A Cu-catalysed synthesis of substituted 3-methyleneisoindolin-1-one

Article abstract of DOI:10.1039/c4ra12782j

A Cu(I)-catalysed synthesis of substituted 3-methyleneisoindolin-1-ones using alkynyl acids as an alkyne source has been developed. The reaction involves the decarboxylative cross-coupling of 2-halobenzamides with aryl alkynyl acids, followed by 5-exo-dig

Full text of DOI:10.1039/c4ra12782j

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: B. K. Patel, A.
Gogoi, S. Guin, S. K. Rout and M. Ganesh, RSC Adv., 2014, DOI: 10.1039/C4RA12782J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 6
RSC Advances
View Article Online
DOI: 10.1039/C4RA12782J
A Cu-catalysed synthesis of substituted 3-methyleneisoindolin-1-one
Anupal Gogoi, Srimanta Guin, Saroj Kumar Rout, Ganesh Majji and Bhisma K. Patel*
O
O
Ph
CO2
CuI, Cs2CO3
N
Ar
CO2H
N
Ph
Ar
+
+
DMSO, 120 o
1, 10-phen
C
H
X
X = Br, I
A Cu-catalysed synthesis of substituted isoindolin-1-one has been achieved via decarboxylative alkynylation–heteroannulation
path.

RSC Advances
Page 2 of 6
Dynamic Article Links ►
Journal Name
View Article Online
DOI: 10.1039/C4RA12782J
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
A Cuꢀcatalysed synthesis of substituted 3ꢀmethyleneisoindolinꢀ1ꢀone†
Anupal Gogoi, Srimanta Guin, Saroj K. Rout, Ganesh Majji and Bhisma K. Patel
*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A Cu(I)ꢀcatalysed synthesis of substituted 3ꢀmethyleneisoindolinꢀ1ꢀones using alkynyl acids as alkyne source has been developed. The
reaction involves decarboxylative crossꢀcoupling of 2ꢀhalobenzamides with aryl alkynyl acids followed by 5ꢀexoꢀdig heteroannulation.
While reactions of 2ꢀiodo benzamides proceeded without ligand, for 2ꢀbromo substrates assistance of a ligand is essential.
10
with concurrent cyclisation.
Introduction
In modern synthetic organic chemistry, transition metal
catalysed decarboxylative crossꢀcoupling reactions using
15 carboxylic acids have received much attention because of their
ready availability and easy handling. In general, such reactions
proceed via the in situ generation of organometallic species along
with the extrusion of CO2 as the side product. This reactive
organometallic intermediate then couples with appropriate
20 counterparts providing alternative routes to C−C or C−heteroatom
bonds.1 As one of the members of carboxylic acids, alkynyl
carboxylic acids are potential candidates for cross–coupling
reactions installing an alkynyl group into the substrates. Unlike
aryl or vinyl carboxylic acids, decarboxylative coupling of
25 alkynyl carboxylic acids can be initiated by a single catalytic
system.1,2 This strategy has been demonstrated by Xue group for
the synthesis of diaryl alkynes via
a copper catalysed
decarboxylative cross−coupling of alkynyl carboxylic acids with
aryl halides.2a Not merely restricted to the synthesis of internal
30 alkynes, the above strategy has much more to offer by
manipulation of the alkynyl group. One way to achieve this is to
activate the in situ generated alkynyl group with a soft metal
followed by an intramolecular nucleophilic attack resulting into a
heterocycle. We envisaged that 2ꢀhalo benzamide with an alkynyl
35 acid under an appropriate condition may result either 3ꢀ
55
Fig. 1 Natural products and biologically active compounds
containing 3ꢀmethyleneisoindolinꢀ1ꢀone.
Substituted 3ꢀmethyleneisoindolinꢀ1ꢀones are medicinally
important heterocyclic scaffold prevalent in many natural
60 products and pharmaceuticals.4 Apart from their significant
biological profile; they also find applications in material
chemistry.5 Some of the natural products and biologically active
molecules having 3ꢀmethyleneisoindolinꢀ1ꢀone as the core unit
are shown in Figure 1. Due to the myriad of applications of this
65 important motif there has been development of numerous
synthetic protocols for their synthesis. The traditional methods
for the synthesis of 3ꢀmethyleneisoindolinꢀ1ꢀone include Hornerꢀ
WadsworthꢀEmmons type of condensation,6 addition/dehydration
of phthalimides,7 5ꢀexoꢀdig cyclisation of preformed 2ꢀ
70 alkynylbenzamides3a,b,c,8 and base triggered addition to
benzonitriles.9 However, they are associated with poor
regioselectivity in case of unsymmetrical substrates or require
number of additional synthetic steps. These shortcomings
stimulated the emergence of transition metal catalysed reactions
75 such as HeckꢀSuzukiꢀMiyaura domino reactions involving
ynamides (path a, Scheme 1),10 Sonagashira couplingꢀ
methyleneꢀisoindolinꢀ1ꢀone via
a 5ꢀexoꢀdig cyclisation or
substituted isoquinolinꢀ1ꢀone via a 6ꢀendoꢀdig cyclisation.3
We initiated our investigation by treating 2ꢀbromobenzamide
(1) with phenyl propiolic acid (a) (1.2 equiv.) in the presence of
o
40 CuI (10 mol %), Cs2CO3 (1.5 equiv.) in DMF solvent at 120 C.
To our delight, the reaction resulted in a selective formation of 5ꢀ
exoꢀdig product, 3ꢀphenylmethylene isoindolinꢀ1ꢀone (1a) in
32% yield. Herein, we report the synthesis of 3ꢀ
methyleneisoindolinꢀ1ꢀones involving decarboxylative crossꢀ
45 coupling of alkynyl carboxylic acids and 2ꢀhalo benzamides
__________________________________________
Department of Chemistry, Indian Institute of Technology Guwahati, 781
039, Assam, India. Fax no. +91-3612690762; E-mail: patel@iitg.ernet.in
†Electronic supplementary information (ESI) available: 1H and 13C NMR
50 spectra For ESI or other electronic format see DOI: 10.1039/xxxxxx.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Page 3 of 6
RSC Advances
View Article Online
DOI: 10.1039/C4RA12782J
carbonylationꢀhydroamination of ortho dihalo arenes (path b,
Table 1). Other solvents such as 1,4ꢀdioxane, 1,2ꢀdichloroethane
(DCE) and Nꢀmethylꢀ2ꢀpyrrolidone (NMP) were found to be
unsuitable for this transformation (entries 16−18, Table 1). Thus,
55 CuI (10 mol%), 1,10ꢀphen (10 mol%), Cs2CO3 (1.5 equiv.) in
DMSO solvent at 120oC was found to be the optimal condition
and rest of the reactions were performed under exactly identical
conditions.
Scheme 1)11 and Ullmann couplingꢀhydroamination of ortho halo
benzamides (path c, Scheme 1).12 Apart from the crossꢀcoupling
strategies, recently You et al. developed a Cu mediated approach
to 3ꢀmethylene isoindolinꢀ1ꢀone that proceeds via tandem
oxidative crossꢀcoupling between (Csp2−H) of arenes with
terminal alkynes followed by an intramolecular annulation.13 In
the latter two crossꢀcoupling strategies (path b and c, Scheme 1),
terminal alkynes have been utilised for the initial alkynylation
5
60 Table 1 Optimisation of reaction conditionsa
10 purpose. However, the use of their acid derivatives to serve as
alkyne surrogates via decarboxylative C−C bond formation for
the synthesis of 3ꢀmethylene isoindolinꢀ1ꢀone is the first
precedence of its kind.14 The use of alkynyl carboxylic acids as
alternatives to terminal alkynes are advantageous because of their
15 superior reactivity and ready availability.15 They are less
susceptible to homocoupling; thereby suppressing the competing
diyne byproduct in Sonogashira reaction.16
Entry
Catalyst
(mol %)
CuI (10)
CuI (10)
CuBr (10)
CuCl (10)
Base (equiv.)
Cs2CO3 (1.5)
Cs2CO3 (1.5) 1,10ꢀphen (10)
Cs2CO3 (1.5) 1,10ꢀphen (10)
Cs2CO3 (1.5) 1,10ꢀphen (10)
Ligand
(mol %)
ꢀ
Solvent Yield
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
32
59
51
43
38
40
49
53
41
<5
35
54
39
46
69
O
H
Ph
CO
Ph
I
N
H
R-NH2
Br
Cu(OAc)2 (10) Cs2CO3 (1.5) 1,10ꢀphen (10)
CuCl2 (10) Cs2CO3 (1.5) 1,10ꢀphen (10)
Br
H
Ph
O
CuBr2(10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
Cs2CO3 (1.5) 1,10ꢀphen (10)
K2CO3(1.5)
K3PO4(1.5)
NEt3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5) 1,10ꢀphen (10)
Cs2CO3 (1.5) 1,10ꢀphen (10) 1,4ꢀdioxane 42
Cs2CO3 (1.5)
Cs2CO3 (1.5)
1,10ꢀphen (10)
1,10ꢀphen (10)
1,10ꢀphen (10)
DEM (10)
Lꢀproline (10)
TMEDA (10)
DMEDA (10)
N
Ph
Ph
HOOC
Ph
PhB(OH)2
O
O
X
Ph
Ph
N
N
H
Br
X = Br, I
1,10ꢀphen (10)
1,10ꢀphen (10)
NMP
DCE
49
53
20 Scheme 1. Various approaches for synthesis of 3ꢀmethyleneisoindolinꢀ1ꢀ
one.
aReactions were monitored by TLC. bIsolated yield.
Results and Discussion
65
After establishing the optimised conditions, the substrate
scope for this decarboxylationꢀheteroannulation methodology
25
Encouraged by the initial success, further optimisations were
carried out to attain an improved yield of the product (1a).
Several reports revealed that for substrates undergoing metal
catalysed crossꢀcoupling reactions involving bromo substituent,
assistance of a ligand often facilitates the process.17 Furthermore,
was explored.
A variety of substituted 3–arylmethylene
isoindolinꢀ1ꢀones has been synthesised as shown in Scheme 2. At
first, the effect of substituents present on the Nꢀaryl ring of
70 benzamide was examined by reacting them with phenyl propiolic
acid (a). The Nꢀaryl ring of amide bearing electronꢀdonating
groups such as 3ꢀMe (2), 3,4ꢀdiMe (3), 4ꢀOMe (4) yielded their
respective products (2a), (3a) and (4a) in 62%, 78% and 66%
respectively (Scheme 2). While benzamides derived from aryl
75 amines possessing moderately electronꢀwithdrawing groups such
as 4ꢀCl (5), 4ꢀBr (6), 4ꢀF (7) provided their corresponding
isoindolinꢀ1ꢀone (5a), (6a) and (7a) in 72%, 73% and 76% yields
respectively (Scheme 2). A comparison between two sets of
substrates one possessing electronꢀdonating groups and other
80 electronꢀwithdrawing groups shows that yields are marginally
better with the latter set with the lone exception being 3,4ꢀdiMe
substrate (3). The structure of the product (5a) has been
confirmed by Xꢀray crystallography.
30 an orthogonal selectivity has been demonstrated during a ligand
assisted Cuꢀcatalysed reaction.17f,i
A
ligand functions by
inhibiting the aggregation of the metal and improve the solubility
of the catalyst/coꢀcatalyst; thereby resulting in better catalytic
activity of the metal. Taking cues from the aforementioned
35 reports, when the coupling between 2ꢀbromobenzamide (1) (1
equiv.) and phenyl propiolic acid (a) (1.2 equiv.) was performed
in the presence of ligand 1,10ꢀphenanthroline (10 mol%), CuI (10
mol%), Cs2CO3 (1.5 equiv.) the product (1a) was obtained in an
improved yield of 59% (entry 2, Table 1). During the catalyst
40 screening CuI was found to be superior over all other Cu(I) and
Cu(II) salts such as CuBr, CuCl, Cu(OAc)2, CuCl2, CuBr2 tested
(entries 3−7, Table 1). Replacement of base Cs2CO3 with other
inorganic bases such as K2CO3, K3PO4 resulted in lower yields
(entries 8 and 9, Table 1). The use of organic base like NEt3 was
45 found to be almost ineffective in bringing about the
transformation (entry 10, Table 1). Other ligands such as
diethylmalonate (DEM), Lꢀproline, tetramethylethylenediamine
(TMEDA), dimethylethylenediamine (DMEDA) tested were
found to be inferior to 1,10ꢀphenanthroline (entries 11−14, Table
50 1). Further, improvement in the yield (69%) was observed when
the reaction was performed in DMSO instead of DMF (entry 15,
85
Fig. 2 ORTEP view of compound (5a).
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 4 of 6
View Article Online
DOI: 10.1039/C4RA12782J
Instead of an aryl group when a benzyl substituent is attached
to the Nꢀatom of the benzamide (8), the product (8a) was
electronꢀdonating 4ꢀOMe group (f) and having electronꢀ
withdrawing 4ꢀBr group (g). Another set of reactions were
obtained in good yield (84%). However, with analogous 25 performed with benzamide possessing electron withdrawing 4ꢀCl
picolinamide (9) there was substantial drop in the yield (68%).
The variation of substituents in aryl alkynyl acids were
scrutinised by reacting them with benzamide (1). Aryl propiolic
acids possessing electronꢀdonating groups such as 4ꢀMe (b), 4ꢀ
group (5) with aryl alkynyl acids bearing electronꢀdonating group
4ꢀMe (b) and having electronꢀwithdrawing 3ꢀF group (h).
However, judging by the yield pattern of products (3f), (3g), (5b)
and (5h) obtained from the aforementioned combinations, again
5
tBu (c) and electronꢀwithdrawing groups such as 4ꢀBr (d), 4ꢀCl 30 no correlation between yields and substituent effect could be
(e) underwent facile reactions with (1) affording their respective
10 products (1b), (1c), (1d) and (1e) in moderate yields as shown in
Scheme 2.
arrived (Scheme 2). To check the efficacy of this transformation
with aliphatic alkynyl acid a reaction was performed between 2ꢀ
bromobenzamide (1) and 2ꢀbutynoic acid. The reaction failed to
give the desired isoindolinꢀ1ꢀone product, instead hydroxylation
35 ortho to amide (1a′) moiety was observed under the reaction
condition (Scheme 3). Similar hydroxylation of oꢀhaloanilides
and oꢀhalo benzamides has been observed during Cu catalysed
reaction in an aqueous medium.18 Due to lesser reactivity of
bromo group towards oxidative addition with aliphatic alkyne
40 species the hydroxylation path is preferred and the possible
hydroxyl source is from the water present in the commercial
grade DMSO.
O
O
CuI ( 10 mol%)
1, 10 phen (10 mol%)
R1
N
N
R1
H
HOOC
(a h)
Ar2
Cs2CO3 (1.5 equiv)
DMSO, 120 oC, 1.5-2 h
X
(X = Br, 1 11)
(1a 11a)
Ar2
(X = I, 1' 3')
O
Me
O
O
N
Me
N
N
Me
b
c
(2a, 62%)
(3a, 78%)
1a,
(
69% /77% )
O
O
O
N
Cl
N
OMe
N
Br
(4a, 66%)
(5a, 73%)
(6a, 72%)
45 Scheme 3. Competative hydroxylation of 2ꢀbromobenzamide.
Me
After successful accomplishment of the present
transformation with 2ꢀbromo benzamides next we turned our
attention towards more reactive 2ꢀiodo benzamides. The reaction
50 of 2ꢀiodo benzamide (1´) with phenyl propiolic acid (a) under
previous optimised conditions provided 3ꢀphenylmethylene
isoindolinꢀ1ꢀone (1a) in 77% isolated yield. Interestingly, the
same reaction when performed in the absence of ligand 1,10ꢀ
phen, proceeded smoothly virtually unaffecting the yield and
55 reaction time. This illustrates the higher reactivity of C−I bond
compared to C−Br bond towards decarboxylative C−C bond
formation. Further, this ligand free condition was then applied for
the reaction of 2ꢀiodo benzamides (2´) and (3´) with phenyl
propiolic acid (a) which provided their corresponding isoindolinꢀ
60 1ꢀone products (2´a) and (3´a) in 73% and 79% yields
respectively. The trend in the yields obtained from 2ꢀiodo
precursors without the involvement of ligand was found to be
identical to that of 2ꢀbromo benzamides with assistance of ligand.
O
O
O
N
N
F
N
N
(7a, 76%)
(8a, 84%)
(9a, 68%)
O
O
O
N
N
N
1d,
(
67%)
(1b, 63%)
(1c, 59%)
Me
tBu
Br
O
O
Me
O
Me
N
N
Me
N
Me
3f,
(
74%)
(1e, 70%)
3g,
(
77% )
Cl
OMe
Br
O
O
N
Cl
N
Cl
(5b, 72%)
5h,
(
76%)
Me
F
O
Cl
O
N
N
Me
c
c
2'a,
3'a,
79% )
(
73% )
(
Scheme 2 Substrate scope of substituted 3ꢀarylmethylene isoindolinꢀ1ꢀ
ones. aYields of isolated pure products are reported. bX = Br. cX = I.
From the trends in products yield it is evident that no significant
15 electronic effect of substituents present in aryl propiolic acids
could be ascertained. An attempt was made to find out whether
some combination of substituents present in Nꢀaryl ring of the
benzamides and aryl ring of alkynyl acids (based on their
electronic effects) could be the most suitable for this
20 transformation. With this motive two independent reactions were
carried out with benzamide containing electronꢀdonating 3,4ꢀ
diMe group in the Nꢀaryl ring (3) with aryl alkynyl acids bearing
65
Scheme 4. Plausible mechanism for the formation of 3ꢀ
methyleneisoindolinꢀ1ꢀone.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Page 5 of 6
RSC Advances
View Article Online
DOI: 10.1039/C4RA12782J
Based on the literature reports,19,2a,2e,14 a plausible mechanism
for the formation of 3ꢀphenylmethyleneisoindolinꢀ1ꢀone is
outlined in Scheme 4. Initially a Cu(I) intermediate (A) is formed
was then cooled to room temperature, admixed with water (5 mL)
and the product was extracted with ethyl acetate (2 x 20 mL). The
organic phase was dried over anhydrous sodium sulphate and
with phenyl propiolic acid (a). This Cu(I) species via a 55 concentrated in vacuo. The crude product was purified over a
5
decarboxylative path gives Cuꢀalkynylide species (B) which
undergoes oxidative addition with 2ꢀbromobenzamide (1) to
produce Cu(III) intermediate (C). Reductive elimination of Cu
from (C) gives the orthoꢀalkynylated product (D). Deprotonation
of the amide N−H of the intermediate (D) and subsequent
column of silica gel and eluted with (19:1 hexane / ethyl acetate
to give (Z)ꢀ3ꢀbenzylideneꢀ2ꢀphenylisoindolinꢀ1ꢀone (1a) (102.5
mg, 69% yield).
Acknowledgement
10 hydroamination20 of C−C triple bond promoted by coꢀordination
of Cu(I) with the alkynyl group results in the formation of 3ꢀ
phenylmethyleneisoindolinꢀ1ꢀone (1a) via the intermediacy of
(E) along with regeneration of Cu(I). The formation of
intermediate species (A), (B), (C) and (D) have been detected by
15 the ESI/MS analysis of reaction aliquot which support the
proposed mechanism in Scheme 4 (see Supporting Information
[SI]).
60 B. K. P acknowledges the support of this research by the
Department of Science and Technology (DST) (SR/S1/OCꢀ
79/2009), New Delhi, and the Council of Scientific and Industrial
Research (CSIR) (02(0096)/12/EMRꢀII). AG, and GM thank
UGC for fellowships. Thanks are due to Central Instruments
65 Facility (CIF) IIT Guwahati for NMR spectra and DSTꢀFIST for
XRD facility.
References
70 1. (a) N. Rodrìguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030;
(b) J. D. Weaver, A. Recio, A. J. Grenning and J. A. Tunge, Chem.
Rev., 2011, 111, 1846; (c) J. Cornella and I. Larrosa, Synthesis, 2012,
44, 653.
2. (a) D. Zhao, C. Gao, X. Su, Y. He, J. You and Y. Xue, Chem.
75
Commun., 2010, 46, 9049; (b) W.ꢀW. Zhang, X.ꢀG. Zhang and J.ꢀH.
Li, J. Org. Chem., 2010, 75, 5259; (c) J. Moon, M. Jang and S. Lee,
J. Org. Chem., 2009, 74, 1403; (d) W. Jia and N. Jiao, Org. Lett.,
2010, 12, 2000; (e) S. Ranjit, Z. Duan, P. Zhang and X. Liu, Org.
Lett., 2010, 12, 4134.
80 3. (a) N. G. Kundu, M.W. Khan and R. Mukhopadhyay, Tetrahedron,
1999, 55, 12361; (b) T. Yao and R. C. Larock, J. Org. Chem., 2005,
70, 1432; (c) S. Mehta, J. P. Waldo and R. C. Larock, J. Org. Chem.,
2009, 74, 1141; (d) S. F. Vasilevsky, T. F. Mikhailovskaya, V. I.
Mamatyuk, G. E. Salnikov, G. A. Bogdanchikov, M. Manoharan and
85
I. V. Alabugin, J. Org. Chem., 2009, 74, 8106.
20
4. (a) G. Blasko´, D. J. Gula and M. J. Shamma, Nat. Prod., 1982, 45,
105; (b) Laboratori Baldacci S. p. A. JP 59046268, Chem. Abstr.,
1984, 101, 54922; (c) Y. Kato, H. Ebiike, K. Achiwa, N. Ashizawa,
T. Kurihara and F. Kobayashi, Chem. Pharm. Bull., 1990, 38, 2060;
(d) Y. Kato, M. Takemoto and K. Achiwa, Chem. Pharm. Bull.,
1999, 47, 529; (e) Y.ꢀC. Chia, F.ꢀR. Chang, C.ꢀM. Teng and Y.ꢀC.
Wu, J. Nat. Prod., 2000, 63, 1160; (f) H. M. Botero Cid, C. Tra¨nkle,
K. Baumann, R. Pick, E. MiesꢀKlomfass, E. Kostenis, K. Mohr and
U. Holzgrabe, J. Med. Chem., 2000, 43, 2155; (g) A. Couture, E.
Deniau, P. Grandclaudon, H. RybalkoꢀRosen, S. Le´once, B. Pfeiffer
and P. Renard, Bioorg. Med. Chem. Lett., 2002, 12, 3557; (h) B.
Hulin, J. C. Parker and D. W. Piotrowski, US2005234065; (i) K.
Toyooka, N. Kanamitsu, M. Yoshimura, H. Kuriyama and T.
Tamura, WO2004048332. (j) J. Weinstock, J. P. Hieble and J. W.
Wilson, Drugs Future, 1985, 10, 645; (k) G. A. Cordell, In The
Alkaloids: Chemistry and Pharmacology; Academic: San Diego,
1998; Vol. 50; (l) K. Achinami, N. Ashizawa and F. Kobayashi, Jpn
Patent JP 03 1991, 133, 955.
5. (a) L. Castedo, E. Guitián, J. M. Saá and R. Suau, Heterocycles,
1982, 19, 279; (b) Y. Kato, M. Takemoto and K. Achiwa, Chem.
Pharm. Bull., 1993, 41, 2003; (c) E. Mertz, S. Mattei and S. C.
Zimmerman, Bioorg. Med. Chem., 2004, 12, 1517; (d) A. Moreau, A.
Couture, E. Deniau and P. Grandclaudon, J. Org. Chem., 2004, 69,
4527; (e) M. Lamblin, A. Couture, E. Deniau and P. Grandclaudon,
Tetrahedron, 2006, 62, 2917; (f) M. Lamblin, A. Couture, E. Deniau
and P. Grandclaudon, Org. Biomol. Chem., 2007, 5, 1466; (g) T. Lei,
Y. Cao, Y. Fan, C.ꢀJ. Liu, S.ꢀC. Yuan and J. Pei, J. Am. Chem. Soc.,
2011, 133, 6099.
Scheme 5. Plausible mechanism for the formation of 3ꢀ
methyleneisoindolinꢀ1ꢀone.
However an alternative mechanism involving initial
25 oxidative addition of Cu(I) with 2ꢀhalobenzamide to give
intermediate (A′) as proposed in Scheme 5 cannot be completely
ruled out. Intermediate (A′) couples with phenylpropiolic acid (a)
to give intermediate (B′). Loss of CO2 from intermediate (B′)
would give intermediate (C) which eventually lead to the
30 formation of desired product (1a) as shown in Scheme 4.
90
95
Conclusion
100
105
110
115
In conclusion, we have developed a Cu(I)ꢀcatalysed synthesis
35 of
substituted
3ꢀmethyleneisoindolinꢀ1ꢀones
involving
decarboxylative crossꢀcoupling of 2ꢀhalobenzamides with aryl
alkynyl acids followed by 5ꢀexoꢀdig heteroannulation. In this
transformation alkynyl acids have been utilised to generate
alkyne intermediate for the synthesis of this important
40 heterocycle scaffold. While reactions of 2ꢀiodo benzamides
proceeded without ligand, for 2ꢀbromo subtrates the assistance of
a ligand is essential.
General procedure for the synthesis of (Z)ꢀ3ꢀbenzylideneꢀ2ꢀ
45 phenylisoindolinꢀ1ꢀone (1a)
6. (a) A. Couture, E. Deniau and P. Grandclaudon, Tetrahedron, 1997,
53, 10313; (b) A. Couture, E. Deniau, P. Grandclaudon and C.
Hoarau, Tetrahedron, 2000, 56, 1491; (c) V. Rys, A. Couture, E.
Deniau and P. Grandclaudon, Tetrahedron, 2003, 59, 6615; (d) M. A.
ReyesꢀGonzalez, A. ZamudioꢀMedina and M. Ordonez, Tetrahedron
Lett., 2012, 53, 5756.
To a solution of 2ꢀbromobenzamide (1) (138 mg, 0.5 mmol) in
DMSO (2 mL) was added CuI (9.5 mg, 0.05 mmol), 1,10ꢀphen (9
mg, 0.05 mmol), Cs2CO3 (245 mg, 0.75 mmol), phenyl propiolic
50 acid (a) (87.6 mg, 0.6 mmol) and the resultant mixture was stirred
o
in a preheated oil bath at 120 C for 2 h. The reaction mixture
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

RSC Advances
Page 6 of 6
View Article Online
DOI: 10.1039/C4RA12782J
7. (a) C. SánchezꢀSánchez, E. PérezꢀInestrosa, R. GarcíaꢀSegura and R.
Suau, Tetrahedron, 2002, 58, 7267; (b) T. Bousquet, J. F. Fleury, A.
Daich and P. Netchitailo, Tetrahedron, 2006, 62, 706; (c) F. Hatoum,
J. Engler, C. Zelmer, J. Wissen, C. A. Motti, J. Lex and M.
Oelgemçller, Tetrahedron Lett., 2012, 53, 5573; (d) N. Kise, S.
Isemoto and T. Sakurai, Tetrahedron, 2012, 68, 8805.
5
10
15
20
25
30
35
40
45
50
8. (a) N. G. Kundu and M. W. Khan, Tetrahedron, 2000, 56, 4777; (b)
C. Koradin, W. Dohle, A. L. Rodriguez, B. Schmid and P. Knochel,
Tetrahedron, 2003, 59, 1571; (c) C. Kanazawa and M. Terada, Chem.
Asian J., 2009, 4, 1668.
9. (a) M. J. Wu, L. J. Chang, L. M. Wei and C. F. Lin, Tetrahedron,
1999, 55, 13193; (b) W. D. Lu, C. F. Lin, C. J. Wang, S. J. Wang and
M. J. Wu, Tetrahedron, 2002, 58, 7315.
10. (a) S. Couty, B. Liegault, C. Meyer and J. Cossy, Org. Lett., 2004, 6,
2511; (b) S. Couty, B. Liegault, C. Meyer and J. Cossy, Tetrahedron,
2006, 62, 3882.
11. H. Cao, L. McNamee and H. Alper, Org. Lett., 2008, 10, 5281.
12. (a) L. Li, M. Wang, X. Zhang, Y. Jiang and D. Ma, Org. Lett., 2009,
11, 1309; (b) M. Hellal and G. D. Cuny, Tetrahedron Letters, 2011,
52, 5508; (c) N. G. Kundu and W. Khan, Tetrahedron, 2000, 56,
4777.
13. J. Dong, F. Wang and J. You, Org. Lett., 2014, 16, 2884.
14. While this manuscript was under preparation, an analogous method
was reported by Lee et al. using 2ꢀiodobenzoic acid, ammonium
acetate and alkynyl carboxylic acid using catalyst CuI. F. M.
Irudayanathan, J. Noh, J. Choi and S. Lee. Adv. Synth. Catal., 2014,
DOI: 10.1002/adsc.201400451.
15. J. P. Das, U. K. Roy and S. Roy, Organometallics, 2005, 24, 6136.
16. P. Siemsen, R. C. Livingston and F. Diederich, Angew. Chem., Int.
Ed., 2000, 39, 2632.
17. (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42,
5400; (b) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009,
48, 2; (c) F. Y. Kwong and S. L. Buchwald, Org. Lett., 2003, 5, 793;
(d) D. W. Ma, Q. Cai and H. Zhang, Org. Lett., 2003, 5, 2453; (e) A.
Shafir and S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 8742; (f)
A. Shafir, P. A. Lichtor and S. L. Buchwald, J. Am. Chem. Soc.,
2007, 129, 3490; (g) H.ꢀJ. Christau, P. Cellier, J.ꢀF. Splinder and M.
Taillefer, Eur. J. Org. Chem., 2004, 695; (h) F. Buchwald and A.
Klapars, X. H. Huang, J. Am. Chem. Soc., 2002, 124, 7421; (i) S. K.
Sahoo, L. Jamir, S. Guin and B. K. Patel, Adv. Synth. Catal. 2010,
352, 2538.
18. (a) N. Khatun, S. Guin, S. K. Rout and B. K.Patel, RSC Adv., 2014, 4,
10770; (b) S. J. Balkrishna and S. Kumar, Synthesis, 2012, 44, 1417.
19. (a) M. Yu, D. Pan, W. Jia, W. Chen and N. Jiao,. Tetrahedron Lett.,
2010, 51, 1287; (b) W. Jia and N. Jiao, Org. Lett., 2010, 12, 2000.
20. (a) A. K. Verma, M. Joshi and V. P. Singh, Org. Lett., 2011, 13,
1630; (b) A. K. Verma, D. Choudhury, R. K. Saunthwal, V. Rustagi,
M. Patel and R. K. Tiwari, J. Org. Chem., 2013, 78, 6657; (c) A. K.
Verma, R. R. Jha, R. Choudhury, R. K. Tiwari, K. S. K. Reddy and
A. Danodia, J. Org. Chem., 2012, 77, 8191.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 |
5