Syntheses of substituted 3-methyleneisoindolin-1-ones by a palladium-catalyzed sonogashira coupling-carbonylation-hydroamination sequence in phosphonium salt-based ionic liquids

Article abstract of DOI:10.1021/ol8021403

(Chemical Equation Presented) Two efficient approaches for the synthesis of isoindolin-1-one derivatives in phosphonium salt ionic liquids are described. The palladium-catalyzed carbonylation-hydroamination reaction of 1-halo-2-alkynylbenzene with amines

Full text of DOI:10.1021/ol8021403

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5281-5284
Syntheses of Substituted
3-Methyleneisoindolin-1-ones By a
Palladium-Catalyzed Sonogashira
Coupling-Carbonylation-Hydroamination
Sequence in Phosphonium Salt-Based
Ionic liquids
Hong Cao, Laura McNamee, and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
howard.alper@uottawa.cas
Received September 15, 2008
ABSTRACT
Two efficient approaches for the synthesis of isoindolin-1-one derivatives in phosphonium salt ionic liquids are described. The palladium-
catalyzed carbonylation-hydroamination reaction of 1-halo-2-alkynylbenzene with amines afforded the substituted 3-methyleneisoindolin-1-
ones in good yields and high selectivities in favor of the Z-isomers. The target molecules could also be synthesized by the Sonogashira
coupling-carbonylation-hydroamination one-pot reaction of dihalides, alkynes, and amines. Both processes can be conducted under mild
conditions and tolerate a wide array of functionalized substrates.
Substituted 3-methyleneisoindolin-1-ones constitute an im-
portant part of a number of naturally occurring compounds,
such as, magallanesine,1 an isoindolobenzazocine that has
been isolated from various Berberis species, enterocarpam
II,2 a member of the aristolactam alkaloids family, and the
secophthalide-isoquinoline ene-lactam fumaridine.3 They are
also found as the key structural feature of biologically active
compounds such as AKS186, which displays vasorelaxant
properties,4 and the 4-acetoxyphenylmethyleneisoindolin-1-
one derivative whose hydrochloride was claimed to exhibit
local anesthetic activity superior to that of procaine.5
Therefore, the synthesis of substituted 3-methyleneisoindolin-
1-ones has generated considerable interest over the past
several decades.6-9
metal complexes as catalysts, has resulted in some effective
and easily separable catalytic systems that were successfully
used for carbonylation reactions.10,11 Most ionic liquids
research has been conducted in nitrogen-based solvents.12
Although beneficial in many cases, ammonium ionic liquids
have been shown to degrade under strong base and sonication
conditions.13 Aromatic rings, part of many N-based ionic
liquids, are also susceptible to aromatic substitution reactions,
which can limit their scope of application.14 For these
reasons, researchers began to focus on developing processes
in phosphonium salt-based ionic liquids (PSILs). When
compared to their ammonium counterparts, PSILs display
increased stability toward thermal and chemical degradation,
making them ideal for use at high temperatures, or in
processes in which the products can be removed by distil-
lation.15 PSILs are also nonvolatile, economical, and avail-
Recently, the combination of task-specific ionic liquids
(TSILs) as versatile and novel reaction media, with transition
10.1021/ol8021403 CCC: $40.75
Published on Web 10/25/2008
2008 American Chemical Society

able on an industrial scale. In the past several years, McNulty
and other groups investigated the application of PSILs in
general, and specifically for palladium-catalyzed processes.16
Our own group has recently reported an efficient application
of PSILs for palladium-catalyzed thiocarbonylation reac-
tions.17
Inspired by our previous research about palladium-
catalyzed carbonylation reactions to synthesize heterocyclic
compounds,18 and aiming to explore the unique capabilities
of PSILs, we designed a simple route to synthesize the
substituted 3-methyleneisoindolin-1-ones. This route includes
carbonylation and intramolecular hydroamination reactions
of an amine and 1-halo-2-alkynylbenzenes in phosphonium
salt ionic liquids. Herein, we report the results obtained from
this investigation and also an alternative synthesis of 3-
methyleneisoindolin-1-ones through a Sonogashira coupling
-carbonylation-hydroamination one-pot approach (Scheme
1).
the ionic liquid also showed better efficiency in the reaction
when compared to THF. By using Pd(OAc)2 as the catalyst
but no added ligand, there was no reaction in THF (Table 1,
entry 3), and with PdCl2(PPh3)2 in THF, the reaction did
occur, but the yield here is lower than those obtained with
ionic liquids (Table 1, entry 11). These results demonstrated
that ionic liquids may not only play the role of reaction
media, but also participate in the reaction as a promoter
ligand.
Table 1. Optimization of Palladium-Catalyzed
Carbonylation-Hydroamination Reaction between
1-Bromo-2-(phenylethynyl)benzene and Benzylaminea
temp
(°C)
CO
(psi)
yieldc
(%)
entry
catalyst
solventb
base
Scheme 1
.
Multistep and One-Pot Synthesis for the Substituted
3-Methyleneisoindolin-1-one
1
2
3
4
Pd(OAc)2/dppb [P+][Br-] Cs2CO3
110
110
110
110
200
200
200
200
46
62
NR
43
Pd(OAc)2
[P+][Br-] Cs2CO3
Pd(OAc)2
THF
Cs2CO3
PdCl2
[P+][Br-] Cs2CO3
Pd2(dba)3,
5
6
CHCl3
[P+][Br-] Cs2CO3
[P+][Br-] Cs2CO3
[P+][Br-] Cs2CO3
[P+][Br-] DBU
[P+][Br-] TEA
[P+][Br-] DBU
110
110
60
110
110
110
110
200
200
200
200
200
1 atm
200
73
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
82
7
NR
84
NT
84
42
8
9
10
11
THF
DBU
In the initial screening, a range of PSILs consisting of the
trihexyl(tetradecyl)phosphonium cation with a range of
common anions were screened for the carbonylation and
intramolecular hydroamination reaction of 1-bromo-2-(phe-
nylethynyl)benzene 1a and benzylamine 2a. The reactions
were conducted under 200 psi of CO, 110 °C, with Pd(OAc)2/
dppb as the catalyst system and Cs2CO3 as the base. The
results reveal that bromide-containing media shows the
greatest efficiency for the reaction, and furnished the target
product 2-benzyl-3-benzylideneisoindolin-1-one 3a in 46%
isolated yield, while the chloride analogue gave the product
in 30% yield. Both reactions provided Z-isomers as the main
a Reaction conditions: 1 (1 mmol), 2 (3 mmol), bases (2 mmol), Pd
catalyst (0.05 mmol), PSIL (2.0 g), 18 h, 110 °C.
The study of the scope of this palladium-catalyzed
carbonylation-hydroamination reaction in the PSIL was
extended to a series of amines and 1-halo-2-alkynylben-
zene (Figure 1). Most of the amines employed in the
reaction showed good reactivities, and consistently pro-
vided the Z-isomer as the main product. Both of the
aromatic and the aliphatic amines were active in the
reactions, with 4-MeOC6H4CH2NH2 providing the best
product yield (92%). Under the same conditions, tert-
butylamine afforded lower yields of the target products
(41%), possibly because of the bulkiness of the tert-butyl
group. Regarding the 1-halo-2-alkynylbenzene, when the
triple bond was substituted with an aromatic ring, the
reaction afforded better yields than substrates without such
substitution. Interestingly, with the 4-methoxylphenyl
group as a substituent of the triple bond, the substrate
was reactive and the desired product was isolated in 82%
yield. As expected, 1-iodo-2-(phenylethynyl)benzene also
gave the product in high yield (88%).
-
products (Z/E ) 96:4). The ionic liquids with [NTf2 ] and
-
[PF6 ] as anions were not effective. The superiority of the
bromide-containing media shown in this reaction is consistent
with the research reported on carbonylation of arene halides
and nucleophiles in PSILs.16
Further optimization of the reaction conditions is shown
in Table 1. We found that in the ionic liquid [P+][Br-], the
Pd(0) catalysis systems such as Pd(OAc)/dppb and
Pd2(dba)3·CHCl3 were both useful in catalyzing the reaction
and provided the product in 46% and 73% yields, respec-
tively (Table 1, entries 1 and 5). Surprisingly, without any
ligand, both Pd(OAc)2 and PdCl2 could also catalyze the
reaction and provide the desired products in 62% and 43%
yields, respectively (Table 1, entries 2 and 4). Without
addition of any extra ligand, PdCl2(PPh3)2 was found to be
the best catalyst for the reaction by furnishing 3a in 84%
yield, under 1 atm of CO, with DBU as base. In this study,
Since similar catalyst systems were employed for the
preparation of the starting material, 1-halo-2-alkynylbenzene,
and for the synthesis of the substituted 3-methyleneisoin-
dolin-1-ones, we wondered whether one could directly access
the products in a one-pot fashion. Therefore, we attempted
the reaction of 1-bromo-2-iodobenzene, phenylacetylene, and
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Org. Lett., Vol. 10, No. 22, 2008

Figure 2. Substrates scope of the one-pot protocol of amine, arene
dihalides, and alkynes. Reaction conditions: arene dihalides (1
mmol), alkyne (1.2 mmol), amine (3 mmol), bases (2 mmol), Pd
catalyst (0.05 mmol), PSIL (2.0 g), 1 atm of CO, 36 h, 110 °C.
Figure 1. Substrates scope of the palladium-catalyzed hydroami-
nation-carbonylation reaction. Reaction conditions: 1a (1 mmol),
2a (3 mmol), bases (2 mmol), Pd catalyst (0.05 mmol), PSIL (2.0
b
g) or THF (5 mL), 18 h, 110 °C. [P+] ) (C6H13)3P+(CH2)13CH3.
cIsolated yields.
the Sonogashira coupling reaction, then the 1-halo-2-alky-
nylbenzenes may go through either path a or b. Path a
involves oxidative addition of PdLn to the C-Br bond,
followed by carbonyl insertion into the Pd-C bond. Attack
of the amine followed by reductive elimination of Pd(0)
would give rise to the amide. Intramolecular hydroamination
of the triple bond, followed by reductive elimination of Pd(0)
results in the formation of the substituted 3-methyleneisoin-
dolin-1-one. The reaction may alternatively proceed via path
b, i.e., Pd(0) coordination to the triple bond, followed by
hydroamination, then carbonyl insertion of the latter, fol-
lowed by intramolecular attack of the NH group, and
reductive elimination of Pd(0) would lead to the desired
products. On the basis of the result of the reaction of
1-chloro-2-iodobenzene, which gave the Sonogashira cou-
pling product as the only product, we think it is more likely
that the reaction would go through path a, as we would
benzylamine with PdCl2(PPh3)2/CuI as the catalyst, DBU as
the base, and [P+][Br-] as solvent, under 1 atm of CO, at
110 °C. We were delighted to obtain the heterocycle in 94%
yield (Scheme 2).
Scheme 2. One-Pot Sonogashira
Coupling-Carbonylation-Intramolecular Hydroamination
Reaction
Scheme 3. Possible Mechanisms for the Sonogashira
Coupling-Carbonylation-Intramolecular Hydroamination
One-Pot Reactions of Amine, Arene Dihalides, and Alkynes
We explored this one-pot protocol by reacting various
amines with alkynes and arene dihalides. The results are
presented in Figure 2. The results indicate that the
PdCl2(PPh3)2/CuI/DBU catalyst system could be success-
fully employed for the one-pot synthesis of a range of
3-methyleneisolindolin-1-ones. All processes were highly
stereoselective, and gave the Z-isomer as the main product.
When different arene dihalides were employed, the 1,2-
diiodobenzene efficiently provided the isoindolin-1-one
derivative in 85% yield, whereas with the 1-chloro-2-
iodobenzene the reaction stopped at the first step and gave
the Sonogashira coupling product as the only isolated
product.
Two pathways can be considered as possible mechanisms
for this reaction (Scheme 3). The first step is likely to be
Org. Lett., Vol. 10, No. 22, 2008
5283

otherwise anticipate the isolation of the hydroamination
product after the Sonogashira coupling reaction.
the target products in high stereoselectivity and good yields.
The application of this reaction for the synthesis of natural
and bioactive compounds is under investigation currently in
our laboratory.
In conclusion, we have developed two effective methods
for the synthesis of substituted 3-methyleneisoindoline-1-
one derivatives under mild conditions. This protocol is based
on a sequential use of Sonogashira coupling, carbonylation,
and hydroamination chemistry. This one-pot protocol gave
Acknowledgment. We are indebted to Cytec Canada Inc.
and NSERC for financial support of this work.
Supporting Information Available: Full experiment
details, characterization for all compounds, and copies of
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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