).
Author Information
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*E-mail: wade.petersen@york.ac.uk
*E-mail: richard.taylor@york.ac.uk
ORCID
Wade F. Petersen: 0000-0003-3215-5560
James R. Donald: 0000-0002-2176-4902
Notes
The authors declare no competing financial interests.
Acknowledgements
We would like to thank Elsevier (J.R.D) and the South African National Research Foundation
(NRF/95404, W.F.P) for their financial support.
References
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