A facile, protic ionic liquid route to N-substituted 5-hydroxy-4-methyl-3- oxoisoindoline-1-carboxamides and N-substituted 3-oxoisoindoline-4-carboxylic acids

Article abstract of DOI:10.1039/b924835h

Treatment of highly decorated bicyclo[2.2.1]heptadienes with the protic ionic liquid, TfOH:TEA effected quantitative conversion to the corresponding N-substituted 5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamides. This approach provides rapid access important chemical space for the rapid development of highly functionalised oxoisoindoline and is highly substrate tolerant.

Full text of DOI:10.1039/b924835h

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PAPER
www.rsc.org/greenchem | Green Chemistry
A facile, protic ionic liquid route to N-substituted 5-hydroxy-4-methyl-
3-oxoisoindoline-1-carboxamides and N-substituted
3-oxoisoindoline-4-carboxylic acids
Christopher P Gordon, Nolene Byrne and Adam McCluskey*
Received 25th November 2009, Accepted 15th April 2010
First published as an Advance Article on the web 5th May 2010
DOI: 10.1039/b924835h
Treatment of highly decorated bicyclo[2.2.1]heptadienes with the protic ionic liquid, TfOH:TEA
effected quantitative conversion to the corresponding N-substituted 5-hydroxy-4-methyl-3-
oxoisoindoline-1-carboxamides. This approach provides rapid access important chemical space
for the rapid development of highly functionalised oxoisoindoline and is highly substrate tolerant.
anticancer activity of 1 and 2 may be retained. We were more
interested, however, in the possibility of developing an elegant
Introduction
Over the past decade or so, our team has developed a keen
entry to substituted oxoisoindolenes (5) which would permit
interest in the rapid access to biologically active materials.
rapid access to chemical space that we had previously not been
Our efforts have ranged from protein phosphatase inhibitors
able to access in any of our medicinal chemistry programs.28–31
as anticancer agents,1–17 through to novel inhibitors of the large
An additional attraction for the synthesis of oxoisoindolenes
GTPase, dynamin.18–23 Pivotal to our efforts is ease of access
and rapid decoration of chemical scaffolds. In this regard we
place synthetic elegance over complexity with highly focused
(5) is that they, potentially, represent advanced intermediates in
the synthesis of the biologically active natural products, lennox-
amine (6), aristoyagonine (7), and neuvamine (8), amongst
library development the driver of each new therapeutic area.
others (Fig. 2).32–38
Here medicinal and synthetic chemistry diverge, with the former
access to compounds addressing diverse chemical space being
more important than the synthesis of complex molecules, which
is more typically the remit of the synthetic chemist. These two
areas, though, are not mutually exclusive.
Our use of scaffolds in chemistry is exemplified by the
development of protein phosphatase inhibitors embodied by the
cantharidin (1) and norcantharidin (2) scaffolds (Fig. 1). In this
arena little skeletal modification that retains or improves on the
biological activity of the parent compounds is possible.8,11,24,25
Fig. 2 Natural products containing an oxoisoindolene core.
The synthesis of functionalised oxoisoindolenes is not well
described in the literature, as such we were keen to explore
rapid access to illustrative examples of 5.28–31 Of the reports of
oxoisoindolenes, the most expedient route commences with the
Fig. 1 Chemical structures of cantharidin (1), norcantharidin (2),
Diels–Alder addition of furfurylamines (formed by the reductive
amination of furfural with a variety of amines) followed by
addition of maleic anhydride.31 The resulting 3-substituted
4-oxo-10-oxa-3-azatricyclo[5.2.1.0]dec-8-ene-6-carboxylic acids
are then subjected to treatment with cH2SO4/CH3OH at reflux
to afford the corresponding oxoisoindolenes. Similar ring open-
ing aromatisation reactions have also been effected by the use
of HCl and CF3SO3H.39,40 As described, these processes have a
number of major limitations including, but not limited to, the
lack of substrate flexibility permitting rapid decoration of the
oxoisoindolene scaffold, and the requirement for acid tolerant
substituents.
tricyclic lactams (3 and 4) and substituted oxoisoindolenes (5).
More recently, increasing attention has been placed on the
development of medicinal chemistry scaffolds in an environ-
mentally benign manner, i.e. green medicinal chemistry. This
and our on-going interest in the cantharidin and norcantharidin
scaffolds led us to investigate the synthesis of the tricyclic lactams
(3 and 4)26,27 rationalising that there was sufficient structural
similarity to suggest that either the protein phosphatase or the
Chemistry, School of Environmental & Life Sciences, The University of
Newcastle, University Drive, Callaghan, NSW 2308, Australia.
E-mail: Adam.McCluskey@newcastle.edu.au; Fax: +61 2492 15472;
Tel: + 61 2492 16486
In the development of novel 1 and 2 analogues, we
have developed
a
rapid access to highly functionalised
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4-oxo-10-oxa-3-azatricyclo[5.2.1.0]dec-8-enes,25 and 4-oxo-
10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic
acid
(described herein) obviating our first limitation, and we believed
that the replacement of cH2SO4/CH3OH (or H3PO4 or HCl or
CF3SO3H) with a protic ionic liquid may bypass the second
limitation.
Scheme 2 Reagents and conditions: (i) 80% H3PO4, microwave, 120 ◦C,
20 min.
The field of ionic liquids has exploded over the past decade
with considerable interest in the tunable nature of these solvents.
Our current interest lies within a discrete subset of these ionic
liquids, protic ionic liquids (pILs).41–49 With pILs their properties
are governed by the free energy of proton transfer from the
Brønsted acid to the Brønsted base during pIL synthesis. The
effective acidity of pILs depends on the values of the transfer
energy, and this quantity controls many aspects of the behaviour
of pILs. In many regards pILs offer a more subtle degree of
tunability with the percentage conversion of the reaction being
tuned by the choice of acid and base components altering the
proton activity of the pIL solution. Thus, with retention of the
base strength whilst varying the acid strength, the proton activity
of the resulting pIL varies.43,45 We rationalised that the use of
pILs of varying degrees of proton activity would influence the
outcomes of the acid catalysed rearrangements of our 4-oxo-10-
oxa-3-azatricyclo[5.2.1.0]dec-8-enes and related azatricyclodec-
8-ene-6-carboxylic acids.
classified as basic. Each pIL in turn was used as both reaction
solvent and transformation catalyst. The data in Table 1 clearly
indicates an efficient transformation from 15 to 16 under acidic
pIL treatment with both H2SO4:TEA and TfOH:TEA resulting
in 100% conversion and 91 and 95% isolated yields respectively
after workup following 20 min heating at 80 ◦C (microwave).
This compares very favourably with our model reaction with
80% H3PO4 at 120 ◦C (microwave heating) for 20 min. It is also
apparent that the proton activity has a significant impact on the
efficiency of the conversion process with neutral AcOH:TFA
only returning unreacted starting material, whilst the basic pILs
H3PO4:TEA and TFA:TEA affording 56 and 30% isolated yields
respectively. These conversion rates are in keeping with the
known relative proton activities of the pILs examined herein.
As one of our drivers to develop these oxoisoindolene
analogues was to examine their potential anticancer activity,
we compared the effect of treating a panel of human carcinoma
cell lines with 15 and 16. These data are shown in Table 2.
Entry into the oxoisoindolene scaffold (15 → 16) resulted in
a 10 to 20 fold reduction in cell death across the panel of cell
lines examined. Hence we chose not to evaluate there potential as
anticancer agents further, but rather chose to focus on examining
Results and discussion
In order to conduct the proposed studies we applied in-house
methodologies for the synthesis of the necessary oxabicy-
clo[2.2.1]heptadiene scaffold as shown in Scheme 1. Initially an
acetylenic amide (13) was synthesised via an Ugi condensation of
2-furaldehyde (12), 2-butynoic acid (11), an isonitile (10), and an
amine (9). Conversion to the oxabicyclo[2.2.1]heptadiene scaf-
fold (14) via an intramolecular Diels–Alder (IMDA) reaction
was effected smoothly under thermal conditions.
Table 1 Optimisation of oxo-bridgehead opening in the conversion of
15 to 16, 2-benzyl-N-cyclohexyl-5-hydroxy-4-methyl-3-oxoisoindoline-
1-carboxamide
pIL
Temp (◦C)
Time (min)
Yield (%)
H2SO4:TEA
TfOH:TEA
AcOH:TEA
H3PO4:TEA
TFA:TEA
80
80
80
80
80
20
20
20
20
20
91
96
0
56
30
Scheme 1 Reagents and conditions: (i) 9, 10, 11, 12, CH3OH, room
Table 2 Evaluation of the anticancer activity of 15 and 16 against a
panel of human carcinoma cell lines
temperature, 30 min; (ii) PhCH3, sealed tube 200 ◦C, 36 h.
15
16
With a well defined route to the required highly substituted
oxabicyclo[2.2.1]heptadiene (14) scaffold, we firstly examined
an acid catalysed rearrangement. After a series of optimisation
reactions we found that the transformation to the oxoisoindo-
lene scaffold was smoothly effected under microwave heating at
120 ◦C for 20 min. We limited our initial examination to the
conversion of (15) to (16) as shown in Scheme 2.
Having established that the desired transformation occurred
under similar conditions to those reported for less decorated
oxoisoindolenes we next turned our attention to the use of pILs
to effect the same transformation.
Human carcinoma cell line
GI50 (mM)
GI50 (mM)
HT29a
SW480a
MCF-7b
A2780c
H460d
3.2 0.1
3.2 0.1
7.5 0.4
4.4 0.3
3.3 0.2
2.9 0.2
2.1 0.3
3.7 0.6
1.7 0.1
23
25
26
24
32
31
52
53
1
1
9
2
0
1
9
2
A431e
DU145f
BE2-Cg
SJ-G2h
41 11
a HT29 and SW480 (colon carcinoma). b MCF-7 (breast carcinoma).
c A2780 (ovarian carcinoma). d H460 (lung carcinoma). e A431 (skin
carcinoma). f DU145 (prostate carcinoma). g BEC-2 (neuroblastoma).
h SJ-G2 (glioblastoma).
Five pILs were surveyed for their ability to effect the desired
transformation. These pILs display varying degrees of acidity
with H2SO4:TEA the most acidic through to AcOH:TEA being
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Table 3 Conversion of highly decorated oxabicyclo[2.2.1]heptadienes
to highly decorated oxoisoindolenes (17–21) upon treatment with
TfOH:TEA
Table 4 Conversion of azatricyclodec-8-ene-6-carboxylic acids
(24–27) to 3-oxoisoindoline-4-carboxylic acid (28–31) upon treatment
with TfOH:TEA
Entry (compound)
R1
Yield (%)
92
1 (28)
2 (29)
95
Entry (compound) R1
R2
R3
Yield (%)
91
1 (17)
3 (30)
4 (31)
88
85
2 (18)
3 (19)
96
87
Access to the precursor azatricyclodec-8-ene-6-carboxylic
acids was readily effected by a simple sequence of imine
formation (microwave heating), reduction using the ThalesNano
H-cube and a microwave mediated Diels–Alder reaction with
maleic anhydride as shown in Scheme 3.
4 (20)
5 (21)
85
95
the scope of the pIL mediated transformation. With this in
mind we selected a small, but diverse subset of highly decorated
oxabicyclo[2.2.1]heptadienes and treated them with TfOH:TEA
(Table 3).
In all instances we observe rapid, clean and substituent
tolerant conversion to the desired oxoisoindolene scaffold. The
N-substituent is delivered via amines (9, Scheme 1), and all
substituents are well tolerated from the electron-withdrawing
aromatic moieties (Table 3 entries 1 (p-chloroaniline) and 2 (p-
nitroaniline)), through to electron-donating, aliphatic and sim-
ple aromatic substituents (Table 3 entries 3 (p-hydroxyaniline),
4 (N,N-dimethylaminopropan-1-amine) and 5 (benzylamine)).
Carboxamide, and ester (Table 3, entries 1–3) substituents are
delivered via isocyanides (10, Scheme 1), and again are well
tolerated, as are simple alkyl substituents on the phenyl ring.
Products are initially accessed by either dichloromethane or
ethylacetate extractive work up.50
While our IMDA approach affords rapid access to the
required oxabicyclo[2.2.1]heptadiene scaffold, we have also de-
veloped a rapid flow and microwave chemistry based approach to
a related series of azatricyclodec-8-ene-6-carboxylic acids (22).
Though lacking the diene moiety that collapses to substituted 5-
hydroxy-3-oxoisoindoline-1-carboxamides (14), we rationalized
that end stage aromatization via extrusion of the –OH moiety
might provide sufficient driving force to allow an expedient
access to isoindoe-5-carboxylic acids (23) (Fig. 3).
Scheme 3 Reagents and conditions: (i) microwaves, 150 W, 100 ◦C,
5 mins; (ii) H-cube hydrogenation, 0.05 M imine in EtOH, 10% Pd/C,
50 ◦C, 50 bar H2 pressure, 1 mL min-1; (iii) toluene, microwaves, 250 W,
60 ◦C, 10 mins, 60–85%.
This three-step conversion proceeded smoothly and in ex-
cellent overall yield (60–85%) with the products collected by
filtration. Subsequent treatment of 24–27, in turn, with the pIL
TfOH:TEA afforded smooth conversion to the corresponding
3-oxisoindoline carboxylic acids (28–31, Table 4) in excellent
yields (85–92%). Products were isolated by extractive work up.
Our approach to substituted oxoisoindolenes is highly ver-
satile with considerable breadth available via the individ-
ual components of the initial bicyclo[2.2.1]heptadiene and
bicyclo[2.2.1]hept-5-ene scaffolds. Of these components, only
the acetylenic dienophiles are poorly represented in the range of
commercially available starting materials.
Conclusions
Herein we have effected, for the first time, an elegantly simple
synthetic entry point to a series of highly decorated oxoisoin-
dolenes. Our approach is highly efficient with excellent yields,
atom economy, and with the use of pILs, microwave irradiation
and flow chemistry approaches, avoids the use of harsh acidic
conditions opening up the use of more acid labile substituents.
Fig. 3 Proposed route to synthetic route to 3-oxoisoindoline-4-
carboxylic acids (23) from azatricyclo-8-ene-6-carboxylic acids (22).
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(DMSO-d6): d 7.98 (1H, d, J = 7.7 Hz), 7.34 (3H, m), 7.20 (3H,
d, J = 7.0 Hz), 7.08 (1H, d, J = 5.2 Hz), 5.43 (1H, d, J =
5.5 Hz), 5.01 (1H, d, J = 15.3 Hz), 4.55 (1H, s), 3.72 (1H, d,
J = 15.3 Hz) 3.61–3.41 (1H, m), 2.07 (3H, s), 1.84–1.41 (6H, m),
1.15 (4H, m); 13C NMR (300 MHz) (DMSO-d6): d 163.3, 156.7,
145.3, 142.6, 142.5, 136.4, 128.7, 127.5, 127.4, 91.4, 90.7, 60.5,
47.8, 44.8, 32.24, 32.19, 25.0, 24.3, 24.2, 13.8; MS (ESI+) m/z
379 (M + 1, 100%); HRMS (ESI+) calculated for C23H27N2O3
379.1943.
Experimental
General experimental
All starting materials were purchased from Aldrich Chemical
Co. and Lancaster Synthesis. Solvents were bulk, and distilled
from glass prior to use. Reaction progress was monitored by TLC
on aluminium plates coated with silica gel with fluorescent indi-
cator (Merck 60 F254), and flash chromatography was conducted
utilising SNAP Biotage KP-SIL columns. H and 13C spectra
1
were recorded on a Bruker Advance AMX 300 MHz spectrom-
eter at 300.13 and 75.48 MHz, respectively. Chemical shifts are
relative to TMS as internal standard. All compounds returned
satisfactory. Mass spectra were obtained using a micromass
liquid chromatography Z-path (LCZ) platform spectrometer.
Mass to charge ratios (m/z) are stated with their peak intensity as
a percentage in parentheses. All mass spectra were obtained via
the ES method thus fragmentation patterns were not observed.
The University of Wollongong, Australia, Biomolecular Mass
Spectrometry Laboratory, analyzed samples for HRMS. The
spectra were run on a micromass QTof2 spectrometer using
polyethylene glycol or polypropylene glycol as the internal
standard.
General procedure 1
(R)-2-Benzyl-N -cyclohexyl-5-hydroxy-4-methyl-3-oxoiso-
indoline-1-carboxamide (16). A suspension of (3S,3aS,6R)-
2-(benzyl)-1,2,3,6-tetrahydro-7-methyl-1-oxo-N-(cyclohexyl)-
3a,6-epoxy-3aH-isoindole-3-carboxamide (15) (0.19 g,
0.50 mmol) in 3.0 mL of H3PO4 (80%) was irradiated with
microwaves (100 ◦C, 200 W) for 40 min. The resulting solution
was diluted with 2 M NaOH, extracted with CH2Cl2 (2 ¥ 25 mL),
dried (MgSO4), and concentrated in vacuo. The crude reaction
mixture was subjected to flash silica gel chromatography
(2 : 3 EtOAc : hexanes) to afford (R)-2-benzyl-N-cyclohexyl-
5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamide (0.14 g,
72%) as an off-white semi-solid.
Microwave heating was conducted using a CEM Discover Mi-
crowave and flow hydrogenation conducted using a ThalesNano
H-Cube flow hydrogenator. Specific conditions are given below.
General procedure 2
(R)-2-Benzyl-N -cyclohexyl-5-hydroxy-4-methyl-3-oxoiso-
indoline-1-carboxamide (16). A suspension of (3S,3aS,6R)-
2-(benzyl)-1,2,3,6-tetrahydro-7-methyl-1-oxo-N-(cyclohexyl)-
Protic Ionic Liquid preparation
Anhydrous trifluoromethanesulfonic acid (> 98%), triethy-
lamine (> 99.5%), phosphoric acid (H3PO4, 85%, ACS grade),
glacial acetic acid (CH3COOH 99%), and sulfuric acid (H2SO4,
95–98%, ACS grade) were obtained from Sigma Aldrich.
Protic Ionic Liquids (PILs) are formed by proton transfer
between a Brønsted acid and a Brønsted base. The addition of
acid, by drop-wise addition to the amine, was carried out by
cooling the amine solution to -78 ◦C using an acetone/dry-
ice bath. The mixture was stirred at room temperature for
several hours. The mixture was then placed in a rotorvap for
several hours at 60 ◦C and vacuum dried at 0.01 mmHg for 24 h
at 60 ◦C.
3a,6-epoxy-3aH-isoindole-3-carboxamide
(15)
(0.2
g,
0.52 mmol) in 2.0 mL of specified pIL was irradiated
with microwaves (80 ◦C, 200 W) for 20 min. The resulting
solution was diluted with 2 M HCl, extracted with CH2Cl2
(2 ¥ 25 mL), dried (MgSO4), and concentrated in vacuo
to afford (R)-2-benzyl-N-cyclohexyl-5-hydroxy-4-methyl-3-
oxoisoindoline-1-carboxamide (0.18 g, 91%) as an off-white
semi-solid. Yields as per Table 1.
1H NMR (300 MHz) (DMSO-d6): d 9.67 (1 H, bs), 8.34 (1 H,
d, J = 7.8 Hz), 7.44–7.22 (3 H, m), 7.18 (2 H, d, J = 7.6 Hz),
7.05 (1 H, d, J = 8.1 Hz), 6.95 (1 H, d, J = 8.1 Hz), 5.14 (1
H, d, J = 15.1 Hz), 4.66 (1 H, s), 3.88 (1 H, d, J = 15.1 Hz),
3.51 (1 H, m), 2.46 (3 H, s), 1.84–1.43 (5 H, m), 1.16 (5 H, m);
13C NMR (300 MHz) (DMSO-d6): d 168.9, 166.0, 155.9, 137.0,
132.3, 129.1, 128.6, 127.8, 127.3, 122.4, 119.7, 177.7, 60.7, 47.7,
44.0, 32.2, 32.1, 25.0, 24.3, 9.2; MS (ESI+) m/z 379 (M + 1,
100%); HRMS (ESI+) calculated for C23H27N2O3; 379.1943.
(3R,3aS,6R)-2-(benzyl)-1,2,3,6-tetrahydro-7-methyl-1-oxo-
N-(cyclohexyl)-3a,6-epoxy-3aH-isoindole-3-carboxamide (15).
A solution of benzylamine (0.13 mL, 1.2 mmol), 2-furaldehyde
(0.10 mL, 1.2 mmol), 2-butynoic acid (0.12 g, 1.4 mmol), cy-
clohexyl isocyanide (0.15 mL, 1.2 mmol) and anhydrous MeOH
(10.0 mL) was stirred at room temperature for 0.5 h. 2-Butynoic
acid (1.2 eq, 1.4 mmol) was added and the resulting mixture was
stirred for 0.5 h prior to the addition of an isocyanide (1 eq,
1.2 mmol). The mixture was stirred at room temperature for 2 h,
quenched with 1 M NaOH (100 mL), extracted with CH2Cl2 (2 ¥
50 mL), dried (MgSO4), and concentrated in vacuo. A sealed tube
was charged with the crude mixture, toluene (80 mL), degassed,
and heated (250 ◦C) for 36 h. The resulting mixture concentrated
in vacuo and subjected to flash silica gel column chromatography.
The crude material was subjected to flash silica gel column
chromatography (3 : 2 EtOAc : hexanes) to S-15 followed by
further elution (2 : 1 EtOAc : hexanes) afforded R-15 (0.74 g,
33%) as an brown solid (m.p. 209–211 ◦C); 1H NMR (300 MHz)
(R)-Ethyl 2-(5-hydroxy-4-methyl-2-(4-chlorophenyl)-3-oxo-
isoindoline-1-carboxamido)acetate
(17). Synthesised
as
described in general procedure 2 from (3S,3aS,6R)-2-(4-
chlorophenyl)-1,2,3,6-tetrahydro-7-methyl-1-oxo-N-(2-ethoxy-
2-oxoethyl)-3a,6-epoxy-3aH-isoindole-3-carboxamide (0.2 g,
0.50 mmol), and 2.0 mL TE:TfOH affording R)-ethyl
2-(5-hydroxy-4-methyl-2-(4-chlorophenyl)-3-oxoisoindoline-1-
carboxamido)acetate as a pale brown solid in a 91% yield.
1H NMR (300 MHz) (DMSO-d6): d 9.62 (1 H, bs), 9.03
(1H, t, J = 5.6 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.42 (2H, d,
J = 8.9 Hz), 7.08 (1 H, d, J = 8.0 Hz), 6.95 (1 H, d, J =
8.0 Hz), 5.03 (1 H, s), 4.07 (2H, q, J = 7.1 Hz) 3.86 (2H, qd,
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J = 17.4, 5.7 Hz), 2.19 (3H, s), 1.14 (3H, t, J = 7.1 Hz); 13C NMR
(75 MHz) (DMSO-d6): d 169.1, 167.5, 162.7, 161.8, 142.9, 142.4,
141.8, 137.2, 129.0, 128.4, 122.9, 119.7, 117.8, 62.9, 60.5, 40.8,
14.0, 13.9; MS (ESI+) m/z 403 (M + 1, 100%); HRMS (ESI+)
calculated for C20H20ClN2O5 403.0982.
procedure 2 from (3S,3aS,6R)-2-(benzyl)-1,2,3,6-tetrahydro-
7-methyl-1-oxo-N-(butyl)-3a,6-epoxy-3aH-isoindole-3-carbo-
xamide (0.2 g, 0.57 mmol), and 2.0 mL TE:TfOH affording
(R)-2-benzyl-N-butyl-5-hydroxy-4-methyl-3-oxoisoindoline-1-
carboxamide as a white solid in a 95% yield.
1H NMR (300 MHz) (DMSO-d6): d 9.67 (1 H, s), 8.57 (1H, t,
J = 5.6 Hz), 7.44–7.22 (3 H, m), 7.18 (2 H, d, J = 7.6 Hz), 7.05
(1 H, d, J = 8.1 Hz), 6.95 (1 H, d, J = 8.1 Hz), 5.06 (1H, d, J =
15.1 Hz), 4.16 (1H, s), 3.74 (1H, d, J = 15.1 Hz), 3.17 (2H, qd,
J = 13.0, 6.5 Hz), 2.13 (3H, s), 1.50–1.16 (4H, m), 0.88 (3H, t, J =
7.2 Hz); 13C NMR (75 MHz) (DMSO-d6): d 166.5, 162.7, 159.0,
142.5, 142.4, 135.9, 132.4, 128.7, 127.9, 127.5, 118.8, 117.3, 61.1,
44.6, 38.3, 30.8, 19.3, 13.8, 13.5; MS (ESI+) m/z 353 (M + 1,
100%); HRMS (ESI+) calculated for C21H25N2O3 353.1787.
(R)-Ethyl-2-(5-hydroxy-4-methyl-2-(4-nitrophenyl)-3-oxoiso-
indoline-1-carboxamido)acetate (18). Synthesised as described
in general procedure 2 from (3S,3aS,6R)-2-(4-nitrophenyl)-
1,2,3,6-tetrahydro-7-methyl-1-oxo-N-(2-ethoxy-2-oxoethyl)-3a,
6-epoxy-3aH-isoindole-3-carboxamide (0.2 g, 0.48 mmol), and
2.0 mL TE:TfOH affording (R)-ethyl-2-(5-hydroxy-4-methyl-
2-(4-nitrophenyl)-3-oxoisoindoline-1-carboxamido)acetate as a
pale brown in a 96% yield.
1H NMR (300 MHz) (DMSO-d6): d 9.61 (1 H, bs), 9.18 (1H,
t, J = 5.7 Hz), 8.24 (2H, d, J = 9.1 Hz), 7.83 (2H, d, J =
9.1 Hz), 7.08 (1 H, d, J = 7.9 Hz), 6.95 (1 H, d, J = 7.9 Hz),
4.94 (1 H, s), 4.05 (2H, q, J = 7.0 Hz), 3.87 (2H, qd, J =
17.6, 5.7 Hz), 2.22 (3H, s), 1.13 (3H, t, J = 7.0 Hz); 13C NMR
(75 MHz) (DMSO-d6): d 169.2, 167.3, 165.2, 162.1, 144.3, 143.1,
142.8, 141.9, 141.8, 124.3, 120.3, 120.2, 118.3, 62.8, 60.6, 40.8,
14.2, 13.9; MS (ESI+) m/z 414 (M + 1, 100%); HRMS (ESI+)
calculated for C20H20N2O7 414.1223.
General procedure 3
3-Benzyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-
carboxylic acid (24). A neat solution of benzylamine (0.20 mL,
1.8 mmol) and 2-furaldehyde (0.17 mL, 1.8 mmol) was irradiated
with microwaves (150 W, 100 ◦C) for 5 min. The resulting mixture
was diluted with EtOH (36 mL) to afford a ~0.05 M solution
which was subsequently hydrogenated with a H-cube system
loaded with 10% Pd/C CatCart, at 50 ◦C, under 50 bar of
H2 pressure, and a flow rate of 1 mL min-1. The eluate was
concentrated in vacuo and to the crude mixture was added
toluene (3.0 mL) and maleic anhydride (0.26 g, 2.7 mmol).
The resulting solution was irradiated with microwaves (250
W, 60 ◦C) for 10 min, cooled (0 ◦C), and the resulting
precipitate was collected and washed with cold diethyl ether to
afford 3-benzyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-
6-carboxylic acid (0.39 g, 76%) as a white solid (m.p. 151–
152 ◦C).
1H NMR (300 MHz) (MeOH): d 7.57–7.07 (5 H, m), 6.55
(1 H, d, J = 5.8 Hz), 6.44 (1 H, dd, J = 5.8, 1.7 Hz), 5.09 (1
H, d, J = 1.7 Hz), 4.81 (1 H, bs), 4.54 (1 H, d, J = 15.2 Hz),
4.44 (1 H, d, J = 15.2 Hz), 3.94 (1 H, d, J = 11.8 Hz), 3.55
(1 H, d, J = 11.8 Hz), 2.92 (1 H, d, J = 9.1 Hz), 2.73 (1 H,
d, J = 9.1 Hz); 13C NMR (75 MHz) (MeOH): d 173.6, 171.6,
135.8, 135.3, 134.8, 127.8, 126.9, 126.6, 88.1, 81.3, 50.5, 47.3,
45.4, 44.1; MS (ESI+) m/z 286 (M+1, 100%); HRMS (ESI+) for
C16H16NO4, calculated 286.2946, found 286.2947.
(R)-Methyl
2-(5-hydroxy-2-(4-hydroxyphenyl)-4-methyl-3-
oxoisoindoline-1-carboxamido)acetate (19). Synthesised as
described in general procedure 2 from (3S,3aS,6R)-2-(4-hydro-
xyphenyl)-1,2,3,6-tetrahydro-7-propyl-1-oxo-N-(2-methoxy-2-
oxoethyl)-3a,6-epoxy-3aH-isoindole-3-carboxamide (0.2 g,
0.54 mmol), and 2.0 mL TE:TfOH, affording (R)-methyl
2-(5-hydroxy-2-(4-hydroxyphenyl)-4-methyl-3-oxoisoindoline-
1-carboxamido)acetate as a pale yellow solid in a 87% yield.
1H NMR (300 MHz) (DMSO-d6): d 9.61 (1 H, bs), 9.32 (1H,
bs) 9.03 (1H, t, J = 5.6 Hz), 7.58 (2H, d, J = 8.9 Hz), 7.42 (2H, d,
J = 8.9 Hz), 7.11 (1 H, d, J = 8.1 Hz), 6.98 (1 H, d, J = 8.1 Hz),
4.97 (1 H, s), 3.75 (2H, qd, J = 17.4, 5.7 Hz), 3.51 (3H, s), 3.35
(3H, s); 13C NMR (75 MHz) (DMSO-d6): d 169.1, 167.5, 162.7,
161.8, 142.9, 141.8, 137.2, 129.0, 128.4, 122.9, 118.2, 117.8, 62.9,
60.5, 40.8, 14.0, 13.9; MS (ESI+) m/z 371 (M + 1, 100%); HRMS
(ESI+) calculated for C19H19N2O6 371.1165.
(R)-2-(3-(Dimethylamino)propyl)-5-hydroxy-3-oxo-N,4-dipen-
tylisoindoline-1-carboxamide (20). Synthesised as described
in general procedure 2 from (3S,3aS,6R)-2-(4-N,N-dimethyl-
aminopropyl)-1,2,3,6-tetrahydro-7-pentyl-1-oxo-N-(pentyl)-
3a,6-epoxy-3aH-isoindole-3-carboxamide (0.2 g, 0.48 mmol),
and 2.0 mL TE:TfOH affording (R)-2-(3-(dimethylamino)-
propyl)-5-hydroxy-3-oxo-N,4-dipentylisoindoline-1-carboxa-
mide as a yellow solid in a 85% yield.
1H NMR (300 MHz) (DMSO-d6): d 9.61 (1 H, bs), 8.47 (1
H, t, J = 5.5 Hz), 7.08 (1 H, d, J = 7.9 Hz), 6.95 (1 H, d, J =
7.9 Hz), 4.94 (1 H, s), 3.89–3.62 (2 H, m), 3.19-2.81 (4 H, m),
2.10 (6 H, s), 1.78-1.53 (2 H, m), 1.53-1.34 (10 H, m), 1.24 (4 H,
m), 0.83 (6 H, m); 13C NMR (300 MHz) (DMSO-d6): d 168.6,
167.4, 155.5, 132.4, 129.3, 127.2, 119.7, 117.8, 61.6, 56.5, 44.9,
38.9, 38.6, 31.4, 29.3, 28.5, 28.4, 25.4, 22.9, 21.9, 21.7, 13.9, 13.8;
MS (ESI+) m/z 418 (M + 1, 100%); HRMS (ESI+) calculated
for C24H40N3O3; 418.2991.
3-(2-Pyridinylmethyl)-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]-
dec-8-ene-6-carboxylic acid (25). Synthesised as described in
general procedure 3 from 2-pyridinylmethanamine (1.30 mL,
12.0 mmol), 2-furaldehyde (1.2 mL, 12 mmol), and maleic
anhydride (1.76 g, 18 mmol) to afford 3-(2-pyridinylmethyl)-4-
oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid
(3.05 g, 60%) as a light brown solid (m.p. 92–94 ◦C). 1H NMR
(300 MHz) (DMSO-d6): d 12.30 (1 H, s), 8.50 (1 H, d, J =
4.5 Hz), 7.74 (1 H, dt, J = 7.8, 1.7 Hz), 7.26 (2 H, m), 6.58 (1 H,
d, J = 5.7 Hz), 6.42 (1 H, dd, J = 5.7, 1.7 Hz), 5.02 (1 H, d, J =
1.5 Hz), 4.54 (1 H, d, J = 15.2 Hz), 4.44 (1 H, d, J = 15.2 Hz),
4.05 (1 H, d, J = 11.6 Hz), 3.57 (1 H, d, J = 11.6 Hz), 2.88 (1 H,
d, J = 9.2 Hz), 2.51 (1 H, d, J = 9.2 Hz); 13C NMR (75 MHz)
(DMSO-d6): d 172.8, 170.7, 156.4, 149.0, 136.8, 136.5, 135.5,
122.2, 120.8, 88.4, 81.0, 49.9, 48.2, 47.3, 44.4; MS (ESI+) m/z
287 (M + 1, 100%); HRMS (ESI+) for C15H15N2O4, calculated
287.0954, found 287.0954.
(R)-2-Benzyl-N-butyl-5-hydroxy-4-methyl-3-oxoisoindoline-
1-carboxamide (21). Synthesised as described in general
1004 | Green Chem., 2010, 12, 1000–1006
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3-[2-(3,4-Dimethoxyphenyl)ethyl]-4-oxo-10-oxa-3-azatricy-
clo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (26). Synthesised
as described in general procedure 3 from 2-furaldehyde
(0.30 mL, 3.66 mmol), (3,4-dimethoxyphenyl)methanamine
(0.61 g, 3.66 mmol), and maleic anhydride (0.54 g, 5.49 mmol)
to afford 3-[2-(3,4-dimethoxyphenyl)ethyl]-4-oxo-10-oxa-3-
azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (1.07 g, 85%)
as an off-white solid (m.p. 134–135 ◦C).
135.5, 128.8, 119.3, 111.52, 110.5, 55.4, 55.2, 50.5, 47.1; MS
(ESI+) m/z 328 (M + 1, 100%); HRMS (ESI+) for C18H18NO5,
calculated 328.3313 found 328.3313.
2-(2-Pyridinylmethyl)-3-oxo-2,3-dihydro-1H-isoindole-5-car-
boxylic acid (30). Synthesised as described in general pro-
cedure
2 from 26 (0.20 g, 0.70 mmol), and 2.0 mL
TEA:TfOH to afford 2-(2-pyridinylmethyl)-3-oxo-2,3-dihydro-
1H-isoindole-5-carboxylic acid (0.18 g, 96%) as an off-white
solid (m.p. 139–140 ◦C).
1H NMR (300 MHz) (DMSO-d6): d 12.31 (1 H, s), 6.86 (1 H,
d, J = 8.2 Hz), 6.80 (1 H, s), 6.75 (1 H, d, J = 8.2 Hz), 6.54 (1 H,
d, J = 5.7 Hz), 6.40 (1 H, dd, J = 5.7, 1.4 Hz), 4.99 (1 H, d, J =
1.2 Hz), 4.49 (1 H, d, J = 15.1 Hz), 4.15 (1 H, d, J = 15.1 Hz),
3.88 (1 H, d, J = 11.6 Hz), 3.70 (6 H, bs), 3.40 (1 H, d, J =
1H NMR (300 MHz) (DMSO-d6): d 8.50 (1 H, d, J = 4.5 Hz),
8.13 (1 H, d, J = 6.7 Hz), 7.85 (1 H, d, J = 6.7 Hz), 7.78 (1
H, t, J = 6.7 Hz), 7.74 (1 H, dt, J = 7.8, 1.7 Hz), 7.26 (2 H,
m), 4.84 (2 H, s), 4.60 (2 H, s); 13C NMR (75 MHz) (DMSO-
d6): d 172.8, 170.7, 156.4, 149.9, 149.0, 138.7, 136.8, 136.5,
135.5, 128.8, 127.3, 122.2, 120.8, 50.8, 46.3; MS (ESI+) m/z
269 (M + 1, 100%); HRMS (ESI+) for C15H13N2O3, calculated
269.2674, found 269.2673.
11.6 Hz), 2.85 (1 H, d, J = 9.2 Hz), 2.49 (1 H, d, J = 9.2 Hz); 13
C
NMR (75 MHz) (DMSO-d6): d 172.9, 170.3, 148.8, 147.7, 136.5,
135.5, 128.7, 119.3, 111.5, 110.6, 88.3, 81.0, 55.3, 55.2, 50.1, 47.1,
44.6, 44.4; MS (ESI+) m/z 346 (M + 1, 100%); HRMS (ESI+)
for C18H20NO6, calculated 346.1212, found 346.1212.
3-(4-Methoxyphenyl)-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]-
dec-8-ene-6-carboxylic acid (27). Synthesised as described in
general procedure 3 from 4-methoxyaniline (0.40 g, 1.9 mmol),
2-furaldehyde (0.60 mL, 1.9 mmol), and maleic anhydride
(0.27 g, 2.8 mmol) to afford 3-(4-methoxyphenyl)-4-oxo-10-oxa-
3-azatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid (0.39 g, 68%)
as an off-white solid (m.p. 134–135 ◦C).
1H NMR (300 MHz) (DMSO-d6): d ppm 12.31 (1 H, s), 7.54
(2 H, d, J = 8.6 Hz), 6.92 (2 H, d, J = 8.6 Hz), 6.61 (1 H, d,
J = 5.5 Hz), 6.46 (1 H, d, J = 4.7 Hz), 5.02 (1 H, s), 4.48 (1
H, d, J = 11.5 Hz), 3.98 (1 H, d, J = 11.5 Hz), 3.72 (3 H, s),
3.01 (1 H, d, J = 8.9 Hz), 2.55 (1 H, d, J = 8.9 Hz); 13C NMR
(75 MHz) (DMSO-d6): 172.8, 169.7, 155.6, 136.8, 135.3, 132.6,
121.0, 113.7, 87.3, 81.2, 55.1, 51.2, 49.3, 45.1; MS (ESI+) m/z
302 (M + 1, 100%); HRMS (ESI+) for C16H15NO5, calculated
301.0950, found 301.0948.
2-(4-Methoxyphenyl)-3-oxo-2,3-dihydro-1H-isoindole-5-car-
boxylic acid (31). Synthesised as described in general proce-
dure 2 from 27 (0.20 g, 0.67 mmol), and 2.0 mL TEA:TfOH to
afford 2-(4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-isoindole-5-
carboxylic acid (0.17 g, 90%) as an off-white solid (m.p. 169–
170 ◦C).
1H NMR (300 MHz) (DMSO-d6): d ppm 8.13 (1 H, d, J =
6.7 Hz), 7.85 (1 H, d, J = 6.7 Hz), 7.78 (1 H, t, J = 6.7 Hz), 7.54
(2 H, d, J = 8.6 Hz), 6.92 (2 H, d, J = 8.6 Hz), 4.60 (2 H, s); 3.72
(3 H, s); 13C NMR (75 MHz) (DMSO-d6): 172.8, 169.7, 155.7,
147.9, 144.2, 136.8, 135.3, 135.2, 131.8, 121.3, 114.4, 113.7, 56.5,
55.1; MS (ESI+) m/z 284 (M + 1, 100%); HRMS (ESI+) for
C16H14NO4, calculated 284.0845 found 284.0842.
Acknowledgements
This work was supported by the Australian Research Council.
We thank Drs Jennette A Sakoff and Jayne Gilbert for growth
inhibition studies on compounds 15 and 16.
2-Benzyl-3-oxo-2,3-dihydro-1H-isoindole-5-carboxylic acid
(28). Synthesised as described in general procedure 2 from
24 (0.20 g, 0.70 mmol), and 2.0 mL TEA:TfOH to afford
2-benzyl-3-oxo-2,3-dihydro-1H-isoindole-5-carboxylic
acid
(0.18 g, 96%) as an off-white solid (m.p. 164–165 ◦C).
Notes and references
1H NMR (300 MHz) (DMSO-d6): d 8.13 (1 H, d, J =
6.7 Hz), 7.85 (1 H, d, J = 6.7 Hz), 7.78 (1 H, t, J = 6.7 Hz),
7.37–7.30 (5 H, m), 4.84 (2 H, s), 4.60 (2 H, s); 13C NMR
(75 MHz) (DMSO-d6): d 168.9, 164.8, 143.1, 135.9, 132.3, 131.7,
128.7, 128.3, 127.9, 127.8, 127.7, 50.8, 46.3; MS (ESI+) m/z
268 (M + 1, 100%); HRMS (ESI+) for C16H14NO3, calculated
268.0895, found 268.0891.
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1006 | Green Chem., 2010, 12, 1000–1006
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©