A green approach for the regio- and stereo-selective syntheses of (Z)-3-methyleneisoindoline-1-ones in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2013.05.004

A high yielding novel methodology was developed for the regio- and stereo-selective syntheses of (Z)-3-methyleneisoindoline-1-ones from substituted 2-phenylethynyl benzamides, generated in situ from 2-(phenylcarbamoyl)phenyl-1- H-imidazole-1-sulfonates and corresponding alkyne by Cu-free Sonogashira cross-coupling-5-exo-dig-cyclization in aqueous medium under sonication. The compound could easily be purified by recrystallization from EtOAc without column chromatography.

Full text of DOI:10.1016/j.tetlet.2013.05.004

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A green approach for the regio- and stereo-selective syntheses of
(Z)-3-methyleneisoindoline-1-ones in aqueous medium
⇑
Nivedita Chatterjee, Swarbhanu Sarkar, Rammyani Pal, Asish Kumar Sen
Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A high yielding novel methodology was developed for the regio- and stereo-selective syntheses of (Z)-3-
methyleneisoindoline-1-ones from substituted 2-phenylethynyl benzamides, generated in situ from 2-
(phenylcarbamoyl)phenyl-1-H-imidazole-1-sulfonates and corresponding alkyne by Cu-free Sonogashira
cross-coupling–5-exo-dig-cyclization in aqueous medium under sonication. The compound could easily
be purified by recrystallization from EtOAc without column chromatography.
Received 1 April 2013
Revised 29 April 2013
Accepted 1 May 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
(Z)-3-Methyleneisoindoline-1-one
Cu-free Sonogashira
2-(Phenylcarbamoyl)phenyl-1-H-
imidazole-1-sulfonates
5-Exo-dig cyclization
Sonication
Aqueous medium
Non-conventional chemistry appears to put forward important
possibilities in the arsenal of environmentally friendly synthetic
methods,1 particularly in connection with the emerging concept
of ‘Green Chemistry’. Among the different technologies, the applica-
tion of water as solvent in organic syntheses and in homogeneous
transition-metal catalyzed reactions has been progressively grow-
ing.2,3 Also, in recent time, interest is growing for the syntheses of
biologically important compounds using sonochemical processes.4
Therefore, syntheses of pharmacophores in aqueous environment
under sonication are a useful alternative.
3-Methyleneisoindolin-1-one is a biologically significant scaf-
fold and is present in a number of natural products and pharmaco-
logically interesting compounds like aristolactam alkaloids,5
fumaridine,6 lennoxamine,7 AKS 186,8 pictonamine,9 pazinaclone.10
Few isoindolinone derivatives also have potent metabotropic gluta-
mate receptor-1 antagonist activity,11 anti-viral,12 anti-leukemic,13
and anti-hypertensive14 activities. It is also a key intermediate in
the total synthesis of lennoxamine. The varied biological activities
of isoindolinone derivatives, have attracted the attention of organic
chemists, and a number of synthetic methodologies have been
developed.15–23 However, these methods have drawbacks24,25 like
low yield, requirement of long reaction time, use of phase transfer
catalyst, hazardous chemicals or external additives.
efficient catalysts for these heteroannulation reactions. Copper-
free Sonogashira cross coupling reactions,25a,26,27 using a combina-
tion of a phosphine ligand or an amine with tetra-butyl ammonium
salts as activator under strict anhydrous reaction conditions served
as suitable alternative. We investigated a fast, efficient yet simple
and green protocol in aqueous medium where domino Sonogash-
ira-5-endo-dig-cyclization reaction was applied for the complete
regio- and stereo-selective synthesis of (Z)-3-methyleneisoindo-
lin-1-one. Generally aryl or alkenyl halides are used as an electro-
philic partner in the Sonogashira reaction. However, oxygen based
electrophiles, owing to their high stability and easy accessibility
through functional group interconversion from readily available
hydroxylated compounds, have attracted attention in recent times.
Our method allows the domino Sonogashira-cyclization of oxygen-
ated electrophilic compounds (7a) and terminal alkynes in water
under sonication using GUAPHOS (1) as ligand (Fig. 1). This meth-
odology not only eliminates the use of copper, high reaction tem-
perature or use of toxic solvents but also do not require any
involvement of quaternary ammonium salts as activator. A library
of (Z)-3-methyleneisoindolin-1-ones could thus be synthesized in
high yield and in short reaction time. The uniqueness of this meth-
odology lies in its environment-friendly operation, short reaction
time, and excellent yield.
Palladium(II) salts, having bidentate N,N- or N,P-ligands in the
presence of amines and copper(I) have been established to be
Systematic studies of the reaction conditions in DMF in the
presence of different palladium catalysts with copper(I) iodide as
co-catalyst and various organic or inorganic bases had been carried
out earlier with poor to moderate yield.23b Therefore, there is
ample scope for the development of new methodologies. We
⇑
Corresponding author. Tel.: +91 33 2499 5720; fax: +91 33 2473 5197.
E-mail addresses: asishksen@yahoo.com, aksen@iicb.res.in (A.K. Sen).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.004
Please cite this article in press as: Chatterjee, N.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.05.004

2
N. Chatterjee et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
Me2N
H
N
Effect of different ligands for the synthesis of 9a
P
Entrya
Ligands
Amount (mol %)
Time (h)
Yieldb (%)
ClH2N
PCy2
OMe
NaO3S
P
MeO
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
3
4
5
6
1.5
2.0
2.5
3.0
3.5
3.0
3.0
3.0
3.0
3.0
1
1
1
1
1
1
1
1
1
1
69
74
80
94
91
71
86
20
76
41
3
3
1
2
tBu
PPh2
Me
PPh2
O
P
P
O
NaO3S
NaO3S
tBu
10
3
Me
6
5
4
The bold values signify the best yields/results obtained.
a
Reactions were performed using 7a (10 mmol), alkyne 8a (10 mmol), PdCl2
(2 mol %), (iPr)2EtN (20 mmol) as base in water under sonication (50 °C) for 1 h.
Products were characterized by spectroscopic and analytical techniques.
Figure 1. Ligands used in the study.
b
Isolated yield (some losses during filtration were unavoidable in certain cases).
envisaged using substituted benzamides (7a–7e) to endow differ-
ent acetylenes (8a–8g) that could subsequently be used in a one-
pot, two-step synthesis of 3-methyleneisoindoline-1-ones. We
used 7a and phenylethyne 8a as model reactants and investigated
the feasibility of the copper-free Sonogashira coupling–cycloiso-
merization domino strategy under sonication in aqueous medium
at 50 °C using PdCl2 as only catalyst (Scheme 1).
Table 2
Effect of different bases for the synthesis of 9a
Entrya
Base
Amount (mol equiv)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Na2CO3
Cs2CO3
NaOAc
Et3N
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
1
1
1
1
1
1
1
1
34
43
56
82
84
81
94
92
The effect of different ligands28 was first investigated (Table 1).
Ligand 1 appeared to be the most efficient when employed in
3.0 mol % affording excellent yield of the product. However, among
the ligands, SPhos ligand 3 as well as ligand 2 and 5 were efficient
as they produce a notable yield of 86%, 71% and 76%, respectively
(Table 1, entry 7, 6, and 9). The use of sterically hindered phosphate
ligand 4, bidentate phosphate derived ligand 6 led to lower yields
(Table 1, entry 8 and 10). The effect of different bases, viz. DBU,
Et3N, NaOAc, KOtBu, (iPr)2EtN, piperidine, and Cs2CO3 was also
investigated (Table 2). (iPr)2EtN appeared to be the most effective
when employed in 2.0 mol equiv affording the product in maxi-
mum yield (Table 2, entry 7). It was concluded that organic bases
were better in comparison to inorganic bases. The effect of external
additives (e.g., NaCl, NaBr, etc.) was also investigated. However, no
significant change in yield was noticed (data not shown). It is
worth mentioning that use of other Pd-catalysts [PdCl2(phos-
phine)2, palladium(II) bathophenanthroline, Pd-C], under the same
reaction conditions gave poor to moderate yield.
To explore the scope and generality of this approach, reactions
with various aryl or aliphatic alkynes were attempted (Table 3).
The Sonogashira-5-exo-dig cyclomerization domino process was
found to be completely regio- and stereo-selective (only Z-isomer
was obtained in all cases) and products were obtained in high yield
in all cases. The reaction was best performed with 7a which gave
maximum yield of 94% with phenyl acetylene (Table 3, entry 1).
Another major advantage of this method is that no dimerized prod-
ucts, normally produced as side products during heteroannulation
reaction, were formed. The reaction was performed in aqueous
medium and the ligands used in this study were soluble in water.
DBU
DMAP
(iPr)2EtN
(iPr)2EtN
The bold values signify the best yields/results obtained.
a
Reactions were performed using 7a (10 mmol), alkyne 8a (10 mmol), PdCl2
(2 mol %), ligand 1 (3.0 mol %), in water under sonication (50 °C) for 1 h. Products
were characterized by spectroscopic and analytical techniques.
b
Isolated yield (some losses during filtration were unavoidable in certain cases).
Hence, compounds can be easily extracted with EtOAc and purified
by recrystallization and no column chromatography was required.
The one-pot reaction thus developed was found to be com-
pletely regio- and stereo-selective and only Z-isomer was obtained.
Neither the 6-membered ring via 6-endo-dig cyclization mode nor
products with E-stereo chemistry were obtained. In the 1H NMR
the olefinic proton (C-4 proton) appeared in the up field (dH
<7 ppm) due to the absence of the deshielding effect of the benzene
ring, indicating the Z-stereochemistry of the exo-cyclic double
bond. The chemical shift (dH) of the vinylic proton for Z-isomer
of 9a and 9i has earlier been reported in the range 6.8 ppm,23b,d,e
where as for E-isomer the signal appears at relatively lower field.30
The NMR of the synthesized compounds confirmed formation of
only Z-stereoisomer. Finally, single crystal X-ray analysis of prod-
uct 9a (CCDC 911875) confirmed the stereochemistry and struc-
ture of (Z)-3-benzylidene-N-(4-phenyl)isoindolin-1-one (9a)
simultaneously (Supplementary data).
Ar
H
O
O
O
X
8
PdCl2 (2.0 mol %)
N
R
R
N
H
R
N
H
Ligand (3.0 mol %),
(iPr)2EtN(20.0 mmol), H2O,
sonication, 50 oC
Ar
Ar
9a-9j
7a R = Ph, X = OSO2imidazol-1-yl
7bR = Ph, X = I
7c R = Ph, X = Br
7d R =m-F-benzyl, X = OSO2imidazol-1-yl
7e R = (CH2)3OCH3, X = OSO2imidazol-1-yl
Scheme 1. One-pot Sonogashira cross-coupling and subsequent intramolecular cyclization to generate 3-methyleisoindoline-1-ones in aqueous medium under sonication.
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N. Chatterjee et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 3
Reactions of 7a–e with terminal alkynes (8a–g) leading to isoindolinones (9a–j) in aqueous medium under sonication
Entrya
Amide
Acetylene
Product
Yieldb (%)
Ref.
O
Y
N
Z
Y
1
2
3
7a
7b
7c
8a Y = H
8a
8a
9a Y = H, Z = H
9a
9a
94
92
90
23b
23b
23b
O
N
F
9b
4
7d
8a
79
29
Ph
9b
O
N
OCH3
9c
5
7e
8b Y = OPh
78
—
9c
OPh
6
7
7a
7a
8c y = C5H11
8d Y = OPh
9d Y = C5H11, Z = OCH3
9e Y = OPh, Z = OCH3
91
92
—
—
O
N
OCH3
8e
9f
8
7a
CO2CH3
68
—
CO2CH3
9f
9
7a
7a
7a
7a
8f Y = NO2
8a
8a
9g Y = NO2, Z = OCH3
9h Y = H, Z = F
91
93
94
92
—
29
23b
23b
10
11
12
9i Y = H, Z = CH3
9j Y = OCH3, Z = H
8g Y = OCH3
a
Reactions were performed using 7a–e (10 mmol), alkynes 8a–g (10–20 mmol), PdCl2 (2 mol %), ligand 1 (3.0 mol %), (iPr)2EtN (20 mmol), water, under sonication (50 °C)
for 1 h. Products were characterized by spectroscopic and analytical techniques.
b
Isolated yield (some losses during filtration were unavoidable in certain cases).
In summary, we have demonstrated a Cu-free domino Sono-
gashira-cyclization reaction of aryl imidazol-1-yl-sulphonates with
aryl and alkyl substituted terminal alkynes using H2O as only sol-
vent for the synthesis of the isoindolinone31,32 scaffold. The green
reaction conditions (aqueous medium under sonication activation),
ease of product separation, and excellent yields of products, made
this protocol a useful one for the preparation of oxindoles.
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2013.05.004.
References and notes
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The authors express their gratitude to the Director, IICB for lab-
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this article can be found in the online version. Crystallographic data
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Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
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31. General procedure for the preparation of (Z)-3-methyleneisoindoline-1-ones (9a–
9j): A mixture of amide (7a–7e, 10 mmol) and alkyne [8a (10 mmol), 8b
(12 mmol), 8c (10 mmol), 8d (10 mmol), 8e (20 mmol), 8f (15 mmol), 8g
(18 mmol)] in water (15 mL) was sonicated in an ultrasonic bath in the
presence of PdCl2 (2 mol %), ligand 1 (3.0 mol %) and (iPr)2EtN (20 mmol) for
1 h at 50 °C. The compounds were then extracted with EtOAc (50 mL Â 2) and
washed thoroughly with water (20 mL Â 3). It was then dried over anhydrous
Na2SO4 and recrystalized (EtOAc). No chromatographic separation was
required.
32. Spectral data of (Z)-3-(4-phenoxybenzylidene)-2-(3-methoxypropyl)isoindolin-1-
one (9c): 1H NMR (CDCl3; 300 MHz): d = 1.48–1.57 (m, 2H), 3.05 (t, J = 6.45 Hz,
2H), 3.15 (s, 3H), 3.82 (t, J = 7.2 Hz, 2H), 6.74 (s, 1H), 7.04 (t, J = 7.5 Hz, 5H), 7.14
(t, J = 7.35, 1H), 7.30–7.39 (m, 3H), 7.48 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H),
7.74 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H) ppm; 13C NMR (CDCl3; 75 MHz):
d = 28.16, 38.64, 58.37, 69.96, 105.94, 118.23, 119.07, 119.18, 123.17, 123.61,
128.21, 128.86, 129.42, 129.81, 130.96, 131.82, 134.54, 138.27, 156.84,
168.69 ppm; HRMS (ESI): m/z calcd for C25H23NO3 [M+Na]+ 408.1576; found:
408.1571.
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