Synthesis and reactivity of the 3-substituted isoindolinone framework to assemble highly functionalized related structures

Article abstract of DOI:10.1002/ejoc.201200678

An efficient potassium carbonate-catalyzed synthesis of 3-substituted isoindolinones through tandem aldol/cyclization reactions of active methylene compounds with 2-cyanobenzaldehyde is described. The utility of the obtained isoindolinones has been demons

Full text of DOI:10.1002/ejoc.201200678

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FULL PAPER
DOI: 10.1002/ejoc.201200678
Synthesis and Reactivity of the 3-Substituted Isoindolinone Framework to
Assemble Highly Functionalized Related Structures
Carmen Petronzi,[a] Selene Collarile,[b] Gianluca Croce,[c] Rosanna Filosa,[b]
Paolo De Caprariis,[b] Antonella Peduto,[b] Laura Palombi,[a] Valentina Intintoli,[a]
Antonia Di Mola,[b] and Antonio Massa*[a]
Keywords: Synthetic methods / Domino reactions / Aldol reactions / Nitrogen heterocycles
An efficient potassium carbonate-catalyzed synthesis of 3-
substituted isoindolinones through tandem aldol/cyclization
reactions of active methylene compounds with 2-cyanobenz-
aldehyde is described. The utility of the obtained isoindol-
inones has been demonstrated through an exploration of the
chemical space by employing a series of interesting method-
ologies that led to diverse, highly functionalized compounds.
Among them,
a surprisingly straightforward potassium
carbonate-catalyzed double tandem reaction led to tricyclic
hemiaminal derivatives.
Introduction
Isoindolinones are interesting heterocyclic compounds
due to their presence in many naturally occurring sub-
stances (Figure 1)[1a,1b] and because of their extensive use
in therapeutic activities[1–4] such as antihypertensive,[1c]
antipsychotic[1d–1f] anesthetic,[1g,1h] anxiolytic,[1i] antivi-
ral,[1j–1l] and antileukemic[1m] agents. In particular, some ex-
amples of biologically active compounds of general formula
I that possess anxiolytic, sedative, hypnotic, and muscle re-
laxant activity, are described in Figure 2.[1n] Therefore,
much attention has been devoted to the development of
new methods for the synthesis of 3-substituted isoindol-
inones, which constitute valuable scaffolds in many syn-
thetic routes.[2,3] However, in spite of the considerable inter-
est in the field, construction of this heterocyclic core often
requires the use of metal catalysts and/or inflexible
multistep syntheses.[1–3]
Figure 1. Some naturally occurring isoindolinone substances.
In this context, as part of our ongoing research on the
challenging aldol additions of active methylene com-
pounds,[4] we have recently reported a series of simple meth-
odologies for the synthesis of 3-substituted isoindol-
inones.[5–7] All these methods are based on the aldol reac-
tion of several classes of readily enolizable 1,3-dicarbonyl
compounds with 2-cyanobenzaldehyde in the presence of
triethylamine,[5] or by conveniently exploiting electroiniti-
ated[6] or organocatalyzed procedures.[7]
Figure 2. Some biologically active isoindolinone derivatives.
[a] Dipartimento di Chimica e Biologia, Università di Salerno,
Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
Fax: +39-089-969-603
Interestingly, based also on Ramström’s works,[8] it has
been demonstrated that these reactions proceed through a
tandem aldol addition/cyclization/rearrangement and a fi-
nal aza-Michael process (Scheme 1). In these studies we
have demonstrated that the intramolecular trapping of the
aldol adduct a is the key requisite that drives these difficult
reactions to completion due to the unstable nature of the
E-mail: amassa@unisa.it
[b] Dipartimento di Scienze Farmaceutiche, Università di Salerno,
Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
[c] DISIT – Università del Piemonte Orientale,
Viale T. Michel 11, 15121 Alessandria, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200678.
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Scheme 1.
aldol intermediates a.[4,5] All the tandem processes are pro- Table 1. Isoindolinone synthesis in the presence of Et3N.[a]
moted by weak bases, which both generate the nucleophilic
species and deprotonate the intermediate b.
Entry Nucleophile
(R)
Et3N
[equiv.]
t [h]
3
Yield [%][b]
The role of the base should not be underestimated and
some limitations have been highlighted in the course of
these studies:[5] (1) one equivalent of Et3N is usually re-
quired to guarantee reasonable reaction time and high
yields; (2) the steric hindrance of both the nucleophile and
the base affects the efficiency of the process. For these
reasons, considering the convenience of this approach, first
we decided to continue the investigation in an effort to over-
come these limitations and, at the same time, to develop a
more convenient synthesis of 3-substituted isoindolinones.
We then broadly tackled the second reactivity with the aim
of demonstrating the utility of these isoindolinones in the
synthesis of molecules with enhanced molecular diversity,
mimicking the structures of valuable compounds already re-
ported in literature. All these aspects are discussed in this
article.
1
2
3
4
Me
Me
tBu
(–)-menthyl
0.2
1.0
1.0
1.0
24
18
18
18
3a
3a
–
40
87
Ͻ 10
no reaction
–
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.33 mmol), Et3N in
CH2Cl2 (2.0 mL). [b] Isolated yield.
Scheme 2.
Based on these findings, we thought that the fine tuning
of both the basicity and the steric bulk of bases such as
K2CO3 could lead to more satisfactory results. In fact,
stronger bases can give side reactions, such as Knoevenagel
condensation, whereas weaker bases are not able to depro-
tonate active methylene compounds. More hindered bases
Results and Discussion
2.1 A New Approach to a More Efficient Tandem Reaction
As anticipated in the previous section, the nature of the such as iPr2NEt were less reactive. Moreover, the use of
base plays an important role in the efficiency of the process K2CO3 has the added value of low cost, ready availability
in terms of catalyst loading and substrate scope (Table 1). and reduced environmental impact. Encouraged by these
In fact, as reported in Table 1, it can be seen that the use results and considering our recent findings on the synthesis
of triethylamine (0.2 equiv.) in dichloromethane (Scheme 2) of 3-substituted isobenzofuranones,[9] in preliminary experi-
led to only 40% yield after 24 h for the reaction of dimethyl ments performed with dimethyl malonate as model nucleo-
malonate, whereas one equivalent was necessary to obtain phile, we tried K2CO3 under different reaction conditions.
high yields (compare in Table 1, entries 1 and 2); moreover, First, a stoichiometric amount of base in dichloromethane
sterically hindered substrates such as di-tert-butyl malonate was used, which gave a low conversion (ca. 20%) in 24 h
and di-(–)-menthyl malonate proved to be almost com- reaction time. Thus, we decided to change the solvent to
pletely unreactive and the starting materials were recovered acetonitrile, which facilitated higher K2CO3 solubility. In
quantitatively after 18 h reaction (Table 1, entries 3 and 4). this way we were pleased to observe that even catalytic
2
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3-Substituted Isoindolinones
amounts of K2CO3 (0.2 equiv.) were particularly effective in easily obtained in high yields by amine displacement reac-
catalyzing the tandem reaction with a wide range of malon- tions with dimethyl malonate (see the Supporting Infor-
ates (Scheme 3, Table 2, entries 1–6). Sterically hindered mation for details). This choice of substrate was made be-
malonates, such as di-tert-butyl malonate and di-(–)-men- cause of the possibility of testing relatively unexplored
thyl malonate were also found to be particularly effective active methylene compounds and because, at the same time,
and, in both cases, high yields were obtained (Table 2, en- nitrogen-containing moieties could be introduced into the
tries 2 and 3, respectively).
isoindolinone scaffold, such as piperazines. These moieties
have particularly interesting properties and applications
also in combination with isoindolinone scaffolds.[3a,3b] Un-
der the optimized reaction conditions, we were pleased to
observe good to high yields of the final adducts also for
these nucleophiles (Table 3), albeit with rather low dia-
stereoselectivity, as previously reported with nonsymmetric
nucleophiles such as β-keto esters.[5]
Scheme 3.
Table 2. Isoindolinone synthesis employing a catalytic amount of
K2CO3 (0.2 equiv.).[a]
2.2 The Second Reactivity of 3-Substituted Isoindolinones
Entry
Nucleophile (R)
t [h]
3
Yield [%][b]
1
2
3
4
5
6
Me
tBu
(–)-menthyl
Et
iPr
Bn
10
30
18
18
18
18
3a
3b
3c
3d
3e
3f
96
A systematic investigation of the second reactivity of the
obtained isoindolinones was then conducted to demon-
strate the possibility of using these compounds in an effec-
tive synthesis of interesting, highly functionalized molecules
that could be suitable for a rational and extensive drug dis-
covery programme. In this investigation, following the Di-
verse Oriented Synthesis (DOS) approach,[10] we explored
the chemical space of isoindolinones reactivity by consider-
ing a sequence of two or three organic transformations to
enlarge the molecular diversity.[11]
88
75 (1:1)[c]
92
93
89
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.33 mmol), K2CO3
(0.06 mmol), MeCN (0.5 mL). [b] Isolated yield. [c] Diastereomeric
ratio was calculated on the basis of 1H NMR spectroscopic analysis
of the crude product.
The catalytic role of K2CO3 is evident considering the
last two steps of the mechanism depicted in Scheme 1. The
iminophthalane intermediate b is subjected to base depro-
tonation to give c, whereas after aza-Michael addition, the
enolate form of 3 is protonated to again give the base, which
can start another catalytic cycle.
2.2.1 Decarboxylation Reactions
First, we considered the possibility of decarboxylation of
the methyl ester derivatives because, in this way, for exam-
On the basis of these results, we then focused our investi- ple, analogues of water-soluble sedative-hypnotic agents can
gation on malonoamide methyl ester derivatives, which are be conveniently obtained from the diastereomeric mixtures
Table 3. Isoindolinone synthesis in the presence of K2CO3.[a]
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.33 mmol), K2CO3 (0.06 mmol), MeCN (0.5 mL). [b] Isolated yield. [c] Diastereomeric ratios
1
were calculated on the basis of H NMR spectroscopic analysis of the crude product.
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of 3g–i (Table 4).[3a,3b] In this investigation we tried a modi- conditions. In fact this mild procedure is reported to work
fication of the known mild methodology developed by on large amounts of substrate.[12] For this reason, the
Krapcho and co-workers,[12] which employs LiCl/water/ DMF/H2O ratio was increased to 5 v/v, which was found
N,N-dimethylformamide (DMF) mixtures. However, by em- to be particularly effective and gave the desired products in
ploying the original procedure in the presence of only high yields also for low amounts of substrate (Scheme 4),
1.0 equiv. water,[12] this method did not give any reaction and in the presence of other functional groups such as pip-
because the limited amount did not allow satisfactory reflux erazines and amides.
Table 4. LiCl/H2O-promoted decarboxylation.[a]
Scheme 4.
2.2.2 NH Arylation
Another important feature for the rational design of new
isoindolinone-based libraries is related to the possibility of
obtaining N-arylated and N-alkylated products in addition
to NH-free compounds. This is relevant for the evaluation
of the biological activity, as reported in many medicinal
chemistry studies,[3a,3b] even if the described synthetic meth-
odologies often focus on limited or particular classes of
compounds. Thus, we tested the well-known copper-cata-
lyzed amidation of aryl halides developed by Buchwald and
co-workers[13] on the decarboxylated substrates 4a,c,d as
well as on the dimethyl malonate derivative 3a, for compari-
son, and 2-iodopyridine as a model aryl compound
(Scheme 5).
Under the conditions described in Scheme 5 and Table 5,
complete conversion of 4a was not observed in the presence
of 5 mol-% CuI. Thus, an increase in the amount of catalyst
to 20 mol-% was necessary to achieve almost complete con-
version of the starting material, demonstrating the effective-
[a] Reaction conditions: 3a and 3g–i (0.14 mmol), LiCl
(0.54 mmol), H2O (0.4 mL), DMF (2.0 mL), reflux. [b] Isolated
yield.
Table 5. CuI-catalyzed NH arylation.[a]
[a] Reaction conditions: CuI (0.029 mmol), K3PO4 (0.292 mmol), A or B (0.058 mmol), 2-iodopyridine (0.175 mmol), 3-substituted iso-
indolinone (0.146 mmol), toluene (1 mL), under N2 atmosphere, 80 °C. [b] Isolated yield.
4
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3-Substituted Isoindolinones
Table 6. Alkylation reaction of 3a.
Entry K2CO3
[equiv.]
CH3I
[equiv.]
t [h] Yield 6 [%][a] Yield 7 [%][a]
1
2
1.5
2.5
1.0
2.5
1
18
61
41
3
58
[a] Isolated yield.
a longer reaction time increased the amount of 7 formed
(Table 6, entry 2), and allowed a range of products to be
obtained that were easily separable by chromatography,
simply by changing the reaction conditions.
2.2.4 Further Evaluation of the Reactivity at the Methine
Group: One-Pot Double Tandem Reactions
Scheme 5. CuI-catalyzed NH arylation.
The reactivity at the acidic methine moiety is an impor-
tant aspect of these isoindolinone derivatives that can en-
large enormously the molecular diversity of this class of
compounds. Thus, we investigated the Michael addition of
acroleine 8 on 3a in the presence of K2CO3. Interestingly,
under the conditions detailed in Scheme 7, we were pleased
to observe the formation of the tricyclic compound with
hemiaminal functionality 9 in high yields and with high dia-
stereoselectivity. This further reaction is clearly due to a
tandem process involving Michael addition followed by a
cyclization at the amide group. It is worth noting that a
similar tricyclic subunit is present in a non-nucleoside HIV-
1 reverse transcriptase inhibitor[3c] and can be considered
to be an analogue of indolizidine compounds.[2g]
ness of Buchwald’s procedure also with structurally com-
plex substrates. The use of two different ligands A and B
gave similar results, whereas 4c was found to be less reactive
and longer reaction times were necessary to obtain satisfac-
tory conversion. However, in all cases, only moderate to
good yields were obtained because of the tendency of the
products to decompose during chromatography (1H NMR
spectroscopic analysis of the crude reaction mixture did not
reveal significant formation of byproducts).
2.2.3 CH vs. NH Alkylation
We then analyzed the reactivity of the acidic methine
group with model alkylation reactions mainly because ob-
taining a quaternary carbon in 3a is not possible directly
through the reaction depicted in Scheme 1. The use of nu-
cleophiles such as dimethyl methylmalonate leads to imino-
phthlane intermediates b[5] (Scheme 1) and the lack of the
acidic CH proton does not allow subsequent base-catalyzed
rearrangement. A possibility to overcome this serious prob-
lem is given by the model reaction of Scheme 6, using
K2CO3 and CH3I.
Scheme 7.
Because this further process is also catalyzed by K2CO3,
we thought to combine the isoindolinone synthesis with the
Michael/cyclization tandem process, as shown in Scheme 8,
simply by adding acrolein after the complete formation of
Scheme 6. Alkylation reaction of 3a.
Under the conditions reported in Table 6, it can be the isoindolinone (detected by TLC analysis).
clearly seen that at short reaction time it is possible to ob- Remarkably, at the end of the entire one-pot, double tan-
tain the monoalkylated compound 6 with good selectively dem process, a high yield of 9 was observed. Furthermore,
and moderate yield, in a mixture with the starting material the procedure was highly diastereoselective, which provides
3a, and only 3% dialkylated 7 (Table 6, entry 1). Con- further opportunities to apply this simple chemistry, mainly
versely, the use of larger amounts of CH3I and K2CO3 and based on the use of K2CO3, to the selective synthesis of
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Scheme 8. One-pot double tandem reaction.
other members of this interesting class of compounds. The
relative configuration of 9 was found to be R,R (and S,S
for the respective enantiomer), which was established on the
basis of X-ray crystallographic analysis of single crystals
(Figure 3).
Experimental Section
General Remarks: All reactions were performed using commercially
available compounds without further purification. Column chro-
matographic purification of products was carried out using silica
gel 60 (70–230 mesh, Merck). NMR spectra were recorded with
Bruker DRX 400, 300, 250 spectrometers (400, 300, and 250 MHz
1
for H, and 100, 75, and 62.5 MHz for 13C) and with Varian AV-
300 or AV-400 spectrometers. Spectra were referenced to residual
CHCl3 (δ = 7.26 ppm for 1H; δ = 77.23 ppm for 13C); coupling
constants (J) are reported in Hz. Yields are given for isolated prod-
ucts showing one spot on a TLC plate and with no detectable impu-
rities in the NMR spectra. Mass spectral analyses were carried out
with an electrospray spectrometer (Waters 4 micro quadrupole).
Exact masses (HRMS) were recorded with a Bruker Daltonics
MicroTof spectrometer (samples in CH3OH as solvent). Elemental
analyses were performed with a FLASHEA 1112 series-Thermo
Scientific for CHNS-O apparatus.
General Procedure for the Synthesis of 3-Substituted Isoindolinones
3a–g: In a round-bottom flask, aldehyde 1 (0.3 mmol) was added to
a solution of malonate ester 2 (1.2 equiv., 0.33 mmol) and K2CO3
(0.2 equiv., 0.06 mmol) in acetonitrile (0.5 or 1.0 mL). After 18 h
(reaction monitored by TLC), the reaction was diluted with
CH2Cl2 (1 mL) and evaporated under reduced pressure to provide,
after purification by flash chromatography, the pure compounds 3.
Figure 3. Ortep structure of 9.
3. Conclusions
Compounds 3a,b and 3d–f are known and were characterized by
We have described an improved approach to the synthe- comparison with published data.[5,6]
sis of 3-substituted isoindolinones by employing a K2CO3-
catalyzed tandem aldol/cyclization/rearrangement reaction
Di-(–)-menthyl
2-(3-Oxo-2,3-dihydro-1H-isoindol-1-yl)malonate
(3c): Purified by chromatography (hexane/ethyl acetate, 8:2) as an
1
of 2-cyanobenzaldehyde with malonates and malonoamide oil; yield 75% (115 mg, 0.22 mmol); mixture of diastereomers. H
methyl esters. Unlike the reaction promoted by R3N,[5] this
NMR (300 MHz): δ = 7.88 (m, 1+1 H), 7.56–7.51 (m, 4 H), 7.47–
7.38 (m, 2 H), 6.80 (br. s, 1 H), 6.75 (br. s, 1 H), 5.21 (m, J =
9.0 Hz, 1+1 H), 4.90–4.79 (m, 2 H), 4.74 (dq, J = 3.0, 12.0 Hz, 2
H), 3.64 (d, J = 6.0 Hz, 1 H), 3.53 (d, J = 9.0 Hz, 1 H), 2.13 (m, 2
H), 2.09 (m, 2 H), 1.73–1.69 (m, 10 H), 1.41–1.38 (m, 4 H), 1.28–
1.25 (m, 3 H), 0.96–0.94 (m, 4 H), 0.92–080 (m, 7+7+20 H), 0.69–
new method also proved to be effective with hindered nu-
cleophiles and under catalytic conditions, giving the final
products in high yields. A systematic study of the second
reactivity highlighted the great flexibility of the approach
and allowed the synthesis of a wide range of diverse, highly
functionalized compounds by employing only a few syn-
thetic steps. This study also provided the opportunity to
develop new methods and to test and adapt well-known
procedures to generate highly functionalized substrates.
0.67 (m, 11 H) ppm. 13C NMR (100 MHz): δ = 171.2, 171.1, 168.6,
168.2, 167.9, 167.5, 145.2, 144.9, 135.5, 133.4, 133.1, 133.0, 130.3,
130.2, 125.4, 125.3, 124.8, 124.4, 77.8, 77.6, 61.6, 57.8, 57.4, 56.3,
56.2, 48.1, 48.0, 47.9, 42.0, 41.9, 41.6, 41.5, 35.3, 35.2, 32.7, 32.6,
32.5, 30.9, 27.2, 27.1, 26.9, 26.7, 24.4, 24.3, 24.2, 24.1, 23.3, 23.2,
6
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3-Substituted Isoindolinones
23.1, 22.2, 22.1 ppm. MS (ESI): m/z = 534.68 [M + Na+].
C31H45NO5 (511.70): calcd. C 72.76, H 8.86, N 2.74; found C
72.88, H 8.80, N 2.80.
N,N-Diisopropyl
(3-Oxo-2,3-dihydro-1H-isoindol-1-yl)acetamide
(4b): Purified by chromatography (chloroform/ethyl acetate, 7:3) as
a very viscous oil; yield 89% (34 mg, 0.12 mmol). 1H NMR
(400 MHz): δ = 7.85 (d, J = 7.5 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1
H), 7.47 (t, J = 7.5 Hz, 1 H), 7.43 (d, J = 7.4 Hz, 1 H), 7.01 (br. s,
1 H), 5.01 (dd, J = 2.4, 10.6 Hz, 1 H), 3.83 (hept, J = 6.9 Hz, 1
H), 3.52–3.45 (m, 1 H), 3.01 (dd, J = 2.9, 16.3 Hz, 1 H), 2.32 (dd,
J = 10.7, 16.3 Hz, 1 H), 1.41 (d, J = 6.7 Hz, 6 H), 1.20 (d, J =
6.7 Hz, 3 H), 1.13 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz):
δ = 171.0, 169.9, 147.9, 133.5, 132.9, 129.6, 125.3, 123.5, 54.7, 49.7,
47.2, 41.9, 22.0, 21.9, 21.8, 21.7 ppm. MS (ESI): m/z = 275.68 [M
+ H+]. C16H22N2O2 (274.36): calcd. C 70.04, H 8.08, N 10.21;
found C 70.16, H 8.00, N 10.29.
Methyl 2-(Diisopropylcarbamoyl)-2-(3-oxo-2,3-dihydro-1H-isoindol-
1-yl)acetate (3g): Purified by chromatography (hexane/ethyl acetate,
8:2) as an oil; yield 76% (75 mg, 0.23 mmol); mixture of dia-
stereomers. 1H NMR (300 MHz): δ = 7.86–7.82 (m, 1 H), 7.54–
7.45 (m, 4 H), 6.95 (br. s, 1 H, major diastereomer), 6.58 (br. s, 1
H, minor diastereomer), 5.38–5.34 (m, 1+1 H), 4.11 (hept, J =
9.0 Hz, 1 H), 3.87 (s, 3 H, minor diastereomer), 3.86–3.85 (m, 1
H), 3.72 (s, 3 H, major diastereomer), 3.65 (d, J = 9.0 Hz, 1 H),
3.51 (d, J = 9.0 Hz, 1 H), 3.42 (m, 1 H), 3.42 (m, 1 H), 1.53 (d, J
= 5.1 Hz, 6 H), 1.44–1.39 (m, 7 H), 1.11 (d, J = 5.1 Hz, 7 H), 0.96
(d, J = 4.8 Hz, 4 H) ppm. 13C NMR (100 MHz): δ = 171.1, 170.9,
169.9, 169.3, 166.3, 165.5, 145.9, 145.7, 133.4, 133.3, 133.2, 132.9,
130.1, 125.4, 125.2, 124.9, 124.2, 57.5, 57.4, 57.2, 56.1, 54.1, 54.1,
50.9, 50.4, 48.1, 47.9, 22.0, 21.9, 21.7, 21.5, 21.4, 21.3, 21.1,
21.0 ppm. MS (ESI): m/z = 333.35 [M + H+]. C18H24N2O4 (332.40):
calcd. C 65.04, H 7.28, N 8.43; found C 65.11, H 7.35, N 8.31.
3-{2-[4-(4-Fluorophenyl)piperazin-1-yl]-2-xoethyl}-2,3-dihydro-1H-
isoindol-1-one (4c): Purified by chromatography (ethyl acetate/hex-
ane 7:3) as a beige waxy solid; yield 89% (44 mg, 0.12 mmol). H
1
NMR (400 MHz): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 8.0 Hz,
1 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.49 (d, J = 7.4 Hz, 1 H), 7.00–6.95
(m, 2 H), 6.89–6.86 (m, 3 H), 5.04 (dd, J = 2.4, 10.3 Hz, 1 H),
3.88–3.83 (m, 2 H), 3.56 (t, J = 4.0 Hz, 2 H), 3.10–3.04 (m, 5 H),
2.43 (dd, J = 10.8, 16.4 Hz, 1 H) ppm. 13C NMR (100 MHz): δ =
171.0, 169.8, 148.7, 147.5, 133.3, 133.1, 129.8, 125.4, 123.5, 120.1,
120.0, 117.1, 116.9, 54.5, 51.9, 51.7, 46.6, 43.0, 40.2 ppm. MS
(ESI): m/z = 375.97 [M + Na+]. C20H20FN3O2 (353.39): calcd. C
67.97, H 5.70, N 11.89; found C 67.85, H 5.60, N 11.80.
Methyl 3-[4-(4-Fluorophenyl)piperazin-1-yl]-3-oxo-2-(3-oxo-2,3-di-
hydro-1H-isoindol-1-yl)propanoate (3h): Purified by chromatog-
raphy (chloroform/ethyl acetate, 9:1) as an oil; yield 90% (111 mg,
0.27 mmol); mixture of diastereomers. 1H NMR (300 MHz): δ =
7.82 (m, 1+1 H), 7.56–7.51 (m, 2+2 H), 7.49 (d, J = 6.0 Hz, 1 H),
7.39 (d, J = 6.0 Hz, 1 H), 7.29 (br. s, 1 H), 6.98–6.93 (m, 4 H),
6.85–6.81 (m, 4+1 H), 5.46 (d, J = 9.0 Hz, 1 H), 5.40 (d, J =
9.0 Hz, 1 H), 3.95–3.92 (m, 2 H), 3.86 (s, 3 H), 3.73 (s, 1 H), 3.65
(s, 3 H), 3.65–3.58 (m, 4 H), 3.52–3.45 (m, 2 H), 3.13 (m, 4 H),
2.99–2.88 (m, 4 H) ppm. 13C NMR (100 MHz): δ = 171.1, 171.0,
169.2, 168.8, 166.1, 165.5, 160.2, 157.8, 148.5, 148.4, 145.7, 145.4,
133.4, 133.3, 133.2, 130.3, 125.5, 125.4, 124.7, 124.2, 120.0, 119.9,
119.8, 117.1, 116.9, 57.0, 56.0, 54.4, 51.9, 51.7, 51.5, 47.6, 47.3,
43.8, 43.6 ppm. MS (ESI): m/z = 433.89 [M + Na+]. C22H22FN3O4
(411.43): calcd. C 64.22, H 5.39, N 10.21; found C 64.32, H 5.47,
N 10.29.
3-[2-(4-Methylpiperazin-1-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-
1-one (4d): Purified by chromatography (dichloromethane/meth-
anol, 9.5:0.5) as a beige waxy solid; yield 88% (34 mg, 0.12 mmol).
1H NMR (300 MHz): δ = 7.87 (d, J = 7.4 Hz, 1 H), 7.55 (t, J =
7.6 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H),
7.11 (br. s, 1 H), 5.01 (dd, J = 3.0, 9.0 Hz, 1 H), 3.78–3.72 (m, 1
H), 3.63–3.60 (m, 1 H), 3.41 (t, J = 6.0 Hz, 2 H), 3.03 (dd, J = 3.0,
15.0 Hz, 1 H), 2.42–2.38 (m, 5 H), 2.30 (s, 3 H) ppm. 13C NMR
(75 MHz): δ = 169.8, 168.4, 146.3, 132.1, 131.7, 128.4, 124.1, 122.2,
54.7, 54.5, 53.2, 45.9, 45.1, 41.6, 38.9 ppm. MS (ESI): m/z = 296.73
[M + Na+]. C15H19N3O2 (273.33): calcd. C 65.91, H 7.01, N 15.37;
found C 65.89, H 6.90, N 15.29.
Methyl 3-(4-Methylpiperazin-1-yl)-3-oxo-2-(3-oxo-2,3-dihydro-1H-
isoindol-1-yl)propanoate (3i): Purified by chromatography (chloro-
form/ethyl acetate, 9:1) as an oil; yield 93% (92 mg, 0.28 mmol);
General Procedure for Arylation of Isoindolinones 3a and 4a, 4c–d:
A Schlenk tube was charged with CuI (0.029 mmol) and K3PO4
(0.292 mmol), evacuated and backfilled with nitrogen. N,N-Di-
methylethylenediamine A or N-methylethylenediamine B
(0.058 mmol), 2-iodopyridine (0.175 mmol), and 3-substituted iso-
indolinones (0.146 mmol) dissolved in toluene (1 mL) were added
under a nitrogen atmosphere. The reaction mixture was heated at
80 °C for 18 or 24 h (reaction monitored by TLC). The resulting
pale-brown suspension was cooled to room temperature. After re-
moving the solvent, the residues were separated by chromatography
on silica gel to afford the desired compounds 5.
1
mixture of diastereomers. H NMR (400 MHz): δ = 7.83 (m, 1+1
H), 7.52–7.46 (m, 2+2 H), 7.34 (d, J = 7.1 Hz, 1 H), 7.27 (d, J =
1.9 Hz, 1 H), 7.14 (br. s, 1 H), 6.73 (br. s, 1 H), 5.40 (d, J = 9.6 Hz,
1 H), 5.34 (d, J = 8.2 Hz, 1 H, minor diastereomer), 3.84 (s, 3 H),
3.70 (s, 3 H), 3,62–3.52 (m, 3 H), 3.46–3.44 (m, 3 H), 3.33–3.29 (m,
1 H), 2.41 (m, 4 H), 2.35–2.33 (m, 3 H), 2.25 (s, 9 H), 2.19–2.17
(m, 1 H) ppm. 13C NMR (100 MHz): δ = 171.2, 171.0, 169.3, 168.8,
165.9, 165.4, 145.7, 145.4, 133.4, 133.3, 133.2, 130.2, 130.1, 125.4,
125.3, 124.7, 124.2, 57.0, 56.0, 55.9, 55.7, 55.6, 54.3, 47.5, 47.2,
47.1, 47.0, 43.7, 43.5 ppm. MS (ESI): m/z = 332.16 [M + H+].
C17H21N3O4 (331.37): calcd. C 61.62, H 6.39, N 12.68; found C
61.53, H 6.30, N 12.58.
Methyl 2-[1-Oxo-2-(pyridin-2-yl)isoindolin-3-yl]acetate (5a): Puri-
fied by chromatography (hexane/ethyl acetate, 5:5) as a waxy solid;
yield 65% (27 mg, 0.095 mmol). H NMR (300 MHz): δ = 8.58 (d,
1
General Procedure for Decarboxylation of 3-Substituted Isoindol-
inones: In a round-bottomed flask equipped with a magnetic bar
and water-cooled condenser, 3-substituted isoindolinones 3a and
3g–i (0.14 mmol), lithium chloride (0.54 mmol), water (0.4 mL),
and DMF (2.0 mL) were placed. The mixture was heated to reflux
with an oil bath and stirred for 5 h. After that time, the mixture
was cooled, diluted with CH2Cl2 (1 mL), and the solvent was evap-
orated under reduced pressure. The residue was purified by column
chromatography on silica gel to provide 4.
J = 6.0 Hz, 1 H), 8.45 (dd, J = 6.0, 3.9 Hz, 1 H), 7.93 (d, J =
6.0 Hz, 1 H), 7.76 (dt, J = 3.0, 6.0 Hz, 1 H), 7.64–7.49 (m, 3 H),
7.07 (dt, J = 3.0, 9.0 Hz, 1 H), 5.99 (dd, J = 3. 0, 9.0 Hz, 1 H),
3.67 (s, 3 H), 3.40 (dd, J = 3.0, 15 Hz, 1 H), 2.71 (dd, J = 9.0,
15.0 Hz, 1 H) ppm. 13C NMR (100 MHz): δ = 172.3, 168.7, 152.1,
148.9, 146.2, 139.2, 134.1, 133.0, 129.9, 125.5, 124.0, 120.8, 116.9,
57.7, 53.0, 39.3 ppm. MS (ESI): m/z = 283.74 [M + H+].
C16H14N2O3 (282.30): calcd. C 68.07, H 5.00, N 9.92; found C
68.18, H 5.13, N 9.85.
Compound 4a is known and was characterized by comparison with
Dimethyl 2-[1-Oxo-2-(pyridine-2yl)isoindolin-3-yl]malonate (5b):
Purified by chromatography (hexane/ethyl acetate, 5:5) as a waxy
published data.[5]
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A. Massa et al.
FULL PAPER
solid; yield 67% (34 mg, 0.099 mmol). 1H NMR (250 MHz): δ =
8.61 (d, J = 5.2 Hz, 1 H), 8.40 (dd, J = 5.0, 3.2 Hz, 1 H), 7.90 (d,
One-Pot Double Tandem Procedure for the Synthesis of 9: In a
round-bottom flask, aldehyde 1 (0.3 mmol) was added to a solution
J = 7.7 Hz, 1 H), 7.78 (m, 2 H), 7.62 (m, 1 H), 7.53 (d, J = 7.5 Hz, of malonate ester 2 (1.2 equiv., 0.33 mmol) and K2CO3 (0.2 equiv.,
1 H), 7.10 (t, J = 5.0 Hz, 1 H), 6.25 (d, J = 3.0 Hz, 1 H), 4.71 (d,
0.06 mmol) in acetonitrile (0.5 mL). After 18 h (reaction monitored
by TLC), acrolein 8 (1.5 equiv., 0.45 mmol) was added to the reac-
J = 3.0 Hz, 1 H), 3.88 (s, 3 H), 3.26 (s, 3 H) ppm. 13C NMR
(100 MHz): δ = 169.7, 168.8, 168.0, 151.8, 149.0, 143.1, 139.4, tion mixture. At the end of the reaction the solvent was evaporated
135.5, 134.0, 130.2, 125.6, 125.1, 120.9, 116.9, 59.3, 54.1, 53.9,
53.4 ppm. MS (ESI): m/z = 341.56 [M + H+]. C18H16N2O5 (340.33):
calcd. C 63.52, H 4.74, N 8.23; found C 63.64, H 4.83, N 8.31.
under reduced pressure to provide, after purification by flash
chromatography, pure 9; yield 88% (25 mg, 0.079 mmol).
Dimethyl
4-Hydroxy-6-oxo-3,4,6,10b-tetrahydropyrido[2,1-a]iso-
3-{2-[4-(4-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}-2-(pyridine-2-
yl)isoindolin-1-one (5c): Purified by chromatography (chloroform/
ethyl acetate, 9.5:0.5) as a waxy solid; yield 59 % (37 mg,
indole-1,1(2H)-dicarboxylate (9): White solid; single diastereoiso-
mer; m.p. 142–143 °C. H NMR (300 MHz): δ = 7.70–7.67 (m, 1
1
H), 7.30–7.40 (m, 3 H), 5.97 (m, 1 H), 5.17 (s, 1 H), 4.68 (m, 1 H),
1
3.87 (s, 3 H), 3.21 (s, 3 H), 2.45–2.42 (m, 2 H), 2.06–2.02 ppm. 13
C
0.086 mmol). H NMR (300 MHz): δ = 8.62 (d, J = 9.0 Hz, 1 H),
8.43 (d, J = 6.0 Hz, 1 H), 7.92 (d, J = 9.0 Hz, 1 H), 7.78–7.76 (m,
1 H),7.73–7.71 (m, 1 H), 7.61 (t, J = 6.0 Hz, 1 H), 7.54 (t, J =
6.0 Hz, 1 H), 7.10–7.06 (m, 1 H), 7.05–7.00 (m, 2 H), 6.97 (t, J =
9.0 Hz, 2 H), 6.13 (dd, J = 3.0, 6.0 Hz, 1 H), 3.89–3.84 (m, 2 H),
3.62–3.56 (m, 3 H), 3.12–3.09 (m, 2 H), 2.98–2.96 (m, 2 H), 2.47
(dd, J = 9.0, 15 Hz, 1 H) ppm. 13C NMR (100 MHz): δ = 169.8,
169.0, 152.3, 149.0, 147.0, 139.2, 134.2, 132.8, 129.8, 125.4, 125.1,
120.7, 119.9, 119.8, 117.1, 116.8, 116.7, 58.4, 52.0, 51.8, 46.8, 43.0,
38.8 ppm. MS (ESI): m/z = 431.78 [M + H+]. C25H23FN4O2
(430.48): calcd. C 69.75, H 5.39, N 13.02; found C 69.67, H 5.45,
N 13.18.
NMR (75 MHz): δ = 170.9, 167.7, 167.2, 143.4, 131.5, 131.2, 128.2,
124.1, 123.2, 69.8, 57.5, 56.7, 53.1, 52.0, 27.1, 26.6 ppm. MS (ESI):
m/z = 320.1 [M + H+]. C16H17NO6 (319.31): calcd. C 60.18, H 5.37,
N 4.39; found C 60.26, H 5.25, N 4.55.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data, cop-
ies of 1H and 13C NMR spectra for all the new compounds and
crystallographic data for compound 9.
3-[2-(4-Methylpiperazin-1-yl)-2-oxoethyl]-2-(pyridin-2-yl)iso-
indolin-1-one (5d): Purified by chromatography (dichloromethane/
methanol, 9.9:0.1) as a waxy solid; yield 69% (36 mg, 0.093 mmol).
1H NMR (300 MHz): δ = 8.59 (d, J = 6.0 Hz, 1 H), 8.42 (d, J =
6.0 Hz, 1 H), 7.91 (d, J = 6.0 Hz, 1 H), 7.79–7.69 (m, 2 H), 7.61
(t, J = 6.0 Hz, 1 H), 7.52–7.47 (m, 1 H), 7.09–7.05 (m, 1 H), 6.10
(dd, J = 3.0, 9.0 Hz, 1 H), 3.73 (m, 2 H), 3.53 (dd, J = 3.0, 15.0 Hz,
1 H), 3.46–3.40 (m, 2 H), 2.45–2.40 (m, 4 H), 2.39 (s, 4 H) ppm.
13C NMR (75 MHz): δ = 168.4, 167.6, 151.0, 147.7, 145.7, 137.9,
132.8, 131.4, 128.4, 124.0, 123.9, 119.3, 115.4, 57.1, 55.0, 54.6, 45.9,
45.3, 41.6, 37.4 ppm. MS (ESI): m/z = 351.46 [M + H+].
C20H22N4O2 (350.42): calcd. C 68.55, H 6.33, N 15.99; found C
68.44, H 6.42, N 15.87.
Acknowledgments
Financial support from the Ministero dell’Università e della
Ricerca (MIUR) (FARB 2011) is gratefully acknowledged.
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Procedure for Alkylation Reaction of 3a: To a solution of 3a
(0.190 mmol, 1.0 equiv.) and K2CO3 (0.285 mmol, 1.5 equiv. or
2.5 equiv.) in DMF (1.0 mL), iodomethane (0.190 mmol, 1.0 equiv.
or 2.5 equiv.) was added dropwise. The reaction was stirred at room
temperature for 1 h or 18 h, respectively. After this time, the reac-
tion mixture was diluted in ethyl acetate (2 mL) and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate, 7:3 to 5:5) to
give 6 (32 mg, 0.114 mmol, 61%, Table 6, entry 1) or both 6 and 7
(Table 6, entry 2) as waxy white solids.
Dimethyl 2-Methyl-2-(1-oxoisoindolin-3-yl)malonate (6): 1H NMR
(400 MHz): δ = 7.84 (d, J = 7.6 Hz, 1 H), 7.53–7.46 (m, 2 H), 7.13–
7.09 (m, 1 H), 5.35 (s, 1 H), 3.89 (s, 3 H), 3.78 (s, 3 H), 1.06 (s, 3
H) ppm. 13C NMR (100 MHz): δ = 172.8, 171.5, 171.2, 143.6,
134.07, 133.3, 130.2, 125.3, 124.1, 59.9, 58.5, 54.57, 54.3, 14.7 ppm.
MS (ESI): m/z = 278.10 [M + H+]. C14H15NO5 (277.28): calcd. C
60.64, H 5.45, N 5.05; found C 60.72, H 5.36, N 5.13.
Dimethyl 2-Methyl-2-(2-methyl-1-oxoisoindolin-3-yl)malonate (7):
1H NMR (400 MHz): δ = 7.84–7.82 (m, 1 H), 7.48–7.44 (m, 2 H),
7.22 (d, J = 5.6 Hz, 1 H), 5.49 (s, 1 H), 3.86 (s, 3 H), 3.83 (s, 3 H),
3.00 (s, 3 H), 0.96 (s, 3 H) ppm. 13C NMR (100 MHz): δ = 171.4,
171.0, 170.5, 142.9, 134.1, 132.9, 130.2, 124.9, 124.3, 66.1, 58.5,
54.5, 54.3, 30.4, 13.9 ppm. MS (ESI): m/z = 292.18 [M + H+].
C15H17NO5 (291.30): calcd. C 61.85, H 5.88, N 4.81; found C
61.91, H 5.73, N 4.68.
[2] Some recent examples of non-asymmetric metal-catalyzed iso-
indolinone synthesis, see: a) C. Zhu, J. R. Falck, Org. Lett.
8
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3-Substituted Isoindolinones
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Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 08-08-12 17:02:45
Pages: 10
A. Massa et al.
FULL PAPER
Nitrogen Heterocycles
C. Petronzi, S. Collarile, G. Croce,
R. Filosa, P. De Caprariis, A. Peduto,
L. Palombi, V. Intintoli, A. Di Mola,
A. Massa* ....................................... 1–10
Synthesis and Reactivity of the 3-Substi-
tuted Isoindolinone Framework to As-
semble Highly Functionalized Related
Structures
Keywords: Synthetic methods / Domino re-
actions / Aldol reactions / Nitrogen hetero-
cycles
Potassium carbonate efficiently catalyses
the synthesis of 3-substituted isoindol-
inones through a tandem aldol/cyclization/
rearrangement reaction. An exploration of
the chemical space of the obtained iso-
indolinones led to diverse, highly func-
tionalized compounds.
10
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