A ligand-free approach to substituted (Z)-3-methyleneisoindolin-1-ones via Cu (I) catalyzed regio- and stereo-selective assembly of 2-iodo benzamide and terminal alkyne

Article abstract of DOI:10.1080/00397911.2020.1753776

A ligand-free and cost-effective synthesis of substituted 3-methyleneisoindolin -1-ones from 2-iodobenzamide and terminal alkyne under copper (I)-catalyzed condition was accomplished. The reaction affords excellent yield of the product at a relatively low

Full text of DOI:10.1080/00397911.2020.1753776

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A ligand-free approach to substituted (Z)-3-
methyleneisoindolin-1-ones via Cu (I) catalyzed
regio- and stereo-selective assembly of 2-iodo
benzamide and terminal alkyne
Rimpa De & Mrinal K. Bera
To cite this article: Rimpa De & Mrinal K. Bera (2020): A ligand-free approach to
substituted (Z)-3-methyleneisoindolin-1-ones via Cu (I) catalyzed regio- and stereo-selective
assembly of 2-iodo benzamide and terminal alkyne, Synthetic Communications, DOI:
10.1080/00397911.2020.1753776
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1753776
A ligand-free approach to substituted (Z)-3-
methyleneisoindolin-1-ones via Cu (I) catalyzed regio- and
stereo-selective assembly of 2-iodo benzamide and
terminal alkyne
Rimpa De and Mrinal K. Bera
Department of Chemistry, Indian Institute of Engineering Science and Technology (IIEST), Howrah, India
ABSTRACT
ARTICLE HISTORY
Received 5 January 2020
A ligand-free and cost-effective synthesis of substituted 3-methyle-
neisoindolin -1-ones from 2-iodobenzamide and terminal alkyne
under copper (I)-catalyzed condition was accomplished. The reaction
affords excellent yield of the product at a relatively lower tempera-
ture and exclusive Z-selectivity was observed in the title compound.
By varying the substitution pattern on N-atom of benzamide or aro-
matic core of the alkyne system, a large array of substituted 3-meth-
yleneisoindolin-1-one derivatives could be accessed employing this
method.
KEYWORDS
Domino reaction; ligand
free; 3-methyleneisoindolin-
1-one; regio- and stereo-
selective cross coupling; Z-
selectivity
GRAPHICAL ABSTRACT
Introduction
Substituted 3-methyleneisoindolin-1-ones are important structural subunits frequently
encountered in naturally occurring substances and medicinally valuable compounds.
These natural products include different aristolactam alkaloids such as piperolactam,[1a]
lennoxamine (an isoindolobenzazepine alkaloid),[1b] pazinaclone,[1c] AKS 186 (a phenyl-
ethyledine derivative),[1d] fumaridine (a secophthalide isoquinoline lactam),[1e] magalla-
nesine (an isoindolobenzazocine alkaloid)[1f] to name a few. Some important natural
products and medicinally significant molecules decorated with 3-methyleneisoindolin-1-
CONTACT Mrinal K. Bera
mrinalkbera26@gmail.com
Department of Chemistry, Indian Institute of Engineering
Science and Technology (IIEST), Botanic Garden, Howrah 711103, India.
Supplemental data for this article is available online at https://doi.org/10.1080/00397911.2020.1753776
ß 2020 Taylor & Francis Group, LLC

2
R. DE AND M. K. BERA
Figure 1. Natural products and biologically important molecules embellished with 3-methyleneisoin-
dolin-1-one framework.
one structural backbone are listed in Figure 1. Apart from their diversified structural
features, substituted 3-methyleneisoindoline-1-one derivatives are also important from
the therapeutic point of view. Amongst various biological activities of 3-methyleneisoin-
dolin-1-one containing compounds, local anesthetic activity,[2] sedative activity,[3] anti-
viral,[4] anti-hypertensive,[5] and anti-leukemic[6] activities are worth mentioning. Some
3-methyleneisoindolin-1-one derivatives are also known to be useful for the treatment
of a psychotic disorder.[7] Apart from medicinal significance, different functionalized
materials are also synthesized from 3-methyleneisoindolin-1-one moiety and find appli-
cation in material chemistry.[8] Due to their diversified structural architecture and bio-
logical significance, a couple of total synthesis of isoindolin-1-one containing natural
products have been surfaced in the literature.[9,10a] As an obvious consequence, several
novel synthetic routes have been developed to construct the 3-methyleneisoindolin-1-
one core structure. Traditionally, 3-methyleneisoindolin-1-one was accessed via aryne
cyclization and Homer–Wadsworth–Emmons type reaction of o-(and m-)halogeno-N-
phosphoryl-methylbenzamide derivatives.[10b] 3-Methyleneisoindolin-1-one may also be
synthesized from phthalimide via photochemical reaction,[11a] electroreductive intermo-
lecular coupling of aldehyde,[11b] photodecarboxylative addition of carboxylates,[11c]
anionic cycloaromatization of 2-alkynylbenzonitrile.[12] Larock et al. demonstrated the
synthesis of isoindoline-1-one via electrophilic cyclization of preformed 2-alkynylbenza-
mide.[13] Electrophilic cyclization of hydrazides of 2-alkynylbenzoic acid led to the for-
mation of differently substituted 3-methyleneisoindolin-1-one derivatives.[14] However,
all the above-mentioned methods are associated with their own drawback such as poor
regioselectivity for unsymmetrical substrate, low yield, longer reaction time, extra syn-
thetic steps, etc. To overcome these shortcomings, transition metal-mediated coupling
reactions have emerged as an efficient tool for the synthesis of title compounds. Alper
et
al.
developed
palladium-catalyzed
Sonogashira
coupling-carbonylation-

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SYNTHETIC COMMUNICATIONSV
3
hydroamination reaction sequence to afford 3-methyleneisoindolin-1-one derivatives.[15]
Cossy and coworkers demonstrated that 3-methyleneisoindolin-1-one derivative could
be
synthesized
from
ynamides
and
boronic
acids
via
Pd-catalyzed
Heck–Suzuki–Miyaura domino reaction.[16]
Apart from Alper and Cossy’s work, there are many more examples of Palladium
promoted synthesis of 3-methyleneisoindolin-1-one under diversified reaction condi-
tions including sonochemical condition, microwave condition and even in an aqueous
micellar medium.[17a–j]
Another elegant strategy toward 3-methyleneisoindolin-1-one was developed by
Lee[18a] and Patel[18b] via decarboxylative cross-coupling of 2-halobenzamide and aryl
alkynyl acids under Cu-catalyzed condition. Cu (II) mediated oxidative alkynylation and
intramolecular annulation is another prominent entry to 3-methyleneisoindolin-1-one
synthesis by You et al.[19] However the substrate scope of arene was restricted to N-
(quinolin-8-yl) benzamide only. Another Cu (II) catalyzed, ligand assisted synthesis of
the title compound was reported by Zeng et al.[20a] though the reaction time was suffi-
ciently prolonged. Recently Surya Praksh and his coworkers[20b] reported a Cu (I) cata-
lyzed tandem desilylation-hydroamination strategy for the synthesis of isoindoline.
Though, the method required higher temperatures and costly starting materials. Other
noteworthy copper-catalyzed methods offering 3-methyleneisoindolin-1-one derivatives
were reported by Phukan,[20c] Yao,[20d] and Kumar[20e] with their own merits and draw-
backs. Though many metal-free and transition metal-catalyzed methods are already
known to access 3-methyleneisoindolin-1-one derivatives, issues like regioselectivity
(5-Exo vs 6-endo cyclization) and chemoselectivity (due to nucleophilicity of O- and N-
atom of amide moiety) are not fully resolved. In fact, a mixture of compounds was
obtained in several cases due to regio- and chemoselectivity issues.[21] Herein, we report
a copper(I) promoted, ligand-free approach to access (Z)-3-methyleneisoindolin-1-one
derivatives with complete regio- and stereo-selectivity.
Results and discussion
Transition metal-catalyzed approaches toward 3-methyleneisoindolin-1-one are mainly
restricted to palladium and copper. And more commonly, a suitable ligand or additives
were used in all the methods reported earlier. According to the reported literature, a
plausible mechanism of this domino reaction (Described in Scheme 1) consisted of
Sonogashira cross-coupling between 2-halobenzamide and terminal alkyne or alkynyl
acid (via copper (l)-acetylide intermediate A, oxidative addition B, and reductive elimin-
ation C), followed by base mediated amide deprotonation. Finally, nucleophilic attacks
of amide anion D on transition metal-alkyne complex complete the intramolecular cyc-
lization to afford 3-methyleneisoindolin-1-one derivatives. Though, a variety of ligands
such as L-proline, N,N-dimethylglycine, pipecolinic acid, 2-picolinic acid, 1,10-phenan-
threne, TMEDA, DMEDA, SPhos, XantPhos, and other phosphine based ligands have
been used in different transition metal assisted approaches, the evidence for the benefi-
cial effect of ligands are not mentioned elsewhere. We anticipated that this domino
reaction may proceed equally well without using any ligand or additive if we start with
the iodoarene substrate. Iodide might play a dual role as Sonogashira coupling partner

4
R. DE AND M. K. BERA
Scheme 1. Plausible mechanism of the formation of 3-methyleneisoindole-1-one derivatives under lig-
and-free conditions.
as well as a ligand in the catalytic cycle as shown in Scheme 1. Therefore we chose 2-
iodobenzamide 1 and phenylacetylene 2 as our model substrate and the reaction was
carried out with 20 mol% of CuI, K2CO3 as the base in DMF as solvent by heating at
70 ꢀC. It was our delight to see that it results in fairly clean conversion only within 6 h
and excellent yield of 3-methyleneisoindole-1-one 3a was obtained after column chro-
matography purification.
To find out the optimum reaction condition, we also carried out the reaction in dif-
ferent solvents like toluene and acetonitrile at the same or elevated temperature but
practically no product was found (Table 1, Entries 1–3,). Ag2CO3 was tested as an alter-
native base keeping the other reaction parameter unaltered (Table 1, Entry 4) but we
ended up with inferior yield. To optimize the temperature, the reaction was performed
under different temperature and we found that 70 ꢀC is the ideal temperature to con-
sume the starting material completely within 6 h. On the other hand, if the temperature
is elevated up to 100 or 120 ꢀC, the yield started decreasing with the formation of
undetected more polar compounds (Table 1, Entries 7–8). Decreasing catalyst loading
to 10 mol% under identical reaction condition, furnished lower yield (Table 1, Entry 9).
Further lowering of catalyst loading to 5 mol%, resulted in incomplete conversion after
6 h heating at 70 ꢀC (Table 1, Entry 10).
Since the reaction was found to be most effective in DMF and non-coordinating sol-
vents were not suitable, the participation of DMF as ligand may not be ruled out.
Being inspired by our preliminary observation, we wanted to examine the substrate
scope of this reaction under ligand-free conditions. Initially, we prepared differently
substituted 2-iodo-N-phenyl benzamide (substitution on amide phenyl group) and they
were subjected to Sonogashira cross coupling-intramolecular cyclo-amination reaction
protocol with phenylacetylene. In all the cases, the reaction went smoothly and we
obtained 3-methyleneisoindol-1-one derivatives 3b–3d with excellent isolated yield and

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SYNTHETIC COMMUNICATIONSV
5
Table 1. Optimization of following coupling reaction by Cu (I) under different condition.a
Entry
CuI(mol%)
Base
Solvent
Temp (oC)
Yield (%)
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
10
5
K2CO3
K2CO3
Ag2CO3
Ag2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Toluen
Acetonitrile
Acetonitrile
DMF
110
80
80
80
90
Trace
ND
ND
60b
85
85
70
DMF
DMF
DMF
DMF
DMF
DMF
70
100
120
70
60
9
10
65
70
45c
aReaction condition: 0.3 mmol of 1, 2.0 equiv.of K2CO3, 1.2 equiv. of alkyne and solvent (2 ml under N2), 6 h; btime 8 h;
cbased on starting material recover.
much shorter reaction time. Similarly, p-tolyl acetylene and 4-tert-butylphenylacetylene
were tested as the terminal acetylene source and corresponding 3-methyleneisoindol-1-
one derivatives 3e–3i (Scheme 2) were isolated with very good-to-excellent yield.
Long-chain substituted phenylacetylene such as 4-n-butylphenylacetylene and 4-n-pen-
tylphenylacetylene were also found to be an excellent partner for this Sonogashira
coupling-cycloamination reaction. Therefore, they were readily coupled under standard
reaction conditions with a variety of 2-iodo-N-phenylbenzamide to afford 3-methylenei-
soindol-1-one derivatives 3j–3q (Scheme 2) with comparable isolated yields. To the best
of our knowledge, compounds 3j–3q are new and are accessible via our ligand-free
approach with superior yield compared to similar compounds. 1-pentyne which was
never tested before as potential terminal alkyne counterpart was found to be an out-
standing candidate for this domino reaction protocol.
Toward this end, 1-pentyne was treated with different 2-iodobenzamide to afford cor-
responding 3-methyleneisoindole-1-one derivatives 3r–3 u (Scheme 2) respectively with
excellent yield. To extend the substrate scope further, phenyl acetylene was once again,
subjected to react under optimum reaction condition with differently substituted 2-iodo-
benzamide derivatives to get title compounds 3v–3x (Scheme 2) with comparable iso-
lated yields.
All the compounds obtained from this reaction are solid and we were interested to
have the crystal structure of any of them for structural confirmation. Compound 3a was
crystallized from 20% ethyl acetate in hexane and we were able to pick up a white crys-
tal suitable for X-ray analysis. Crystallographic analysis [CCDC 1849593] established the
structure and stereo-chemistry unambiguously, Figure 2.

6
R. DE AND M. K. BERA
Scheme 2. Substrate scope of methyleneisoindole-1-one derivatives. Yields of isolated (By column
chromatography) products have been reported.
Conclusion
In conclusion, we have developed a simpler way of making (Z)-3-methyleneisoindole-1-one
derivatives exclusively starting from 2-iodo-N-phenylbenzamide and terminal alkyne under

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SYNTHETIC COMMUNICATIONSV
7
Figure 2. ORTEP diagram of compound 3a with 50% probability.
mild ligand-free condition. The reaction proceeds via Sonogashira cross-coupling followed
by 5-exo-dig heteroannulation. In this transformation, aliphatic alkyne may also be
employed as an alkyne counterpart which was not used before in a similar reaction.
Excellent yield and shorter reaction time are the other attractive features of this method.
Experimental
To an oven-dried 25 ml round bottom flask fitted with a reflux condenser containing 2-
Iodo N-phenyl benzamide(1.0 mmol) in dry DMF (2.0 ml) was added potassium carbon-
ate (2.0 mmol) and copper iodide (20 mol%) with stirring at room temperature under
nitrogen atmosphere. A solution of aryl acetylene (1.2 mmol) in DMF was added to the
reaction mixture and the flask was placed in an oil bath at 70 ꢀC for 5–6 h. After start-
ing material was fully consumed (TLC monitoring), the reaction mixture was cooled to
room temperature and diluted with ethyl acetate and water. The compound was
extracted with ethyl acetate (3 ꢁ 50 ml). The combined organic layer was washed with
brine solution (5 ml) and dried over anhydrous sodium sulfate. After removal of the
solvent in vacuo, the residue was purified by silica gel chromatography (Ethylacetate:pet
ether ¼ 4:1) to obtain the desired product.
Acknowledgments
We sincerely thank the Sophisticated Analytical Instruments Facility (SAIF), Indian Institute of
Engineering Science and Technology (IIEST) Shibpur for the XRD facility.
Funding
The present work is financially supported from DST-SERB, New Delhi [SB/S1/OC-15/2014] and
CSIR, New Delhi [02(0270)/16/EMR-II].
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