Expedited microwave-assisted N-alkylation of isatins utilizing DBU

Article abstract of DOI:10.3998/ark.5550190.p008.205

The N-alkylation of a variety of isatins with alkyl or benzylic halides can be effected under microwave irradiation in ethanol using 1,8-diazabicyclo[5.4. 0]undec-7-ene (DBU) as a base. The conditions employed allow for the expedited synthesis of such substrates wherein the products precipitate from the reaction mixture in high yields and high purity after simple filtration. As will be described, microwave irradiation provides a relatively rapid means of effecting N-alkylations of isatin with a variety of benzylic halides, propargyl bromide and ethyl bromoacetate in times ranging from 10-25 min at 140 oC in closed vials. This report involves the first reported use of DBU for this purpose, and in contrast to other methods, allows for the facilitated isolation of pure products while avoiding extractive or chromatographic purification steps. ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.p008.205

General Papers
ARKIVOC 2014 (iv) 183-192
Expedited microwave-assisted N-alkylation of isatins utilizing DBU
Carly A. Jordan, Krystyna B.Wieczerzak, Kyle J. Knisley, and Daniel M. Ketcha*
Department of Chemistry, Wright State University, 3640 Colonel Glenn Hwy,
Dayton, OH 45435, USA
E-mail: daniel.ketcha@wright.edu
DOI: http://dx.doi.org/10.3998/ark.5550190.p008.205
Abstract
The N-alkylation of a variety of isatins with alkyl or benzylic halides can be effected under
microwave irradiation in ethanol using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base. The
conditions employed allow for the expedited synthesis of such substrates wherein the products
precipitate from the reaction mixture in high yields and high purity after simple filtration. As will
be described, microwave irradiation provides a relatively rapid means of effecting N-alkylations
of isatin with a variety of benzylic halides, propargyl bromide and ethyl bromoacetate in times
o
ranging from 10-25 min at 140 C in closed vials. This report involves the first reported use of
DBU for this purpose, and in contrast to other methods, allows for the facilitated isolation of
pure products while avoiding extractive or chromatographic purification steps.
Keywords: Isatin, N-alkylation, microwave, DBU, expedited synthesis
Introduction
Increased attention is being devoted to exploiting the chemistry1,2 and bioactivity3 of the highly
diversifiable isatin nucleus.4,5 The “privileged”6 nature of this scaffold and its central role as
progenitor to other classes of biologically active heterocycles,7,8 provides incentive for the
development of expedient protocols for the embellishment of this core structure, especially in
terms of N-alkylation.9 To that end, several groups have devised parallel methods for such an
operation, minimizing purification and amenable to automation under thermal or microwave
conditions. Noteworthy examples include a parallel microwave procedure employing K2CO3/KI
in acetonitrile (160 oC, 10 min)10 and an analogous process in DMF (150 oC, 5-15 min).11
Alternatively, with regard to devising highly efficient and rapid solution phase
methodologies for the parallel synthesis of diverse isatins, Shuttleworth utilized polymer-
supported
2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine
(BEMP) on polystyrene for the preparation of a library of serine protease inhibitors,12 while
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Chibale et al. employed the less expensive solid-supported base potassium fluoride on alumina
(KF/Al2O3).13 More recently, we reported the use of KF/Al2O3 in acetonitrile (ACN) for the N-
o
alkylation of isatins under thermal conditions or microwave-irradiation (180 C).14 Whereas all
three of the above methods allow for facilitated purification by filtration from the solid bases
employed, they also necessitated standard means of workup or purification after that point. It was
therefore envisaged that if a soluble organic base were employed in a solvent from which the
product might spontaneously crystallize, a substantial saving in time-consuming steps would be
realized.
Results and Discussion
In devising highly efficient and rapid solution phase methodologies for the parallel preparation
of diverse isatins, it was envisaged that the use of a soluble base under microwave conditions
might constitute a useful expedient. Since it appeared that the N-alkylation of isatin had yet to be
conducted under microwave irradiation using DBU, it was decided to examine the use of this
basic catalyst in ethanol (EtOH) under microwave irradiation in a CEM Discover microwave
(300 watts). The initial parameters involved using DBU (1.1 equiv) for the model reaction of
isatin (0.3 g, 2.00 mmol) and benzyl chloride (1.5 equiv) to yield 1-benzylindoline-2,3-dione in
EtOH (3 mL) in a microwave vial (10 mL). Reactions were conducted at temperatures from
120°C to 140°C in 10 degree increments and at time intervals of 10 and 25 min after which
reactions were monitored by GC/MS to ascertain completeness. For the prototype reaction
above, it was found that complete conversion was effected at 140°C for 10 min. Using these
optimal parameters for temperature and time, it was found that increasing the amount of DBU to
1.5 equiv did not result in substantially enhanced conversion. Therefore, these conditions were
employed to conduct other N-alkylation reactions using isatin and DBU to produce the desired
N-alkylated isatins (Scheme 1).
Table 1 displays a summary of the microwave irradiation process providing a rapid means of
effecting N-alkylations of isatins with a variety of benzylic halides, propargyl bromide, and ethyl
bromoacetate. The yields listed are a summation of the pure solid obtained upon the first
crystallization and that obtained by chromatographic purification of the filtrate. In all instances,
the material obtained by crystallization from the reaction medium was pure, as determined by
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GC/MS and in most cases provided sufficient amounts of material to be carried on in subsequent
steps if desired.
In general, alkylation of isatins bearing electron-withdrawing substituents at the C-5 position
could be effected at lower temperatures albeit with longer reaction times. Additionally, electron
withdrawing groups on the benzylic halides also served to enhance observed reactivity in
comparison to those rings not similarly substituted or the propargyl halide. In the case of the N-
propargylation of isatin itself (entry 2), it was determined that the use of a ramp technique in the
microwave allowed for a higher yield but such a protocol was unnecessary in other reactions. It
is also noteworthy that ethyl 2-(5-chloro-2,3-dioxoindolin-1-yl)acetate (6) formed rapidly at
room temperature upon mixing of the reactants.
Scheme 1
Table 1. Optimization of reaction conditions
Substituents in
Time Temp.
Scheme 1
Entry
MP (°C)
Yield
Lit. MP (°C)
(min)
(°C)
R1
H
R
CO2Et
124-12914
157-15815
128-13314
175-18014
154-15614
1
2
10
10
10
10
10
20
20
20
20
20
25
25
140
140
140
140
140
120
120
120
120
120
120
120
105-110
147-149
129-134
181-186
155-158
126-128
157-159
130-133
232-235
171-174
128-131
132-134
47%
81%
61%
93%
84%
68%
64%
71%
84%
72%
88%
82%
H
C≡CH
3
H
Ph
4
H
2,6-Cl2C6H3
2,6-F2C6H3
CO2Et
5
H
130-13514
6
Cl
Cl
Cl
Cl
Cl
F
Ref. 16
7
C≡CH
13414
233-23514
172-17714
8
Ph
9
2,6-Cl2C6H3
2,6-F2C6H3
Ph
10
11
12
130-13317
Ref. 10
F
2,6-F2C6H3
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Thus, the use of the soluble base DBU in conjunction with a suitable crystallizing solvent
under microwave conditions allows for the expedited construction of a small library of N-
alkylated isatins which could be isolated in a pure state and in synthetically useful yields by
simple filtration.
Conclusions
The development of a convenient synthesis of N-alkylated isatins with various alkyl halides
under microwave irridiation was examined using the soluble liquid base DBU. With the use of
this soluble base, an expedited synthetic protocol was devised wherein product isolation could be
effected by simple filtration of the reaction mixture.
Experimental Section
General. Melting points were determined via the use of open capillaries with an Electrothermal
melting point apparatus. The 1H and 13C NMR data were obtained on a Bruker Avance 300 MHz
NMR in DMSO-d6 solution. Chemical shifts for proton NMR are reported in δ (ppm) downfield
from tetramethylsilane as an internal standard and 13C NMR shifts are calibrated on the DMSO-
d6 resonance at 39.50 ppm. Coupling constants (J) are in Hz. The following abbreviations are
used to describe peak patterns where appropriate: s, singlet; d, doublet; dd, double doublet; t,
triplet; q, quartet; dt, double triplet; m, multiplet. GC/MS measurements were performed using
Hewlett-Packard 6890 Series GC with auto injection and mass fragments are reported as mass
per charge, m/z. The GC was coupled with a mass spectrometer with Hewlett-Packard 5973 mass
selective detector/quadrupole system. Flash column (Silica Gel, Premium Rf, 200-400 mesh,
Sorbent Technologies) and thin layer chromatography reactions were performed on silica gel
with indicated solvent systems. Microwave reactions were performed in a monomode MARS
Glasschem 300 Watt system by CEM with sample absorption set to “normal”.
Note: Identities of compounds previously prepared in this laboratory14 were confirmed by
GC/MS as well as 1H and 13C NMR comparisons.
Ethyl 2-(2,3-dioxoindolin-1-yl)acetate (1). To a 10 mL microwave vial charged with ethanol (3
mL) and a magnetic stir bar was added isatin (0.3111 g, 2.11 mmol), DBU (325 μL, 1.1 eq) and
ethyl bromoacetate (257 μL, 1.1 eq). The reaction vessel was sealed and heated under
microwave irradiation in standard mode for 10 min at 140 oC with a pre-stirring 30 sec. After
cooling to rt, the reaction vessel was allowed to stand overnight in a freezer and then vacuum
filtered to afford the pure (TLC, GC/MS) product as a light orange solid (0.1049 g, 21%): mp
o
105-110 ºC (lit.14mp 124-129 C); Rf = 0.21 (hexanes/EtOAc, 1:1). The filtrate was then
evaporated under reduced pressure to afford an oil which was purified by silica gel
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chromatography (hexanes/EtOAc, 70:30) to provide additional product (0.1130 g) for a
combined overall yield of 47%; 1H NMR (300 MHz DMSO-d6) δ 7.62 (td, J = 7.83 Hz, 1.35 Hz,
1H), 7.55 ppm (dd, J = 7.6 Hz, 0.8 Hz, 1H), 7.20 (td, J = 7.5 Hz, 0.7 Hz, 1H), 6.88 (d, J = 7.9
13
Hz, 1H), 4.54 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H); C NMR (75 MHz
DMSO-d6) δ 182.3, 167.1, 158.2, 150.1, 138.5, 124.5, 123.7, 117.3, 111.3, 61.3, 41.1, 14.0 ppm;
MS (m/z) 233 (M+), 132 (100%).
1-(Prop-2-yn-1-yl)indoline-2,3-dione (2). To a 10 mL microwave vial charged with ethanol (3
mL) and a magnetic stir bar was added isatin (0.3064 g, 2.08 mmol), DBU (342 μL, 1.1 eq) and
propargyl bromide (210 μL, 1.1 eq). The reaction vessel was sealed and heated under microwave
irradiation in dynamic mode where the mixture was heated in 5 stages with pressure and high
power being held constant throughout the run time at 130 psi and 200 watts, respectively. The
o
o
first stage of heating was set at 110 C for 3 min, the second stage of heating was set at 120 C
for 2 min, the third stage of heating was set at 100 oC for 1 min, the fourth stage of heating was
set at 120 oC for 2 min, and the final stage of heating was set at 95 oC for 6 min. The first stage
had high stirring while the final 4 stages had a low stir setting. The pre-stirring for this setup was
high for 1 min. After cooling to rt, the reaction vessel was placed in the freezer overnight and
vacuum-filtered to afford the pure product (GCMS/TLC) as an orange solid (0.1277 g, 33.1%):
o
o
mp 147–149 C (lit.15mp 157-158 C); Rf = 0.46 (hexanes/EtOAc, 1:1). The filtrate was then
evaporated under reduced pressure and purified by silica gel chromatography (hexanes/EtOAc,
70:30) to give additional product (0.1844 g) for a combined overall yield of 81%; 1H NMR (300
MHz DMSO-d6) δ 7.75 (td, J = 1.3 Hz, J = 7.8 Hz, 1H), 7.61 (dd, J = 0.5 Hz, J = 1.2 Hz, 1H),
7.58 (dd, J = 0.5 Hz, J = 1.2 Hz, 1H ), 7.24 (d, J =7.9 Hz, 1H), 7.21 (dd, J = 0.8 Hz, J = 15.0 Hz,
13
1H), 7.19 (d, J = 0.7 Hz, 1H), 4.55 (d, J = 2.5 Hz, 2H); C NMR (75 MHz DMSO-d6) δ 182.5,
157.3, 149.4, 138.1, 124.5, 123.6, 117.6, 111.1, 77.2, 74.8, 28.9; MS: m/z 185 (M+), 129 (100%).
1-Benzylindoline-2,3-dione (3). To a 10 mL microwave vial charged with ethanol (3 mL) and a
magnetic stir bar was added isatin (0.2943 g, 2.00 mmol), DBU (329 μL, 1.1 eq) and benzyl
chloride (257μL, 1.1 eq). The reaction vessel was sealed and heated under microwave irradiation
in standard mode for 10 min at 140 oC with a pre-stirring 30 sec. After cooling to rt, the reaction
vessel was allowed to stand overnight in a freezer and then vacuum filtered to afford the pure
o
(TLC, GC/MS) product as a light orange solid (0.0536 g, 11%): mp 129-134 C (lit.14mp 128-
o
133 C); Rf = 0.41 (hexanes/EtOAc, 1:1). The filtrate was then evaporated under reduced
pressure to afford an oil which was purified by silica gel chromatography (hexanes/EtOAc,
70:30) to provide additional product (0. 2895 g) for a combined overall yield of 61%; 1H NMR
(300 MHz DMSO-d6) δ 7.60 (td, J = 7.8 Hz, 1.3 Hz, 1H), 7.44 (dd, J = 7.2 Hz, 0.8 Hz, 1H),
7.37-7.28 (m, 5-H), 7.14 (td, J = 7.5 Hz, 0.8 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 4.91 (s, 1H); 13C
NMR (75 MHz DMSO-d6) δ 183.1, 158.3, 150.3, 137.9, 135.5, 128.6, 127.5, 127.3, 124.4,
123.3, 117.7, 111.0, 42.9; MS (m/z) 237 (M+), 146 (100%).
1-(2,6-Dichlorobenzyl)indoline-2,3-dione (4). To a 10 mL microwave vial charged with ethanol
(3 mL) and a magnetic stir bar was added isatin (0.3062 g, 2.08 mmol), DBU (342 μL, 1.1 eq)
and 2,6-dichlorobenzyl bromide (0.5711 g, 1.1 eq). The reaction vessel was sealed and heated
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under microwave irradiation in standard mode for 10 min at 140 oC with a pre-stirring 30 sec.
After cooling to rt, the reaction vessel was allowed to stand overnight in a freezer and then
vacuum filtered to afford the pure (TLC, GC/MS) product as an orange solid (0.4151 g, 65%):
o
mp 181-186 ºC (lit.14mp 175-180 C); Rf = 0.57 (hexanes/EtOAc, 1:1). The filtrate was then
evaporated under reduced pressure and purified by silica gel chromatography (hexanes/EtOAc,
1
70:30) to provide additional product (0.1787 g) for a combined overall yield of 93%; H NMR
(300 MHz, DMSO-d6) δ 7.65 (td, J = 7.8 Hz, 1.4 Hz, 1H), 7.58 ppm (dd, J = 7.5 Hz, 0.8 Hz,
1H), 7.44 (d, J = 8.31Hz, 1H), 7.15 (d, J = 7.23Hz, 1H), 7.13 (t, J = 6.51Hz, 1H), 7.08 (t, J =
13
7.56Hz, 1H), 6.93 (d, J = 7.89Hz, 1H), 5.26 (s, 2H); C NMR (75 MHz DMSO-d6) δ 182.7,
157.7, 150.6, 138.4, 135.4, 130.8, 129.7, 129.1, 124.7, 123.4, 117.9, 110.8, 40.4; MS (m/z) 305
(M+), 270 (100%).
1-(2,6-Difluorobenzyl)indoline-2,3-dione (5). To a 10 mL microwave vial charged with ethanol
(3 mL) and a magnetic stir bar was added isatin (0.2962 g, 2.01 mmol), DBU (329 μL, 1.1 eq)
and 2,6-difluorobenzyl bromide (0.5278 g, 1.1 eq). The reaction vessel was sealed and heated
under microwave irradiation in standard mode for 10 min at 140 oC with a pre-stirring 30 sec.
After cooling to rt, the reaction vessel was allowed to stand overnight in a freezer and then
vacuum filtered to afford the pure (TLC, GC/MS) product as yellow-orange solid (0.2469 g,
o
45%): mp 155-158 ºC (lit.14mp 154-156 C); Rf = 0.32 (hexanes/EtOAc, 1:1). The filtrate was
then evaporated under reduced pressure to afford an oil which was purified by silica gel
chromatography (hexanes/EtOAc, 70:30) to provide additional product (0.2100 g) for a
1
combined overall yield of 84%; H NMR (300 MHz DMSO-d6) δ 7.70 (t, J = 7.8 Hz, 1H),7.57
ppm (dd, J = 7.5 Hz, 0.8 Hz, 1H), 7.49 (m, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 8.2 Hz, 1H),
4.96 (s, 1H); 13C NMR (75 MHz DMSO-d6) δ: 182.8, 162.7-159.3 (dd, J = 7.8 Hz), 157.6, 150.3,
138.3, 130.8-130.6 (t, J = 10.4 Hz), 124.6, 123.4, 117.6, 111.9-111.65 (d, J = 7.4 Hz), 110.8,
110.40-110.36 (t, J = 7.8 Hz), 32.1; MS (m/z): 273 (M+), 146 (100%).
Ethyl 2-(5-chloro-2,3-dioxoindolin-1-yl)acetate (6). To a 10 mL microwave vial charged with
ethanol (3 mL) and a magnetic stir bar was added 5-chloroisatin (0.3689 g, 2.00 mmol), DBU
(329 μL, 1.1 eq) and ethyl bromoacetate (243 μL, 1.1 eq). The reaction vessel was sealed and
heated under microwave irradiation in standard mode for 20 min at 120 oC with a pre-stirring 30
sec. After cooling to rt, the reaction vessel was allowed to stand overnight in a freezer and then
vacuum filtered to afford the pure (TLC, GC/MS) product as a light orange solid (0.1662 g,
o
31%): mp 126-128 ºC (lit.14mp 130-135 C); Rf = 0.63 (hexanes/EtOAc, 1:1). The filtrate was
then evaporated under reduced pressure to afford an oil which was purified by silica gel
chromatography (hexanes/EtOAc, 70:30) to provide additional product (0.1965 g) for a
combined overall yield of 68%; 1H NMR (300 MHz DMSO-d6) δ 7.77 ppm (dd, J = 8.6 Hz, 2.2
Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 4.62 (s, 2H), 4.20 (q, 7.1 Hz, 2H),
13
1.23 (t, J = 7.1 Hz, 3H); C NMR (75 MHz DMSO-d6) δ 181.5, 167.3, 157.8, 148.9, 137.3,
127.9, 124.1, 118.6, 112.9, 61.4, 41.3, 13.9; MS (m/z) 267 (M+), 28 (100%).
5-Chloro-1-(prop-2-yn-1-yl)indoline-2,3-dione16 (7). To a 10 mL microwave vial charged with
ethanol (3mL) and a magnetic stir bar was added isatin (0.3632 g, 2.00 mmol), DBU (329 μL,
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1.1 eq) and propargyl bromide (201 μL, 1.1 eq). The reaction vessel was sealed and heated under
o
microwave irradiation in standard mode for 20 min at 110 C with pre-stirring 30 sec. After
cooling to rt, the reaction vessel was placed in the freezer overnight and then vacuum filtered to
afford a pure (GCMS/TLC) orange solid (0.0521 g, 12%): mp 157-159 ºC; Rf =
0.51(hexanes/EtOAc, 1:1). The filtrate was then evaporated under reduced pressure to afford an
orange oil which was purified by silica gel chromatography (hexanes/EtOAc, 70:30) to give
additional product (0.3145 g) for a combined overall yield of 64%: 1H NMR (300 MHz DMSO-
d6) δ 7.79 (dd, J = 2.2 Hz, J = 8.4 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H),
13
4.56 (d, J = 2.5 Hz, 2H), 4.35 (t, J = 5.0, 1H); C NMR (75 MHz DMSO-d6) δ 181.4, 157.1,
147.9, 136.9, 127.8, 124.0, 119.1, 112.8, 77.0, 75.1, 29.1; MS (m/z) 219 (M+), 28 (100 %). Anal.
Calcd for C11H6ClNO2: C, 60.16; H, 2.75; N, 6.38; Found: C, 59.98; H, 2.73; N, 6.33.
1-Benzyl-5-chloroindoline-2,3-dione (8). To a 10 mL microwave vial charged with ethanol (3
mL) and a magnetic stir bar was added 5-chloroisatin (0.3785 g, 2.08 mmol), DBU (329 μL, 1.1
eq) and benzyl chloride (257 μL, 1.1 eq). The reaction vessel was sealed and heated under
microwave irradiation in standard mode for 20 min at 140 oC with a pre-stirring 30 sec. After
cooling to rt, the reaction vessel was placed in the freezer overnight but did not afford a solid.
The resulting orange-red liquid was then evaporated under reduced pressure to afford an orange
oil which was purified by silica gel chromatography (hexanes/EtOAc, 70:30) to afford a pure
o
(GC-MS/TLC) orange red solid (0.3875 g, 71%): mp 130-133 ºC (lit.14mp 134 C); Rf = 0.65
1
(hexanes:EtOAc,1:1). H NMR (300 MHz DMSO-d6) δ 7.63 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 7.44
ppm (d, J = 2.2 Hz, 1H), 7.37-7.28 (m, 5-H), 6.98 (d, J = 8.3 Hz, 1H), 4.91 (s, 2H); 13C NMR (75
MHz DMSO-d6) δ 181.9, 158.1, 148.8, 136.7, 135.1, 129.7, 128.6, 127.5, 127.2, 123.9, 119.1,
112.6, 42.9; MS (m/z) 271 (M+), 180 (100%).
1-(2,6-Dichlorobenzyl)-5-chloroindoline-2,3-dione (9). To a 10 mL microwave vial charged
with ethanol (3 mL) a magnetic stir bar was added 5-chloroisatin (0.3658 g, 2.01 mmol), DBU
(329 μL, 1.1 eq) and 2,6-dichlorobenzyl bromide (0.5310 g, 1.1 eq). The reaction vessel was
sealed and heated under microwave irradiation in standard mode for 20 min at 120 oC with a pre-
stirring 30 sec. After cooling to rt, the reaction vessel was placed in the freezer for 2 h and then
vacuum filtered to afford the pure (TLC, GC/MS) product as an orange-red solid (0.5772 g,
o
1
84%): mp 232-235 ºC (lit.14mp 233-235 C); Rf = 0.60 (hexanes/EtOAc, 1:1). H NMR (300
MHz DMSO-d6) δ 7.73 ppm (dd, J = 8.5 Hz, 2.3 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.55 (d, J =
8.0 Hz, 1H), 7.44 (t, 7.9 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.12 (s, 2H); 13C NMR (75 MHz
DMSO-d6) δ 181.6, 157.5, 149.2, 137.3, 135.4, 130.8, 129.5, 129.1, 127.6, 124.2, 118.9, 112.6,
40.4; MS (m/z) 339 (M+), 180 (100%).
1-(2,6-Difluorobenzyl)-5-chloroindoline-2,3-dione (10). To a 10 mL microwave vial charged
with ethanol (3 mL) and a magnetic stir bar was added 5-chloroisatin (0.3650 g, 2.00 mmol),
DBU (329 μL, 1.1 eq) and 2,6-difluorobenzyl bromide (0.4554 g, 1.1 eq). The reaction vessel
was sealed and heated under microwave irradiation in standard mode for 20 min at 120 oC with a
pre-stirring 30 sec. After cooling to rt, the reaction vessel was placed in the freezer overnight and
then vacuum filtered to afford the pure (TLC, GC/MS) product as a red solid (0.4091 g, 66%):
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o
mp 171-174 ºC (lit.14mp 172-177 C); Rf = 0.56 (hexanes:EtOAc, 1:1). A second crop afforded
additional product (0.0339 g) for a combined overall yield of 72%. 1H NMR (300 MHz DMSO-
d6) δ 7.76 ppm (dd, J = 2.2 Hz, J = 8.5 Hz, 1H), 7.63 (d, 2.2 Hz, 1H), 7.49-7.39 (m, 1H), 7.15 (t,
J = 8.2 Hz, 1H), 7.10 (d, 8.6 Hz, 1H), 4.94 (s, 2H) 13C NMR (75 MHz DMSO-d6) δ 181.7, 162.7-
159.4 (dd, J = 8.2 Hz), 157.5, 148.8, 137.1, 130.9-130.6 (t, J = 10.5 Hz), 127.6, 124.0, 119.0,
112.2-112.1 (t, J = 2.6 Hz), 111.9-111.6 (d, J = 17.8 Hz), 110.6, 32.2; MS (m/z) 307 (M+), 127
(100%).
1-Benzyl-5-fluoroindoline-2,3-dione (11). To a 10 mL microwave vial charged with ethanol (3
mL) and a magnetic stir bar was added 5-fluoroisatin (0.3310 g, 2.00 mmol), DBU (330 μL, 1.1
eq) and benzyl chloride (254 μL, 1.1 eq). The reaction vessel was sealed and heated under
microwave irradiation in standard mode for 25 min at 120 oC with a pre-stirring of 30 sec. After
cooling to room temperature, the reaction vessel was placed in the freezer overnight and then
vacuum filtered to afford a pure (GCMS/TLC) dark red solid (0.1408 g, 28%): mp 128-131 ºC
o
(lit.17mp 130-133 C); Rf = 0.64 (hexanes:EtOAc, 1:1). The filtrate was then evaporated under
reduced pressure to afford a red oil which was purified by silica gel chromatography
(hexanes/EtOAc, 70:30) to give a dark red solid (0.3073 g) for a combined overall yield of 88%:
1H NMR (300 MHz DMSO-d6)  7.57 ppm (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.2 Hz, 2.2 Hz,
1H), 7.39-7.28 (m, 1H), 6.96 (t, J = 8.1 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 4.94 (s, 2H); 13C NMR
(75 MHz DMSO-d6) δ 182.4, 160.09-156.86 (d, J = 241 Hz), 158.35-158.33 (d, J = 1.4 Hz),
146.5-146.4 (d, J = 1.6 Hz), 135.3, 128.6, 127.5, 127.3, 123.9-123.6 (d, J = 24.0 Hz), 118.7-
118.6 (d, J = 7.2 Hz), 112.4-112.3 (d, J = 7.4 Hz), 111.6-111.3 (d, J = 24.3 Hz), 42.9; MS (m/z)
255 (M+), 164 (100%).
1-(2,6-Difluorobenzyl)-5-fluoroindoline-2,3-dione10 (12). To a 10 mL microwave vial charged
with ethanol (3mL) and a magnetic stir bar was added 5-fluoroisatin (0.3294 g, 1.99 mmol),
DBU (329 μL, 1.1 eq) and 2,6-difluorobenzyl bromide (0.4594 g, 1.1 eq). The reaction vessel
was sealed and heated under microwave irradiation in standard mode for 25 min at 120 oC with a
pre-stirring of 30 sec. After cooling to rt, the reaction vessel was placed in the freezer overnight
and then vacuum filtered to afford a dark red solid (0.2133 g, 37%): mp 132-134 oC. The filtrate
was then evaporated under reduced pressure to afford a red oil which was purified by silica gel
chromatography (hexanes/EtOAc,70:30) to give additional product (0.2612 g) for a combined
1
overall yield of 82%; H NMR (300 MHz, DMSO): δ .7.60 (ddd, J = 2.8 Hz, J = 8.7 Hz, 1H ),
7.49 (dd, J = 2.7 Hz, J = 7.0 Hz, 1H), 7.44 (dd, J = 1.7 Hz, J = 6.8 Hz, 1H) 7.15 (t, 3H), 7.25 (dd,
J = 2.7 Hz, J = 8.6 Hz, 1H), 6.98 (t, J = 8.1 Hz, 1H), 6.91 (dd, J = 3.5 Hz, J = 8.6 Hz, 1H), 4.96
(s, 2H); 13C NMR (75 MHz DMSO-d6) δ 182.19-182.16 (d, J = 2.1 Hz), 167.7, 162.6-159.2 (dd,
J = 7.7 Hz), 160.0-156.8 (d, J = 241 Hz), 157.73-157.71 (d, J = 1.7 Hz), 146.56-146.54 (d, J =
1.6 Hz), 130.9-130.6 (t, J = 10.5 Hz), 124.41-124.0 (d, J = 24.1 Hz), 118.5-118.4 (d, J = 7.1 Hz),
111.9-111.7 (d, J = 7.3 Hz), 111.6-111.4 (d, J = 17.7 Hz), 110.9-110.4 (t, J = 18.7 Hz), 32.2 (t, J
= 3.9 Hz); MS (m/z) 291 (M+), 164 (100%).
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ARKIVOC 2014 (iv) 183-192
Acknowledgements
CAJ gratefully acknowledges receipt of a WSU 2012 Undergraduate Research and Independent
Project Support Grant. The authors wish to thank Professor Eric Fossum for helpful discussions
regarding NMR and Jenin Jaber for review of this manuscript.
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