A way to avoid using precious metals: The application of high-surface activated carbon for the synthesis of isoindoles via the diels-alder reaction of 2 H -pyran-2-ones

Article abstract of DOI:10.1021/jo3000783

The application of activated carbon (Darco KB) for the acceleration and direction of the transformation of various 2H-pyran-2-ones with N-substituted maleimides toward isoindole derivatives through the reaction sequence cycloaddition/elimination/dehydroge

Full text of DOI:10.1021/jo3000783

Article
pubs.acs.org/joc
A Way to Avoid Using Precious Metals: The Application of High-
Surface Activated Carbon for the Synthesis of Isoindoles via the
Diels−Alder Reaction of 2H-Pyran-2-ones
Marko Krivec, Martin Gazvoda, Kristof Kranjc, Slovenko Polanc, and Marijan Kocevar*
̌
̌
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ask
̌
erce
̌
va 5, SI-1000 Ljubljana, Slovenia
S
* Supporting Information
ABSTRACT: The application of activated carbon (Darco
KB) for the acceleration and direction of the transformation of
various 2H-pyran-2-ones with N-substituted maleimides
toward isoindole derivatives through the reaction sequence
cycloaddition/elimination/dehydrogenation is described. In
this reaction, the catalyst mainly influences the dehydrogen-
ation step, which is essential to avoid the formation of
bicyclo[2.2.2]octenes as the other possible products. We found
that the combination of Darco KB, as the metal-free catalyst,
and decalin, as the solvent in a closed vessel, represents the
most successful conditions. A comparison of the effect of various dehydrogenation catalysts and reaction conditions is also
presented. In addition, we have proven that the aromatization occurs via a hydrogen transfer from the cyclohexadiene
intermediate to the maleimide derivative (therefore producing succinimides). This transfer is facilitated by the active surface of
the heterogeneous carbon-based catalyst.
Scheme 1. Reaction Pathway Leading to the
Benz[e]isoindoles 4
INTRODUCTION
■
Isoindoles and their fused derivatives represent a very
important class of compounds with a wide scope of applications
and biological activity, ranging from effects on the cardiovas-
cular and cerebral systems to dopamine agonist, anticancer,
antibiotic, anticonvulsive, and anti-inflammatory effects.1 One
of the most notorious examples of such a biologically important
isoindole compound is thalidomide,2 which was licensed in the
1950s as a sedative drug, typically used to cure morning
sickness, but withdrawn in 1961 because of its teratogenicity.
Because of the importance of isoindoles, various synthetic
approaches1a,2e,3 were developed, further stimulating our
interest in the Diels−Alder reactions of 2H-pyran-2-ones and
their fused analogues, as they could represent attractive
precursors for the synthesis of isoindole derivatives. Previously,
we conducted a preliminary investigation of such a pathway,
starting from the 5,6,7,8-tetrahydro-2H-1-benzopyran-2-ones 1
and various maleimides 2 leading to the formation of the fused
isoindoles (i.e., benz[e]isoindoles) 4 or the bridged double
cycloadducts (fused bicyclo[2.2.2]octene derivatives) 5
(Scheme 1).4 It is worth mentioning that in a special case,
where X = CO, the first efficient, substituent-driven
aromatization of an intermediary-formed cycloadduct was
observed, resulting in the substituted benz[e]isoindoles 4.
The same type of aromatization could also be achieved in an
unprecedented catalysis with rhodium on activated carbon
(Rh/C).
substituted maleimides 2 in order to obtain the isoindoles 9
as single or predominant products (Scheme 2). In a close
analogy with our previous results, the reaction sequence leading
to the isoindoles 9 should include a primary cycloaddition step
of an appropriate dienophile 2 (N-substituted maleimides) with
the substituted 2H-pyran-2-ones 6 as the diene to give a CO2-
bridge-containing intermediate 7. In the second step, a retro-
Diels−Alder reaction (the elimination of CO2) should give the
next intermediate 8, which could be either aromatized
(dehydrogenated) to give the isoindole derivative 9 or a new
cycloaddition takes place, yielding the bicyclic adduct 10. The
As a continuation of the above investigation, we planned to
use the appropriately substituted 2H-pyran-2-ones 6 as dienes
and react them in a Diels−Alder reaction with the N-
Received: January 11, 2012
Published: February 21, 2012
© 2012 American Chemical Society
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bicyclo[2.2.2]octenes 10. To prevent this second cycloaddition
step, it is necessary to use a sink for the hydrogen and an
appropriate catalyst that facilitates the formal transfer of a
molecule of hydrogen from the cyclohexadiene intermediate,
thus yielding the final aromatized isoindole product 9.4 To
enable this transfer, we surmised that it should be necessary to
have a catalyst with an active surface that is as large as possible.
With this in mind and in accordance with some previous
literature reports,6,7 we were not completely convinced that a
precious metal was indispensable. As a result, a plethora of
relatively cheap carbon-based materials would suddenly seem to
be an attractive choice for the dehydrogenation catalysis. In
addition, it is important to note that in the case of fused pyran-
2-ones, the second cycloaddition step is, in contrast to the
aromatization (elimination of hydrogen), a reversible trans-
formation.4,8
Scheme 2. Reaction Pathway Leading to the Isoindoles 9a−s
RESULTS AND DISCUSSION
last reaction step toward 9 is the most crucial one, as it does not
take place easily on its own but needs an appropriate catalyst.
As already mentioned, we found that Rh/C is a successful
heterogeneous dehydrogenation catalyst;4 however, it has some
major drawbacks, its high price being one of the most
important ones. Therefore, the quest for more appropriate
heterogeneous dehydrogenation catalysts continued.
■
The transformation most probably starts with the cycloaddition
between the appropriately substituted 2H-pyran-2-one 6 and
the N-substituted maleimide 2, yielding the primary CO2-
bridged 2-oxabicyclo[2.2.2]oct-5-ene derivative 7 (Scheme 2).
With the thermally induced, spontaneous, retro-Diels−Alder
elimination of the CO2 from 7, the cyclohexadiene intermediate
8 is obtained, which is further aromatized into the final
isoindole product 9. Alternatively, the intermediate 8 can act as
a new diene system, and therefore, a new molecule of
dienophile 2 can cycloadd to yield the undesired bicyclo[2.2.2]-
octene 10, representing the double cycloadduct. According to
ref 4, both cycloaddition steps (6 ⇆ 7 and 8 ⇆ 10) should be
reversible, but the irreversible elimination of CO2 from 7 shifts
On the basis of our experiences with such transformations,4,5
we anticipated that the thermal reaction conditions necessary
for the cycloaddition would also suffice for the second step, i.e.,
the retro-Diels−Alder reaction (the elimination of CO2),
yielding the key cyclohexadiene intermediates 8. In the absence
of a dehydrogenation catalyst, the compounds 8 would react
with another molecule of a dienophile, leading to the
Table 1. Comparison of the Reaction Conditions and Dehydrogenation Catalysts for the Transformation between the 2H-
Pyran-2-one 6a (R1 = H; R2 = COMe; R3 = Me) (1 mmol) and N-Ethylmaleimide (2a) (2 mmol) in Decalin (8 mL) Yielding 9a
a
a
run
catalyst
Rh/C
m (cat.)/mg
t/h
T/°C
conversion (%)
ratio 9a:10a
b
1
820
820
820
820
250
250
820
820
60
4
150
150
150
150
150
150
150
150
150
150
150
150
150
180
180
180
180
95
85
1:0.9
1:1
b
2
Pd/C
4
b
3
activated carbon
MWNT
4
93
0.4:1
0.5:1
0.15:1
0.1:1
b
4
4
77
b
5
MWNT
4
88
b
6
SWNT
4
95
b
c
7
NDP
4
81
1:0.2
b
8
TiO2
4
91
0.8:1
0.3:1
0.7:1
1:0.3
1:0
b
9
Darco KB
Darco KB
Darco KB
Darco KB
Darco KB
Darco KB
activated carbon
Darco KB
4
90
b
10
11
12
13
14
15
16
17
410
820
4
95
b
4
100
100
100
100
93
d
b
820
4
e
820
820
820
820
4
1:0.1
1:0.05
1:0.7
1:0.05
0.1:1
e
4
e
4
e
6
100
>95
e
24
a
b
1
The ratio was estimated from H NMR spectra of a crude reaction mixture. Round-bottom flask with reflux condenser, decalin (8 mL) in an oil
c
d
e
bath. With the extensive formation of side products. With 0.5 mmol of 6a and 1 mmol of 2a in decalin (4 mL). Closed ACE pressure tube (15
mL), decalin (8 mL) in an oil bath.
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the first cycloaddition reaction far away from the starting
compound 6. The second cycloaddition (i.e., 8 ⇆ 10) should
also be reversible, therefore enabling the eventually formed
double cycloadduct 10 to be transformed back into the
intermediate 8 and so having another chance for the
aromatization into 9; however, our studies with 6 show
somewhat different results (see below).
conditions (Table 1, run 15) decreased the conversion to 93%
and the ratio of 9a to 10a to 1:0.7, therefore showing that the
activated carbon is a less effective dehydrogenation catalyst.
On the basis of some literature reports,6,7,11 we decided to
determine the effect of oxygen on these transformations. We
carried out the reaction of 6a with 2a under inert conditions
(bubbling argon through the reaction mixture) and also with
the bubbling of oxygen, both in open vessels (for safety
reasons). After 4 h at 180 °C, the conversion was, in the case of
inert conditions, around 67%, and exclusively 9a was detected.
However, under the oxygen atmosphere, the conversion toward
9a was around 23% (without any 10a), albeit accompanied by a
large quantity of degradation products. These results show that
a larger amount of oxygen in our case does not enable selective
oxidation (dehydrogenation of 8a into 9a): at most, it probably
causes an unselective overoxidation. In contrast, the majority of
the examples described in the literature6,7,11 were accelerated by
the application of an oxygen atmosphere.
Comparison of the Efficiency of Various Dehydrogen-
ation Catalysts and Reaction Conditions. First, we decided
to examine various materials with a large specific surface7b as
potential dehydrogenation catalysts and also to study the effects
of the changing reaction conditions on the model conversion of
6a into the isoindole product 9a and/or into the corresponding
double cycloadduct 10a. As potentially interesting catalysts, we
selected two types of activated carbon (ordinary and Darco
KB), Rh/C, and Pd/C, as well as multi- and single-wall carbon
nanotubes (MWNTs and SWNTs),9 nanodiamond powder
(NDP), and titanium dioxide powder. On the basis of our
previous experiences, we chose decalin as the most appropriate
solvent; the preliminary reactions were carried out in an open,
round-bottom flask equipped with a reflux condenser that was
heated for 4 h in an oil bath at 150 °C (Table 1, runs 1−12).
The crude reaction mixtures were analyzed by 1H NMR
spectroscopy, and the results have shown that the conversion
toward 9a was the highest when the Darco KB was applied.
Understandably, the best results were obtained with the largest
amount of Darco KB (Table 1, run 12); however, with such a
large amount of Darco KB (and without an increase in the
volume of the solvent), the reaction mixture was exceedingly
viscous, thus preventing efficient stirring and decreasing the
yields. Therefore, as the most appropriate conditions for further
optimization, we selected those presented as run 11 (Table 1).
NDP was the only other catalyst also yielding an appreciable
amount of isoindole 9a (Table 1, run 7); however, its
application was not appropriate, as it caused the extensive
formation of side products. All the other combinations proved
to be even less successful.
The observed activities of the various heterogeneous
dehydrogenation catalysts correlate well with the values of
the specific surface areas as measured by the surface-area
analyzer,10 for the catalysts we applied: the BET surface area as
determined by the adsorption of nitrogen for the Darco KB was
found to be above 1320 m2/g, for the Rh/C it was around 832
m2/g, and for the active carbon it was only 700 m2/g. The
better results for dehydrogenation obtained with the Rh/C
might, therefore, be mainly attributed to the higher specific area
of the carbon component of the Rh/C in comparison with the
metal-free active carbon (Table 1, runs 1 and 3). This
comparison clearly shows that there is no appreciable effect
of metals (precious and others present on the carbon7b) on the
dehydrogenation step; the results are also consistent with those
from the literature.7b,c
Insights into the Dehydrogenation Activity of Darco
KB. To elucidate the exact dehydrogenation activity of the
activated carbon Darco KB, we first tried to isolate the N-
substituted succinimide 11 that should have been formed if the
dehydrogenation takes place as described above. Indeed, in the
reaction of 6a and 2a (in the molar ratio 1:2) after 4 h at 180
°C, we could detect signals clearly belonging to the N-
1
ethylsuccinimide (11a) in the H NMR spectrum of the crude
reaction mixture. We also proved this by adding to the reaction
mixture an authentic sample of 11a. Unfortunately, we were not
able to isolate 11a, as it is prone to sublimation during the
removal of the solvent (decalin) under reduced pressure.
Additionally, in the same reaction, we managed to prove the
quantitative formation of 11a via an HPLC analysis of the crude
acetone extract of the reaction mixture (molar ratio of 11a:9a
approximately 0.95:1, as determined by the addition of standard
11a). These results clearly show that the N-substituted
maleimides 2 really act as the scavengers for the hydrogen
that is liberated by the aromatization of 8. It means that oxygen
is not (at least not predominantly) involved in the
aromatization step.
This is further supported by the data obtained from the
reaction of 6a and 2a (however in the molar ratio 1:1), where
after 4 h at 180 °C in a closed vessel, an appreciable amount of
the starting 6a remained unreacted.
However, we were still somewhat perplexed as to why the
increase of the reaction time (compare runs 14 and 16, Table
1) did not appreciably change the ratio between the isoindoles
9 and the double cycloadducts 10, as previously reported.4
Therefore, we decided to check the proposition that the last
cycloaddition step (i.e., 8 → 10) is not reversible (as opposed
to the case of the fused pyran-2-ones)4 under the reaction
conditions applied, and 9 cannot form from 10 accordingly. In
this regard, a solution of the double cycloadduct 10a (0.5
mmol) was heated in decalin (8 mL) at 180 °C in a closed
Since the N-substituted maleimides 2 are prone to
sublimation, we decided to examine the transformation
between 6a and 2a in a closed vessel (ACE pressure tube)
under the previously determined most successful conditions
(with Darco KB). Indeed, the ratio 9a:10a after 4 h of heating
in a closed vessel in an oil bath at 150 °C was improved (Table
1, run 13). Furthermore, with an increase in the temperature to
180 °C, the results obtained were even better: the ratio
between 9a and 10a was 1:0.05, and the conversion was again
complete (Table 1, run 14). On the other hand, substituting
Darco KB with activated carbon under otherwise identical
1
vessel and after 24 h analyzed by H NMR spectroscopy.
Surprisingly, there was not even a trace of the aromatized
isoindole 9a (and also not of the cyclohexadiene intermediate
8a). In the case of fused pyran-2-ones,4 under comparable
conditions there was an around 10% conversion to the
corresponding aromatized product. In order to see if there
might be an effect of the activated carbon on this trans-
formation, we analogously heated a mixture of the double
cycloadduct 10a (0.5 mmol) and Darco KB (820 mg) in
decalin (8 mL) at 180 °C in a closed vessel. After 24 h (and
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Table 2. Reaction Conditions and Yields for the Synthesis of 9 Starting from 6a−j (1 mmol) and N-Substituted Maleimides 2
starting compound 6
a
b
c
run
R1
R2
R3
t/h
2
product
yield (%)
1
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
Me
H
H
H
H
COMe
COPh
CO2Me
CO2Et
CO2Me
CO2Et
H
Me
Me
Me
Me
6a
6b
6c
6d
6e
6f
4
3
3
4
4
4
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
9a
9b
9c
9d
9e
9f
82
84
64
63
2
3
4
d
5
CH2CO2Me
CH2CO2Et
Ph
59
6
71
d
7
6g
6h
6i
9g
9h
9i
52
e
d
8
H
2-furyl
2-thienyl
2-pyridyl
Me
11
41
e
d
9
H
16
62
10
11
12
13
14
15
16
17
18
19
H
6j
6
4
4
9j
73
76
80
73
66
70
85
87
73
71
COMe
COPh
CO2Me
CO2Et
H
6a
6b
6c
6f
9k
9l
Me
Me
4.5
4
9m
9n
9o
9p
9q
9r
9s
CH2CO2Et
2-pyridyl
Me
6j
6
COMe
COPh
CO2Me
CO2Et
6a
6b
6c
6f
4
Me
4
Me
5
CH2CO2Et
4
a
b
Reaction times were optimized for each run separately. Darco KB (820 mg), solvent decalin (8 mL) in a closed ACE pressure tube (15 mL)
c
d
heated with oil bath (180 °C). Yield of isolated product (crude products contained up to 4% of the corresponding 10). In this case, the crude
products contained around 8−10% of the corresponding 10.5c,d At 200 °C.
e
also after 100 h), there were again no traces of the
corresponding isoindole derivative 9a (as above). However,
as proved previously,4 it might be necessary to have some
additional 2H-pyran-2-one in the reaction mixture to scavenge
the liberated maleimide. In the next experiment, therefore, we
mixed an equimolar amount of 6a and 10a (0.5 mmol each) in
decalin (8 mL) and heated the mixture at 200 °C under
otherwise identical conditions as those above. After 24 h, there
was again no sign of a conversion from 10a to 9a. Even with the
addition of activated carbon Darco KB (820 mg) to the above-
mentioned mixture of 6a and 10a (0.5 mmol each) in decalin
(8 mL) after 24 h (at 200 °C), there was no trace of 9a (and
also not of 8a); the starting compounds remained unchanged.
Additional experiments analogous to those described above
were also carried out with 10c. All these results have clearly
shown that in contrast to the results previously obtained with
fused pyran-2-ones,4 the double cycloadducts 10 of the
bicyclo[2.2.2]octene type are far more stable and do not
undergo the retro-Diels−Alder reaction at the reaction
temperatures applied (180−200 °C) for their formation. On
the other hand, in the case of 10h the results were different:
when an equimolar mixture of the double cycloadduct 10h and
the starting 2H-pyran-2-one 6h (0.5 mmol each) with the
addition of Darco KB (820 mg) in decalin (8 mL) was heated
between 180 and 200 °C, whereas in all the other cases it is
above 200 °C.
Therefore, starting from the cyclohexadiene intermediate 8 at
temperatures below 200 °C, there are two irreversible reaction
pathways, one leading to the desired isoindoles 9 (8 → 9) and
the other to the double cycloadducts 10 (8 → 10). Since both
steps are irreversible, there is no way to influence their ratio
9:10 by just changing reaction time; when the products are
formed, they cannot be transformed back into the intermediate
8 and therefore also not into the product 10. To obtain the
products 9 in a higher yield, it would be preferential to execute
the syntheses of 9 (and not of 10) at temperatures that would
be above the temperature threshold necessary for the
cycloaddition 8 → 10 to be reversible (and would therefore
preferentially lead to the formation of the thermodynamically
more stable isoindole products 9). However, this is not viable
in practice, as such high temperatures would cause the excessive
degradation of the starting compounds and also the products.
As expected, in a separate experiment starting from the
isoindole 9e and the succinimide 11a in decalin and in the
presence of Darco KB, we also confirmed that the isoindoles 9,
when formed, cannot be reconverted (hydrogenated) into the
intermediates 8.
The importance of the dehydrogenation catalyst is, in these
cases, even more important than in the series of fused pyran-2-
ones, and it is obvious that the intermediate 8 has to be
dehydrogenated as soon as it is formed to prevent its
transformation into 10. This conclusion also shows why it
was necessary to employ such large amounts of the
dehydrogenation catalyst and why the amount of isoindole 9
did not increase solely with a prolonged reaction time.
Synthesis of Isoindole Products 9 from 6 and 2. The
selected conditions as found in run 14 (Table 1) using Darco
KB as the dehydrogenation catalyst were further applied for the
synthesis of a set of novel isoindoles 9a−s from the variously
substituted 2H-pyran-2-ones 6a−j and N-substituted malei-
1
(for 24 h) in a closed vessel at 200 °C and analyzed by H
NMR spectroscopy, the formation of the isoindole product 9h
was clearly proved (approximate ratio 9h:10h:6h = 0.33:1:1;
25% of the starting 6h and 10h having reacted). For the same
transformation at a lower temperature (180 °C) (under
otherwise identical conditions as above), however, the results
were completely different: just a negligible amount of 9h could
1
be observed in the H NMR spectrum of the crude reaction
mixture. Analogous behavior was found for 9i as well.
Obviously, the temperature plays a crucial role, and the
temperature threshold to achieve the reversibility for the
transformation 8 → 10 is, in the cases of 9h,i, somewhere
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Chart 1. Isoindole Products 9a−s
mides 2a−c. The reactions were carried out in closed vessels
that were heated for 3−16 h in an oil bath at 180−200 °C
(Table 2) followed by a continuous extraction with toluene
from the dehydrogenation catalyst, yielding the products 9a−s
(Chart 1) in 41−87% isolated yields. The best results (the
highest conversions and highest ratio 9:10) were obtained with
those 2H-pyran-2-ones 6 where R3 is a mildly electron-donating
substituent, such as a methyl (6a−d); similar results were also
obtained with the alkoxycarbonylmethyl group (6e,f). On the
other hand, when R3 is an electron-withdrawing heterocyclic
moiety (2-furyl, 2-thienyl) (6h,i), the reactions proceed far
more slowly (Table 2, runs 8 and 9), whereas with R3 being a
phenyl or 2-pyridyl group (6g,j), intermediate results were
obtained. These data, further supported by the fact that the
double bond of the dienophiles 2 is electron-deficient (because
of both carbonyl groups), point to the cycloaddition with a
normal electron demand.12 On this basis, cycloaddition of 2a
with electron-rich dienes (2H-pyran-2-ones) should proceed
even faster; however, in this case also the second cycloaddition
step (i.e., of 2 on the intermediate 8) might be influenced. The
effects of the groups R1 and R2 that are not bound to the
terminal carbon atoms of the diene system 6, as also suggested
by the literature data,12c are far less pronounced.
more, to the best of our knowledge, our results represent some
of the first examples of the use of activated carbon for a key
dehydrogenation step, being part of a one-pot sequence
incorporating various transformations (including a Diels−
Alder cycloaddition forming C−C bonds and the elimination
of CO2 as a retro-Diels−Alder reaction followed by a
dehydrogenation). Additionally, we have corroborated the
results of Hayashi and others,6,7c which indicate that in many
cases a precious-metal-free active-carbon surface suffices for an
efficient dehydrogenation step. Finally, when a scale-up is
desired and larger amounts of the catalyst are necessary, we
believe that the catalyst could be easily reused.
EXPERIMENTAL SECTION
■
Melting points were determined on a micro-hot-stage apparatus and
are uncorrected. 1H NMR spectra were recorded at 29 °C and 300 or
500 MHz using Me4Si as an internal standard. 13C NMR spectra were
recorded at 75.5 MHz and are referenced against the central line of the
solvent triplet (CDCl3 at 77.0 ppm). The coupling constants (J) are
given in Hz. IR spectra were obtained as KBr pellets for all compounds
(except for 11a). The starting compounds 6 were prepared according
to the published procedures.13 All other reagents and solvents were
used as received from commercial suppliers.
Thermal Synthesis of the Products 9. A suspension of the
starting 2H-pyran-2-one 6 (1 mmol), maleimide 2 (2 mmol), and
Darco KB (820 mg) in decalin (8 mL) was placed in a glass ACE
pressure tube (15 mL), closed with a Teflon screwed stopper, and
heated in an oil bath (at 180 °C for all cases, except for 9h,i at 200 °C)
for 3 h (for 9b,c), 4 h (for 9a,d−g,k,l,n,p,q,s), 4.5 h (for 9m), 5 h (for
9r), 6 h (for 9j,o), 11 h (for 9h), or 16 h (for 9i). The entire mixture
(in the cases of the preparation of 9e,g,h,i containing around 8−10%
of the corresponding bicyclo[2.2.2]octene adduct 10, as shown by 1H
CONCLUSIONS
■
We have presented the application of activated carbon Darco
KB as a very efficient dehydrogenation catalyst for the
preparation of a set of novel isoindole derivatives 9a−s via a
one-pot Diels−Alder reaction starting from substituted 2H-
pyran-2-ones and various N-substituted maleimides. Further-
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NMR of the crude mixture; in all other cases less than 4% of the
corresponding 10 was detected) was transferred into a Soxhlet
apparatus and continuously extracted with toluene (120 mL) for 8 h.
The extract was evaporated under reduced pressure, and the crude
product was treated with 3−4 mL of acetone and then filtered to
obtain pure 9.
N-(6-Acetyl-2-ethyl-7-methyl-1,3-dioxo-2,3-dihydro-1H-iso-
indol-4-yl)benzamide (9a). Yield: 287 mg (82%) as a very pale
yellow solid; mp 204−206 °C (EtOH); IR (KBr) ν 1757, 1692, 1622,
1539 cm−1; 1H NMR (300 MHz, CDCl3) δ (ppm) 1.31 (t, J = 7.2 Hz,
3H), 2.66 (s, 3H), 2.74 (s, 3H), 3.75 (q, J = 7.2 Hz, 2H), 7.59 (m,
3H), 8.03 (m, 2H), 9.22 (s, 1H), 10.64 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 13.9, 14.3, 30.3, 33.0, 117.8, 124.1, 127.3, 129.1,
129.2, 131.8, 132.7, 133.2, 135.4, 146.9, 165.7, 167.7, 169.5, 201.2; MS
(EI) m/z (%) = 350 (26) [M+], 105 (100). Anal. Calcd for
C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.29; H, 4.91; N,
8.13.
N-(6-Benzoyl-2-ethyl-7-methyl-1,3-dioxo-2,3-dihydro-1H-
isoindol-4-yl)benzamide (9b). Yield: 346 mg (84%) as an off-white
solid; mp 227−228 °C (acetone); IR (KBr) ν 3445, 1762, 1699, 1686,
1672, 1621, 1596, 1581, 1539, 1493 cm−1; 1H NMR (300 MHz,
CDCl3) δ (ppm) 1.33 (t, J = 7.2 Hz, 3H), 2.56 (s, 3H), 3.78 (q, J = 7.2
Hz, 2H), 7.56 (m, 6H), 7.85 (m, 2H), 8.01 (m, 2H), 8.91 (s, 1H),
10.67 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 13.9, 14.2,
33.0, 117.1, 123.4, 127.3, 128.8, 129.0, 130.1, 130.7, 132.6, 133.3,
134.2, 135.3, 136.2, 147.9, 165.5, 167.8, 169.8, 196.1 (1 signal hidden);
MS (ES−) m/z (%) = 411 (100) [M − H]−. Anal. Calcd for
C25H20N2O4: C, 72.80; H, 4.89; N, 6.79. Found: C, 72.83; H, 4.78; N,
7.09.
N-(2-Ethyl-6-methoxycarbonyl-7-methyl-1,3-dioxo-2,3-dihy-
dro-1H-isoindol-4-yl)benzamide (9c). Yield: 234 mg (64%) as a
pale yellow solid; mp 190−191 °C (acetone); IR (KBr) ν 3339, 1762,
1734, 1698, 1675, 1618, 1580, 1536 cm−1; 1H NMR (300 MHz,
CDCl3) δ (ppm) 1.30 (t, J = 7.2 Hz, 3H), 2.82 (s, 3H), 3.74 (q, J = 7.2
Hz, 2H), 3.95 (s, 3H), 7.57 (m, 3H), 8.01 (m, 2H), 9.33 (s, 1H), 10.57
(s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 13.8, 14.5, 33.0, 52.6,
118.4, 126.4, 127.3, 128.8, 129.0, 132.6, 133.2, 134.0, 135.1, 138.5,
165.4, 166.4, 167.6, 169.4; MS (ES+) m/z (%) = 367 (100) [M + H]+.
Anal. Calcd for C20H18N2O5: C, 65.57; H, 4.95; N, 7.65. Found: C,
65.47; H, 4.97; N, 7.65.
118.4, 127.0, 127.3, 129.0, 129.5, 129.7, 132.7, 133.2, 136.4, 138.5,
165.5, 165.6, 167.5, 169.4, 170.6 (1 signal hidden); MS (ES+) m/z
(%) = 453 (25) [M + H]+, 475 (100) [M + Na]+. Anal. Calcd for
C24H24N2O7: C, 63.71; H, 5.21; N, 6.16. Found: C, 63.81; H, 5.21; N,
6.16.
N-(2-Ethyl-1,3-dioxo-7-phenyl-2,3-dihydro-1H-isoindol-4-
yl)benzamide (9g). Yield: 192 mg (52%) as a yellow solid; mp 201−
1
203 °C (EtOH); IR (KBr) ν 1759, 1686, 1625, 1608, 1530 cm−1; H
NMR (300 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.2 Hz, 3H), 3.73 (q, J
= 7.2 Hz, 2H), 7.55 (m, 8H), 7.68 (d, J = 8.7 Hz, 1H), 8.07 (m, 2H),
9.01 (d, J = 8.7 Hz, 1H), 10.84 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
δ (ppm) 13.9, 32.9, 116.9, 124.9, 126.7, 127.4, 128.1, 128.6, 129.0,
129.3, 132.6, 133.5, 135.8, 135.9, 136.9, 138.0, 165.6, 167.1, 170.3; MS
(EI) m/z (%) = 370 (55) [M+], 105 (100). Anal. Calcd for
C23H18N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.40; H, 4.84; N,
7.56.
N-[2-Ethyl-7-(2-furyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-
yl]benzamide (9h). Yield: 148 mg (41%) as an orange-green solid;
mp 203−205 °C (EtOH); IR (KBr) ν 1745, 1694, 1682, 1625, 1531
cm−1; 1H NMR (300 MHz, CDCl3) δ (ppm) 1.32 (t, J = 7.2 Hz, 3H),
3.78 (q, J = 7.2 Hz, 2H), 6.58 (dd, J = 3.5, 1.8 Hz, 1H), 7.56 (m, 4H),
7.88 (dd, J = 3.5, 0.6 Hz, 1H), 8.05 (m, 2H), 8.22 (d, J = 9.0 Hz, 1H),
9.00 (d, J = 9.0 Hz, 1H), 10.92 (s, 1H); 13C NMR (75.5 MHz, CDCl3)
δ (ppm) 13.9, 33.0, 112.3, 113.7, 116.6, 123.4, 124.1, 125.1, 127.3,
128.9, 132.5, 133.40, 133.42, 136.4, 143.0, 148.7, 165.4, 167.0, 170.0;
MS (EI) m/z (%) = 360 (36) [M+], 105 (100). Anal. Calcd for
C21H16N2O4: C, 69.99; H, 4.48; N, 7.77. Found: C, 69.88; H, 4.58; N,
7.91.
N-[2-Ethyl-7−1,3-dioxo-(2-thienyl)-2,3-dihydro-1H-isoindol-
4-yl]benzamide (9i). Yield: 233 mg (62%) as an orange solid; mp
183−184 °C (acetone); IR (KBr) ν 3355, 1748, 1692, 1679, 1625,
1
1603, 1593, 1531, 1516, 1494 cm−1; H NMR (300 MHz, CDCl3) δ
(ppm) 1.31 (t, J = 7.2 Hz, 3H), 3.76 (q, J = 7.2 Hz, 2H), 7.16 (m, 1H),
7.44 (m, 1H), 7.58 (m, 3H), 7.85 (m, 2H), 8.06 (m, 2H), 8.97 (d, J =
9.0 Hz, 1H), 10.90 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
13.8, 33.0, 117.0, 125.1, 125.5, 127.2, 127.3, 127.8, 128.4, 129.0, 129.4,
132.5, 133.4, 136.8, 137.37, 137.40, 165.5, 167.0, 170.0; MS (ES+) m/
z (%) = 377 (100) [M + H]+. Anal. Calcd for C21H16N2O3S: C, 67.00;
H, 4.28; N, 7.44. Found: C, 67.07; H, 4.03; N, 7.44.
N-[2-Ethyl-5-methyl-1,3-dioxo-7-(2-pyridyl)-2,3-dihydro-1H-
isoindol-4-yl]benzamide (9j). Yield: 281 mg (73%) as a pale yellow
solid; mp 204−205 °C (acetone); IR (KBr) ν 3414, 1764, 1725, 1700,
1686, 1644, 1600, 1578, 1531, 1511, 1486 cm−1; 1H NMR (300 MHz,
CDCl3) δ (ppm) 1.24 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 3.68 (q, J = 7.2
Hz, 2H), 7.35 (m, 1H), 7.58 (m, 3H), 7.80 (m, 1H), 7.88 (m, 1H),
7.97 (s, 1H), 8.07 (m, 2H), 8.75 (m, 1H), 9.48 (s, 1H); 13C NMR
(75.5 MHz, CDCl3) δ (ppm) 13.8, 20.0, 32.9, 123.0, 123.2, 125.5,
127.1, 127.8, 128.9, 132.5, 133.6, 135.3, 135.8, 136.2, 139.1, 141.8,
149.6, 153.4, 165.9, 167.0, 169.1; MS (ES−) m/z (%) = 384 (100) [M
− H]−. Anal. Calcd for C23H19N3O3: C, 71.68; H, 4.97; N, 10.90.
Found: C, 71.53; H, 4.83; N, 10.91.
N-(6-Acetyl-2-methyl-7-methyl-1,3-dioxo-2,3-dihydro-1H-
isoindol-4-yl)benzamide (9k). Yield: 255 mg (76%) as a pale yellow
solid; mp 187−188.5 °C (acetone); IR (KBr) ν 3435, 1756, 1690,
1620, 1582, 1536, 1493 cm−1; 1H NMR (300 MHz, CDCl3) δ (ppm)
2.64 (s, 3H), 2.69 (s, 3H), 3.17 (s, 3H), 7.56 (m, 3H), 7.99 (m, 2H),
9.18 (s, 1H), 10.55 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
14.3, 23.8, 30.2, 117.7, 124.1, 127.2, 129.0, 129.1, 131.9, 132.7, 133.0,
135.3, 146.7, 165.5, 167.8, 169.5, 201.0; MS (ES+) m/z (%) = 337
(100) [M + H]+. Anal. Calcd for C19H16N2O4: C, 67.85; H, 4.79; N,
8.33. Found: C, 67.81; H, 4.70; N, 8.29.
N-(2-Ethyl-6-ethoxycarbonyl-7-methyl-1,3-dioxo-2,3-dihy-
dro-1H-isoindol-4-yl)benzamide (9d). Yield: 239 mg (63%) as a
pale yellow solid; mp 164−166.5 °C (MeOH); IR (KBr) ν 1760,
1723, 1699, 1619, 1536 cm−1; 1H NMR (300 MHz, CDCl3) δ (ppm)
1.31 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 2.84 (s, 3H), 3.75 (q,
J = 7.2 Hz, 2H), 4.43 (q, J = 7.2 Hz, 2H), 7.58 (m, 3H), 8.03 (m, 2H),
9.33 (s, 1H), 10.61 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm)
13.9, 14.2, 14.5, 33.0, 61.8, 118.3, 126.2, 127.3, 128.8, 129.0, 132.6,
133.4, 133.7, 135.2, 139.3, 165.5, 166.2, 167.8, 169.6; MS (EI) m/z
(%) = 380 (31) [M+], 105 (100). Anal. Calcd for C21H20N2O5: C,
66.31; H, 5.30; N, 7.36. Found: C, 66.02; H, 5.11; N, 7.29.
N-(2-Ethyl-6-methoxycarbonyl-7-methoxycarbonylmethyl-
1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)benzamide (9e). Yield:
224 mg (59%) as a yellow-green solid; mp 167−169.5 °C (EtOH); IR
1
(KBr) ν 1761, 1737, 1692, 1626, 1541 cm−1; H NMR (300 MHz,
CDCl3) δ (ppm) 1.31 (t, J = 7.2 Hz, 3H), 3.74 (m, 5H), 3.94 (s, 3H),
4.60 (s, 2H), 7.59 (m, 3H), 8.04 (m, 2H), 9.55 (s, 1H), 10.63 (s, 1H);
13C NMR (75.5 MHz, CDCl3) δ (ppm) 13.8, 32.9, 33.2, 52.1, 52.8,
118.6, 127.2, 127.3, 129.1, 129.6, 129.7, 132.8, 133.2, 136.4, 137.8,
165.5, 166.0, 167.5, 169.3, 171.1; MS (EI) m/z (%) = 380 (31) [M+],
105 (100). Anal. Calcd for C22H20N2O7: C, 62.26; H, 4.75; N, 6.60.
Found: C, 62.46; H, 4.66; N, 6.76.
N-(6-Acetyl-2,7-dimethyl-1,3-dioxo-2,3-dihydro-1H-isoin-
dol-4-yl)benzamide (9l). Yield: 318 mg (80%) as an off-white solid;
mp 219−220 °C (acetone); IR (KBr) ν 3446, 1764, 1687, 1672, 1620,
N-(2-Ethyl-6-ethoxycarbonyl-7-ethoxycarbonylmethyl-1,3-
dioxo-2,3-dihydro-1H-isoindol-4-yl)benzamide (9f). Yield: 321
mg (71%) as a yellow-orange solid; mp 183−185 °C (EtOH); IR
1
1597, 1537, 1493 cm−1; H NMR (300 MHz, CDCl3) δ (ppm) 2.55
1
(KBr) ν 1761, 1737, 1692, 1626, 1541 cm−1; H NMR (300 MHz,
(s, 3H), 3.21 (s, 3H), 7.56 (m, 6H), 7.84 (m, 2H), 7.99 (m, 2H), 8.90
(s, 1H), 10.63 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 14.2,
23.8, 117.1, 123.5, 127.3, 128.8, 129.0, 130.1, 130.7, 132.6, 133.2,
134.2, 135.2, 136.1, 147.9, 165.5, 168.0, 169.9, 196.0 (1 signal hidden);
MS (ES−) m/z (%) = 397 (100) [M − H]−. Anal. Calcd for
CDCl3) δ (ppm) 1.29 (m, 6H), 1.42 (t, J = 7.2 Hz, 3H), 3.75 (q, J =
7.2 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.58 (s,
2H), 7.59 (m, 3H), 8.04 (m, 2H), 9.52 (s, 1H), 10.62 (s, 1H); 13C
NMR (75.5 MHz, CDCl3) δ (ppm) 13.8, 14.14, 14.16, 33.1, 61.0, 62.0,
2862
dx.doi.org/10.1021/jo3000783 | J. Org. Chem. 2012, 77, 2857−2864

The Journal of Organic Chemistry
Article
C24H18N2O4: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.03; H, 4.49; N,
7.03.
3459, 1765, 1732, 1721, 1704, 1682, 1622, 1599, 1536, 1502, 1493
cm−1; 1H NMR (300 MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.2 Hz, 3H),
1.44 (t, J = 7.2 Hz, 3H), 4.18 (q, J = 7.2 Hz, 2H), 4.43 (q, J = 7.2 Hz,
2H), 4.63 (s, 2H), 7.53 (m, 8H), 8.04 (m, 2H), 9.61 (s, 1H), 10.72 (s,
1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 14.15, 14.17, 33.2, 61.1,
62.1, 117.9. 126.6, 127.4, 128.6, 129.0, 129.2, 129.3, 130.0, 130.8,
132.8, 133.1, 137.0, 139.1, 165.6, 166.6, 168.6, 170.5 (2 signals
hidden); MS (ES+) m/z (%) = 501 [M + H]+, 286 (100). Anal. Calcd
for C28H25N2O7: C, 67.19; H, 4.83; N, 5.60. Found: C, 67.23; H, 4.81;
N, 5.62.
N-(2-Methyl-6-methoxycarbonyl-7-methyl-1,3-dioxo-2,3-di-
hydro-1H-isoindol-4-yl)benzamide (9m). Yield: 257 mg (73%) as
a yellow solid; mp 211−213 °C (acetone); IR (KBr) ν 3445, 1764,
1731, 1701, 1677, 1617, 1580, 1534 cm−1; 1H NMR (300 MHz,
CDCl3) δ (ppm) 2.85 (s, 3H), 3.19 (s, 3H), 3.96 (s, 3H), 7.58 (m,
3H), 8.03 (m, 2H), 9.37 (s, 1H), 10.58 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 14.5, 23.8, 52.6, 118.3, 126.3, 127.2, 128.8, 128.9,
132.6, 133.1, 134.0, 135.0, 138.4, 165.2, 166.3, 167.8, 169.4; MS (ES+)
m/z (%) = 353 (100) [M + H]+. Anal. Calcd for C19H16N2O5: C,
64.77; H, 4.58; N, 7.95. Found: C, 64.50; H, 4.62; N, 7.93.
N-(2-Methyl-6-ethoxycarbonyl-7-ethoxycarbonylmethyl-
1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)benzamide (9n). Yield:
289 mg (66%) as a very pale orange solid; mp 157−159 °C (Me2CO);
IR (KBr) ν 3451, 1770, 1727, 1697, 1626, 1541 cm−1; 1H NMR (300
MHz, CDCl3) δ (ppm) 1.28 (t, J = 7.2 Hz, 3H), 1.42 (t, J = 7.2 Hz,
3H), 3.19 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H),
4.57 (s, 2H), 7.59 (m, 3H), 8.04 (m, 2H), 9.52 (s, 1H), 10.59 (s, 1H);
13C NMR (75.5 MHz, CDCl3) δ (ppm) 14.11, 14.14, 23.9, 33.1, 61.0,
N-Ethylsuccinimide (11a).14a,b Compound 11a (which is also
commercially available) was prepared by a modification of a procedure
described by Johnson and co-workers.14c In a 250 mL hydrogenation
vessel, the solution of N-ethylmaleimide (2a) (628 mg, 5.02 mmol) in
methanol (25 mL) was flushed with argon. The Pd/C (240 mg) was
added, the walls were washed with additional methanol (5 mL), and
the reaction mixture was hydrogenated for 4 h at 55 psi hydrogen.
Thereafter, the mixture was filtered, and the volatile components were
removed under vacuum, yielding the product N-ethylsuccinimide
(11a) as a colorless, viscous oil. Yield: 490 mg (77%); mp 24−25 °C;
lit.14a mp 26 °C; IR (neat on a NaCl plate) ν 3455, 2982, 2943, 1770,
62.0, 118.4, 127.0, 127.3, 129.0, 129.5, 129.7, 132.7, 133.1, 136.3,
138.5, 165.5, 165.6, 167.7, 169.4, 170.5; MS (ES+) m/z (%) = 439
(31) [M + H]+. Anal. Calcd for C23H22N2O7: C, 63.01; H, 5.06; N,
6.39. Found: C, 62.83; H, 5.05; N, 6.40.
1
1697, 1443, 1405, 1379, 1348 cm−1; H NMR (300 MHz, CDCl3) δ
(ppm) 1.17 (t, J = 7.2 Hz, 3H), 2.70 (s, 4H), 3.56 (q, J = 7.2 Hz, 2H).
ASSOCIATED CONTENT
N-[2,5-Dimethyl-1,3-dioxo-7-(2-pyridyl)-2,3-dihydro-1H-iso-
indol-4-yl]benzamide (9o). Yield: 260 mg (70%) as an off-white
solid; mp 217−218 °C (acetone); IR (KBr) ν 3337, 1759, 1713, 1698,
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for products 9a−s are
1
1663, 1584, 1530, 1520, 1493 cm−1; H NMR (500 MHz, CDCl3) δ
given. This material is available free of charge via the Internet at
http://pubs.acs.org.
(ppm) 2.49 (s, 3H), 3.11 (s, 3H), 7.35 (m, 1H), 7.55 (m, 2H), 7.61
(m, 1H), 7.83 (m, 2H), 7.95 (s, 1H), 8.06 (m, 2H), 8.73 (m, 1H), 9.48
(s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 20.0, 23.8, 123.2,
123.3, 125.4, 127.7, 128.9, 132.4, 133.6, 135.3, 135.9, 136.2, 139.1,
141.9, 149.6, 153.4, 165.9, 167.2, 169.1 (1 signal hidden); MS (ES+)
m/z (%) = 372 [M + H]+, 236 (100). Anal. Calcd for C22H17N3O3: C,
71.15; H, 4.61; N, 11.31. Found: C, 70.96; H, 4.42; N, 11.27.
N-(6-Acetyl-7-methyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-
isoindol-4-yl)benzamide (9p). Yield: 338 mg (85%) as a very pale
yellow solid; mp 266−267 °C (Me2CO); IR (KBr) ν 3441, 1758,
AUTHOR INFORMATION
Corresponding Author
*Fax: +386 (0) 1 24 19 220. E-mail: marijan.kocevar@fkkt.uni-
■
lj.si.
Notes
The authors declare no competing financial interest.
1
1692, 1618, 1597, 1536, 1493 cm−1; H NMR (300 MHz, CDCl3) δ
(ppm) 2.69 (s, 3H), 2.78 (s, 3H), 7.55 (m, 8H), 8.03 (m, 2H), 9.31 (s,
1H), 10.74 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 14.4,
30.4, 117.2, 124.4, 126.6, 127.3, 128.6, 129.1, 129.3, 131.0, 132.3,
132.8, 133.1, 136.0, 147.6, 165.8, 166.8, 168.8, 201.2 (1 signal hidden);
MS (ES−) m/z (%) = 397 [M − H]−. Anal. Calcd for C24H18N2O4: C,
72.35; H, 4.55; N, 7.03. Found: C, 72.20; H, 4.45; N, 6.94.
ACKNOWLEDGMENTS
■
We thank the Ministry of Higher Education, Science and
Technology of the Republic of Slovenia and the Slovenian
Research Agency for financial support (P1-0230-0103). Dr. B.
̌
Kralj and Dr. D. Zigon (Center for Mass Spectroscopy, “Jozef
̌
Stefan” Institute, Ljubljana, Slovenia) are gratefully acknowl-
edged for the mass measurements. We are indebted to Prof. Dr.
N-(6-Benzoyl-7-methyl-1,3-dioxo-2-phenyl-2,3-dihydro-1H-
isoindol-4-yl)benzamide (9q). Yield: 402 mg (87%) as an off-white
solid; mp 254−255 °C (acetone); IR (KBr) ν 3433, 1763, 1703, 1676,
̌ ̌
V. Kaucic and his group (National Institute of Chemistry,
1
1620, 1597, 1535, 1502, 1493 cm−1; H NMR (300 MHz, CDCl3) δ
Ljubljana, Slovenia) for the determination of specific surface
area of catalysts. This work was also partially supported with
infrastructure of EN → FIST Center of Excellence, Ljubljana.
(ppm) 2.60 (s, 3H), 7.55 (m, 11H), 7.87 (m, 2H), 8.00 (m, 2H), 9.00
(s, 1H), 10.76 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ (ppm) 14.3,
116.6, 123.8, 126.6, 127.3, 128.3, 128.5, 128.90, 128.99, 129.3, 130.1,
131.0, 131.2, 132.7, 133.1, 134.3, 135.8, 136.1, 148.5, 165.5, 166.8,
169.0, 195.9; MS (ES+) m/z (%) = 461 (100) [M + H]+. Anal. Calcd
for C29H20N2O4: C, 75.64; H, 4.38; N, 6.08. Found: C, 75.34; H, 4.25;
N, 6.00.
N-(6-Methoxycarbonyl-7-methyl-1,3-dioxo-2-phenyl-2,3-di-
hydro-1H-isoindol-4-yl)benzamide (9r). Yield: 302 mg (73%) as a
pale yellow-green solid; mp 226−228 °C (acetone); IR (KBr) ν 3453,
1767, 1729, 1699, 1681, 1626, 1599, 1539, 1504, 1494 cm−1; 1H NMR
(300 MHz, CDCl3) δ (ppm) 2.85 (s, 3H), 3.94 (s, 3H), 7.50 (m, 8H),
7.99 (m, 2H), 9.41 (s, 1H), 10.65 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) δ (ppm) 14.6, 52.7, 117.9, 126.6, 126.7, 127.3, 128.3, 128.5,
129.0, 129.2, 130.9, 132.7, 133.0, 134.5, 135.6, 139.1, 165.4, 166.4,
166.7, 168.7; MS (ES+) m/z (%) = 415 (100) [M + H]+. Anal. Calcd
for C24H18N2O5: C, 69.56; H, 4.38; N, 6.76. Found: C, 69.56; H, 4.27;
N, 6.72.
REFERENCES
■
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