Geometry Driven Intramolecular Oxidative Cyclization of Enamides: An Umpolung Annulation of Primary Benzamides with Acrylates for the Synthesis of 3-Methyleneisoindolin-1-ones

Article abstract of DOI:10.1021/acs.joc.7b00966

A palladium-catalyzed tandem oxidative annulation of primary benzamides with acrylates via intermolecular N-alkenylation followed by intramolecular C-alkenylation yielded a stereoselective synthesis of (E)-3-methyleneisoindolin-1-ones. The study unveils, for the first time, that only E-enamides could undergo intramolecular oxidative cyclization under the optimized conditions to give isoindolinones. The current strategy represents an umpolung strategy when compared to the literature approaches that use benzamides.

Full text of DOI:10.1021/acs.joc.7b00966

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Article
Geometry Driven Intramolecular Oxidative Cyclization of
Enamides: An Umpolung Annulation of Primary Benzamides
with Acrylates for the Synthesis of 3-Methyleneisoindolin-1-ones
Joydev K. Laha, Mandeep Kaur Hunjan, Rohan A. Bhimpuria, Deepika Kathuria, and Prasad V. Bharatam
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00966 • Publication Date (Web): 26 Jun 2017
Downloaded from http://pubs.acs.org on June 26, 2017
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Geometry Driven Intramolecular Oxidative Cyclization of Enamides: An Umpolung
Annulation of Primary Benzamides with Acrylates for the Synthesis of 3-
Methyleneisoindolin-1-ones
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Joydev K. Laha,*# Mandeep Kaur Hunjan,# Rohan A. Bhimpuria,# Deepika Kathuria,± and
Prasad V. Bharatam*±
#Department of Pharmaceutical Technology (Process Chemistry),
±Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research,
S. A. S. Nagar, Punjab 160062, India
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ABSTRACT
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A palladiumꢀcatalyzed tandem oxidative annulation of primary benzamides with acrylates via
intermolecular Nꢀalkenylation followed by intramolecular Cꢀalkenylation yielded
a
stereoselective synthesis of (E)ꢀ3ꢀmethyleneisoindolinꢀ1ꢀones. The study unveils, for the first
time, that only Eꢀenamides could undergo intramolecular oxidative cyclization under the
optimized conditions to give isoindolinones. The current strategy represents an umpolung
strategy when compared to the literature approaches that use benzamides.
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INTRODUCTION
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Despite their structural simplicity, 3ꢀmethyleneisoindolinꢀ1ꢀones (1) bearing a free (NH) group
display unique structural features: for example, a) their exocyclic double bond adopts a preferred
geometry, b) they can be readily converted to saturated isoindolinones by hydrogenation of the
double bond, c) by virtue of their use as Michael acceptors, they undergo nucleophilic addition
forming a quaternary center at Cꢀ3, and d) they offer lateꢀstage functionalization at nitrogen
(Figure 1). While pharmaceutical relevance of 3ꢀmethyleneisoindolinꢀ1ꢀones is yet to be
investigated,1 the corresponding saturated isoindolinꢀ1ꢀones represent a class of privileged
medicinal agents with significant therapeutic potentials as rennin inhibitor (2), antibiotic
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(pestalachloride
A
3), anxiolytic drug (pazinaclone 4), TNFꢀα inhibitor, 5ꢀHT
antagonistic/antidepressant, PARPꢀ1 inhibitor, and as histone deacetylase inhibitor.2 Noticeably,
isoindolinꢀ1ꢀones that contain a free (NH) group have been demonstrated to contribute a major
role in pharmacophoric activities. These structural features, coupled with their promise to assume
pharmaceutical significance, make compounds 1 viable synthetic targets.
O
late stage
functionalization
O
NH
N
H
O
N
N
H
2
N
H
O
MeO
Cl
hydrogenation
O
N
N
H
OMe
N
R
functionalization
N
HO
Cl
(Z/E)-isomerism
3-Methyleneisoindolin-1-one (1)
O
Cl
Pestalachloride A (3)
N
O
Pazinoclone (4)
O
Figure 1. Pharmacophores Containing an Isoindolinꢀ1ꢀone Moiety.
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3ꢀMethyleneisoindolinꢀ1ꢀones have been synthesized using phthalimides,3 by rutheniumꢀ
catalyzed annulation of benzimidates,4 and various metalꢀcatalyzed annulation of orthoꢀalkynyl
benzamides.5 However, the control of regioselectivity, competitive formation of byꢀproducts, and
the requirement of using preactivated aryl halides could limit the practice of these protocols.
More recently, metalꢀcatalyzed oxidative annulations of benzamides with alkenes have appeared
to be elegant for the synthesis of isoindolinone derivatives (Scheme 1).6 While these methods
avoid using any preactivated substrates, many of them require a directing group yielding Nꢀ
substituted isoindolinꢀ1ꢀones. Therefore, development of an approach that largely avoids an
elaborated synthetic strategy, including installation and subsequent removal of the directing
group, and stepwise preparation of 3ꢀmethyleneisoindolinꢀ1ꢀones, would be beneficial for the
preparation of 3ꢀmethyleneisoindolinꢀ1ꢀones that have a free NHꢀgroup. Remarkably, Rhꢀ6d or
Ruꢀcatalyzed6e oxidative annulations of primary benzamides (or, generated in situ from aryl
nitriles6e) to the synthesis of (NH)ꢀ3ꢀmethyleneisoindolinꢀ1ꢀones are available. However, they
suffer from limited substrate scope and the requirement of an acidic condition. More importantly,
these annulations are reported to occur by oxidative orthoꢀ Cꢀalkenylation via CꢀH bond
activation followed by intramolecular oxidative Nꢀalkenylation.
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Scheme 1. Tandem Oxidative Annulations of Benzamides for the Synthesis of
Isoindolinones
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From this perspective, a complementary tandem approach to 3ꢀmethyleneisoindolinꢀ1ꢀones,
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involving oxidative N alkenylation of primary benzamides7, followed by intramolecular
oxidative cyclization of enamides, would be a subject of further investigation. Our previous
experiences on regioꢀ and chemoselective direct orthoꢀbenzylation of primary benzamides,9
oxidative Cꢀalkenylations in indole and 7ꢀazaindoles,10 and renewed interest in the concise
synthesis of fused nitrogenꢀcontaining heterocycles11 prompted us to develop a workable access
to 3ꢀmethyleneisoindolinones with a free NH group. Herein, we describe a complementary
approach that includes palladiumꢀcatalyzed oxidative Nꢀalkenylation of primary benzamides
followed by intramolecular oxidative cyclization of enamides, providing access to 3ꢀ
methyleneisoindolinꢀ1ꢀones with a free NH group that are amenable to functionalization at
nitrogen. The key features that are clearly distinct from the current literature include a) the
formation of Nꢀalkenylated product exclusively over Cꢀalkenylated product under the optimized
conditions, b) the exclusive formation of Eꢀenamides as opposed to Zꢀenamides, and c) only Eꢀ
enamides could undergo intramolecular oxidative cyclization to give isoindolinones.
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RESULTS AND DISCUSSION
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Our initial investigations were directed to identify a condition for tandem oneꢀpot synthesis of 3ꢀ
methyleneisoindolinꢀ1ꢀone 7a from the reaction of primary benzamide 5a and methyl acrylate
6a. Our efforts were primarily focused on utilizing a palladiumcatalyst and a sacrificial oxidant,
which could form 7a via intermolecular oxidative Nꢀalkenylation of 5a followed by
intramolecular oxidative cyclization of enamides formed in situ in the reaction. Unlike a previous
report,7 reaction of 5a and methyl acrylate (6a, 3 equiv) in the presence of PdCl2(CH3CN)2
(5mol%) and CuCl (10 mol%) in DME at 70 °C for 48 h gave 8a (Eꢀisomer) in 68% yield
(Table 1, entry 1). A more frequently used palladiumꢀcatalyst, Pd(OAc)2 in the presence of
AgOAc as oxidant in dioxane at room temperature resulted in E/Z mixture of enamides (entry
2).Interestingly the reaction, when conducted at an elevated temperature (70 °C), afforded
isoindolinꢀ1ꢀone 7a in 40% yield in addition to Eꢀ and Zꢀenamides (entry 3). Further increasing
the temperature to 110 °C, however, reducing the time from 48 h to 24 h, resulted in a similar
distribution of products (entry 4). The formation of 7a was markedly increased upon continuing
the reaction for a longer time (48 h, entry 5). The catalytic effect of AgOAc in combination with
a terminal oxidant [K2S2O8 or Cu(OAc)2] is similar to that observed in entry 4 (entries 6ꢀ7).
Cu(OAc)2 alone produced the similar result (entry 8). However, improvement in the formation of
7a occurred when 5a and 6a were reacted in the presence of an additive, PivOH or pyridine,
affording 7a in 64 and 87% yields, respectively (entries 9 and 10). Notably, the formation of Zꢀ
enamide is largely suppressed under these conditions. Predictably, the reaction of 2,6ꢀ
disubstituted benzamide 5b and methyl acrylate 6a gave only Eꢀenamide 8b in 43% yield, as
intramolecular oxidative cyclization is prohibited. A marked difference in reactivity of 5a and 6a
was observed under a condition described in entry 11, resulting in the formation of 9a as the
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exclusive product. Central to this investigation was the identification of reaction conditions that
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control the formation of isoindolinꢀ1ꢀone 7a, Eꢀenamide 8a, or Zꢀenamide 8b exclusively.
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Table 1.Optimizations Studya
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Entry Catalyst
Oxidant
Additive
Yields (%)
7a
ꢀ
8a
68
50
35
30
5
9a
21
40
18
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20
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23
ꢀ
1b
2c
3d
4e
5
PdCl2(CH3CN)2 Air
CuCl
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2
ꢀ
ꢀ
ꢀ
40
42
71
42
ꢀ
ꢀ
6f
7g
8h
9i
K2S2O8
32
25
26
ꢀ
Cu(OAc)2 42
ꢀ
42
64
Cu(OAc)2 PivOH
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Pd(OAc)2
Pd(OAc)2
Cu(OAc)2 Pyridine
87
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ꢀ
ꢀ
3
4
5
6
11k
Cu(OTf)2 PhI(OAc)2
ꢀ
60
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9
a
5 (0.25 mmol), 6 (0.5 mL), Pdꢀcatalyst (10 mol%), oxidant (2 equiv), additive (if any), 1,4ꢀ
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b
dioxane (250 mM), 110 °C., 48 h. PdCl2(CH3CN)2 (5 mol%), air, CuCl (10 mol%), DME (250
mM), 70 °C. c room temperature, d 70 °C. e 24 h. f AgOAc (50 mol %), K2S2O8(3 equiv). g AgOAc
(50 mol%), Cu(OAc)2 (3 equiv). h Cu(OAc)2 (3 equiv). PivOH (1 equiv), DMF/DMSO (9:1).
i
j
Pyridine (20 mol%). k Cu(OTf)2/PhI(OAc)2 (0.02/2 equiv), 24 h.
Next, we investigated the substrate scope that could participate in the tandem oneꢀpot synthesis
of isoindolinꢀ1ꢀones. Under our optimized conditions, reaction of benzamide 5a and ethyl
acrylate 6b gave 7b in 67% yield (Scheme 2, entry 1). An alkyl group at the orthoꢀ, metaꢀ, or
paraꢀposition of primary benzamides 5c-5e also produced isoindolinꢀ1ꢀones 7c-7e in 58ꢀ68%
yield. It is interesting to note that metaꢀsubstituted benzamide 5d gave only one regioisomer 7d,
adding value to the current protocol. While benzamide 5f containing an electronꢀdonating alkoxy
group at the orthoꢀposition did not give isoindolinꢀ1ꢀone 7f, benzamide 5g with an alkoxy group
at the paraꢀposition resulted in the isolation of isoindolinꢀ1ꢀones 7g in 60% yield. However,
benzamide 5f reacted with acrylate to give Nꢀalkenylated product 8c in 59% yield.
Similar to metaꢀsubstituted benzamide 5d, reaction of 3,4ꢀdimethylbenzamide 5h and 6a or 6b
gave isoindolinꢀ1ꢀones 7h-7i regioselectively in 61ꢀ68% isolated yield. 3,4ꢀDiethoxybenzamide
5i reciprocated the reactivity as that of 3,4ꢀdimethylbenzamide 5h affording isoindolinꢀ1ꢀone 7j
in 76% yield. However, reaction of 3,4ꢀdimethoxybenzamide 5j and methyl acrylate 6a gave
isoindolinꢀ1ꢀone 7k although in moderate yield. Notably, the oxidative cyclization occurred at
the orthoꢀpositionto the OMe group, which is in contrast to the other examples. While the
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moderate yield in this reaction could be explained on the basis of sluggish reactivity of
benzamide, intramolecular oxidative cyclization to the orthoꢀposition of OMe group is especially
interesting. When 2,4ꢀdifluorobenzamide 5k was subjected to the reaction with 6a, only Nꢀ
alkenylated product 8d was isolated in 42% yield. In this case, intramolecular oxidative Heck
reaction did not occur probablybecause of poor CꢀH bond activation orthoꢀ to amidegroup.
Interestingly, reaction of 5a and a disubstituted alkene 6c did not give the desired isoindolinꢀ1ꢀ
one7m. However, the reaction gave isoindolinꢀ1ꢀone 7m in 67% yield, which could occur by the
loss of the olefinic methyl group. Identification of a reasonable explanation is a subject of further
investigation.
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Scheme 2. Substrate Scope for the Synthesis of 3-Methyleleisoindolin-1-ones
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To understand the origin of the formation of isoindolinꢀ1ꢀone 7a, the two enamides were
independently subjected to the optimized conditions (Scheme 3). A complete conversion of Eꢀ
enamide 8a to isoindolinꢀ1ꢀone 7a was observed. However, Zꢀenamide 9a did not undergo
intramolecular oxidative cyclization to give 7a. Interestingly, primary benzamides did not react
with alkenes that did not have carbonyl groups. These reactions even did not produce the
corresponding Nꢀalkenylated products. These experiments suggest that alkenes containing
carbonyl groups are compatible for isoindolidinone synthesis. However, reaction of benzylamine
and methyl acrylate also did not give the corresponding cyclised product under the standard
condition. The two substrates, benzene sulfonamide and Nꢀmethoxy benzene sulfonamide, were
also exposed to the optimized conditions independently in the presence of methyl acrylate.
However, no significant reaction was observed in these cases. This experiment suggests that a
carbonyl functionality is required for ortho CꢀH palladation. Importantly, isomerization of one
enamide to the other was not observed under the optimized conditions. Pivotal feature to this
study was the observation that only Eꢀenamide 8a could undergo cyclization to give isoindolinꢀ
1ꢀone 7a and both carbonyl functionalities are required on both substrates.
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Scheme 3. Intramolecular Cyclization of Enamides
O
(E)-8a
optimized condition
NH
(Z)-9a
X
MeO2C
(E)-7a
O
O
R
NH2
NH
optimized condition
R = -SO2Ph (6d)
= -Ph (6e)
= -OAc (6f)
5a
R
7n (00%)
CO2Me
NH2
NH
optimized condition
R
7o (00%)
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To rationalize the experimental observation, quantum chemical analysis was performed, based
on the rich experience in our lab on several similar studies.12 Density Functional Analysis (DFT)
using B3LYP/6ꢀ311+G(d,p) level was performed to verify the hypothesis that only Eꢀenamides
undergo cyclization (and not Zꢀenamides) to give isoindolinꢀ1ꢀones.. The optimized 3D
structures of the important intermediates are given in Figure 2. The energy difference between E
(8a) and Zꢀenamides (9a) is 5.24 kcal/mol (in favor of Zꢀisomer).The extra stability of Zꢀisomer
9a can be rationalized from the observed intramolecular hydrogen bond.7
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Figure 2. The 3D Structures of palladium complexes 8a-Pd-1, 8a-Pd-2 and 9a-Pd-1 (bond
lengths in Angstrom (Å)).
The E and Zꢀenamides can be further activated by Pd(OAc)2 to form 8a-Pd-1, 8a-Pd-2 and 9a-
Pd-1. The geometrical features of these activated species 8aꢀPd (8a-Pd-1 and 8a-Pd-2) and 9aꢀ
Pd (9a-Pd-1) are quite different, and they strongly influence the next course of the reaction, i.e.,
intramolecular cyclization. The Eꢀenamide can form two different palladium coordinated species
between C4ꢀO7 (8a-Pd-1) and C4ꢀO1 (8a-Pd-2), whereas the Zꢀenamide can form only one
complex between C4ꢀO7 (9a-Pd-1) (Figure 2). For the formation of isoindolinones by
intramolecular cyclization, there must be a possibility of rotation across C6ꢀN5 bond (by 180°)
so that the ArꢀH can be in close proximity to Pd for activation. The rotation across C6ꢀN5 in 8a-
Pd-2 can lead to conformer 8a-Pd-3 (Scheme 4). However, such rotation is hindered in the case
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of 8a-Pd-1 and 9a-Pd-1. Though the 9a-Pd-1 is energetically more favored than 8a-Pd-2 (14.23
kcal/mol), it cannot lead to intramolecular cyclization due to hindered rotation across C6ꢀN5
(Scheme 4). The 3D structure of 8a-Pd-3 clearly suggests that the palladium and ArH are in
close proximity and hence the activation of ArH is easy. Thus, 8a-Pd-3 is a reactive intermediate
that can lead to cyclization via Int-1, but not 9a-Pd-1. Finally, Int-1 will undergo cyclization to
give rise to desired product 7a via TS1 with barrier of 28.08 kcal/mol and an overall energy
barrier is 19.79 kcal/mol. This hypothesis is further supported by the experimental fact that
acrylates are the only viable alkenes that could participate in the reaction. This could explain the
observed differences in the geometry driven selectivity toward the formation of 3ꢀ
methyleneisoindolinꢀ1ꢀones. However, a detailed study is required to establish the geometry
driven cyclization of enamides.
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Scheme 4. A Proposed Pathway (The numerical value in red color represents the
activation barrier and the given energy values are in kcal/mol)
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In conclusion, a palladiumꢀcatalyzed tandem oxidative Nꢀalkenylation of primary benzamides
with acrylates gave Eꢀenamides regioselectively, which upon subsequent intramolecular
oxidative cyclization gave 3ꢀmethyleneisoindolinꢀ1ꢀones. Our investigation reveals, for the first
time, that intramolecular oxidative cyclization of enamides depends upon the geometry of the
enamides. Only Eꢀenamides undergo intramolecular oxidative cyclization to yield 3ꢀ
methyleneisoindolinꢀ1ꢀones. Distinct from the current literature, our protocol does not require a
directing group in benzamides and is an umpolung strategy to the literature approaches. The
current study should prompt further investigations on geometryꢀdriven intramolecular oxidative
cyclization of other systems.
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EXPERIMENTAL SECTION
General Methods. Unless noted otherwise, all reagents and solvents were purchased from
commercial sources and used as received. All palladiumꢀcatalyzed reactions were performed in a
screwꢀcap vial. The (1H) and (13C) NMR spectra were obtained using a 400 MHz and 100 MHz
spectrometer respectively with Me4Si as an internal standard. Coupling constants (J values) are
reported in hertz (Hz). The chemical shifts (δ) values are reported in parts per million (ppm).
Column chromatography was performed using silica gel (100ꢀ200 mesh). High resolution mass
spectra (HRMS) were obtained using electron spray ionisation (ESI) technique and as TOF mass
analyser. All melting points were taken using a melting point apparatus equipped with a
calibrated thermometer and are uncorrected. New compounds were characterized by melting
point, 1H NMR, 13C NMR, IR, and HRMS data.
General Procedure for the Synthesis of Isoindolinone and NꢀAlkenylated derivatives. In an ovenꢀ
dried screw cap vial equipped with a magnetic stir bar, benzamides (0.25 mmol), Pd(OAc)2 (10
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mol%), Cu(OAc)2.H2O (0.5 mmol), pyridine (20 mol%), alkene (0.5 mL) and 1,4 Dioxane (1
mL) was added and reaction mixture was heated at 110 ºC for 48 h. The reaction mixture was
allowed to cool to room temperature and then it was diluted with ethyl acetate (10 mL) and water
(5 mL) was added, the layers were separated. The organic layer was dried (Na2SO4),
concentrated under reduced pressure, and purified by column chromatography on silica using
(ethyl acetate/ hexane = 1:9 – 2:8) as an eluent to give the desired product.
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Methyl (E)-2-(3-oxoisoindolin-1-ylidene)acetate (7a): White solid; Yield 87% (49 mg); mp
1
123ꢀ125 ºC; H NMR (CDCl3): δ 9.63 (s, 1H), 7.92ꢀ7.91 (d, J= 8.4 Hz, 1H), 7.89ꢀ7.71 (d, J=8.1
Hz, 1H), 7.67ꢀ7.63 (m, 2H), 5.80 (s, 1H), 3.84 (s, 3H); 13C NMR (CDCl3): δ 168.0, 167.9, 147.5,
136.4, 132.4, 131.8, 129.6, 124.1, 121.0, 91.2, 51.8; HRMS(ESI) m/z calcd for C11H10NO3
[M+H]+ 204.0661, found 204.0659; IR (KBr): 3774, 2924, 1729, 1464, 1247, 710 cmꢀ1.
1
Ethyl (E)-2-(3-oxoisoindolin-1-ylidene)acetate (7b)7: White solid;Yield 67% (36 mg); H
NMR (CDCl3): δ 9.64 (s, 1H), 7.91 (dd, J = 6.6, 1.6 Hz,1H), 7.72 (dt, J = 6.3, 1.1 Hz, 1H), 7.66ꢀ
7.61 (m, 2H), 5.80 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); HRMS(ESI) m/z
calcd for C12H12NO3 [M+H]+ 218.0817, found 218.0809.
Methyl (E)-2-(4-methyl-3-oxoisoindolin-1-ylidene)acetate (7c): Yellow solid; Yield 64% (35
1
mg); mp 133ꢀ139 ºC; H NMR (CDCl3): δ 9.54 (s, 1H), 7.53ꢀ7.48 (m, 2H), 7.37 (d, J= 7.6 Hz,
13
1H), 5.74 (s, 1H), 3.83 (s, 3H), 2.72 (s, 3H); C NMR (CDCl3): δ 168.9, 168.1, 147.6, 138.5,
136.9, 133.8, 132.3, 126.5, 118.5, 90.1, 51.6, 17.2; HRMS (ESI) m/z calcd for C12H12NO3
[M+H]+218.0817, found 218.0811; IR (KBr): 3386, 2925, 1734, 1693, 1651, 1194, 793 cmꢀ1.
Methyl (E)-2-(5-methyl-3-oxoisoindolin-1-ylidene)acetate (7d): White semiꢀsolid; Yield 68%
1
(37 mg); H NMR (CDCl3): δ 9.55 (s, 1H), 7.67 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.45 (d, J= 7.9
Hz, 1H), 5.72 (s, 1H), 3.81 (s, 3H), 2.49 (s, 3H); 13C NMR (CDCl3): δ 168.2, 168.0, 147.7, 133.8,
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133.7, 129.9, 124.4, 120.8, 90.6, 51.7, 21.8; HRMS(ESI) m/z calcd for C12H12NO3 [M+H]+
218.0817, found 218.0815; IR (KBr): 3329, 1747, 1697 1488,1126, 786 cmꢀ1.
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Methyl (E)-2-(6-isopropyl-3-oxoisoindolin-1-ylidene)acetate (7e): White solid; Yield 58% (35
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mg); mp 150ꢀ159 ºC; H NMR (CDCl3): δ 9.54 (s, 1H), 7.79 (d, J= 7.5 Hz, 1H), 7.53 (s, 1H),
7.48 (d, J = 7.5 Hz, 1H), 5.78 (s, 1H), 3.81 (s, 3H), 3.06ꢀ3.03 (m, 1H), 1.31 (d, J = 6.4 Hz, 6H);
13C NMR (CDCl3):δ 168.1, 168.0, 154.8, 147.9, 136.8, 130.3, 127.4, 124.0, 118.8, 90.7, 51.7,
34.6, 23.8; HRMS (ESI) m/z calcd for C14H16NO3 [M+H]+ 246.1130 found 246.1129; IR (KBr):
3263, 2954, 2343, 1694, 1385, 1272, 790 cmꢀ1.
Methyl (E)-2-(6-methoxy-3-oxoisoindolin-1-ylidene)acetate (7g):White solid; Yield 60% (35
mg); mp 142ꢀ144 ºC; 1H NMR (CDCl3): δ 9.48 (s, 1H), 7.89 (d, J = 8.3 Hz,1H), 7.16 (d, J = 1.9
13
Hz, 1H), 7.13 (dd, J = 8.3, 2.0 Hz, 1H), 5.74 (s, 1H), 3.97 (s, 1H), 3.85 (s, 3H); C NMR
(CDCl3): δ167.9, 163.8, 147.6, 138.7, 125.5, 122.0, 117.8, 114.4, 105.9, 90.8, 55.9, 51.7;
HRMS(ESI) m/z calcd for C12H12NO4 [M+H]+ 234.0766, found 234.0759; IR (KBr): 3256,
1734, 1685, 1267, 1014, 836 cmꢀ1.
Methyl (E)-2-(5,6-dimethyl-3-oxoisoindolin-1-ylidene)acetate (7h):White solid; Yield 68%
1
(43 mg); mp 170ꢀ175 ºC; H NMR (CDCl3): δ 9.49 (s, 1H), 7.62 (s,1H), 7.44 (s, 1H), 5.70 (s,
1H), 3.81 (s, 3H), 2.39 (s, 6H); 13C NMR (CDCl3): δ 168.4, 168.1, 148.0, 142.5, 141.2, 134.5,
127.5, 124.7, 121.9, 94.8, 90.3, 51.6, 20.6, 20.4; HRMS(ESI) m/z calcd for C13H14NO3[M+H]+
232.0974, found 232.0977; IR (KBr): 2925, 1718, 1433, 1258 cmꢀ1.
Ethyl (E)-2-(5,6-dimethyl-3-oxoisoindolin-1-ylidene)acetate (7i):Cream solid; Yield 61% (37
1
mg); mp 168ꢀ170 ºC; H NMR (CDCl3): δ 9.49 (s, 1H), 7.62 (s,1H), 7.43 (s, 1H), 5.70 (s, 1H),
13
4.28ꢀ4.26 (q, 2H), 2.39 (s, 6H), 1.37 (t, 3H); C NMR δ = 168.46, 167.73, 147.81, 142.46,
141.17, 134.57, 127.57, 124.73, 121.87, 90.79, 60.50, 29.69, 28.46, 20.63, 20.39, 14.34; HRMS
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(ESI) m/z calcd for C14H16NO3 [M+H]+ 246.1130, found 246.1125; IR (KBr): 3327, 1721, 1467,
845 cmꢀ1.
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Methyl (E)-2-(5,6-diethoxy-3-oxoisoindolin-1-ylidene)acetate (7j):Yellowish solid; Yield 76%
(60 mg); mp 112ꢀ113 ºC; 1H NMR (CDCl3): δ9.40 (s, 1H), 7.3 (s,1H), 7.16 (s, 1H), 5.67 (s, 1H),
4.23ꢀ4.17 (q, 4H), 1.6ꢀ1.5 (t, 6H);13C NMR (CDCl3): δ 168.5, 168.0, 152.9, 152.1, 148.0, 129.6,
122.6, 106.6, 104.2, 90.1, 65.0, 64.9, 51.6, 14.6, 14.5; HRMS (ESI) m/z calcd for C15H17NO5Na
[M+Na]+ 314.1004, found 314.1011; IR (KBr): 3298, 3079, 2924, 1687, 1052 cmꢀ1.
Methyl (E)-2-(6,7-dimethoxy-3-oxoisoindolin-1-ylidene)acetate (7k)6e: White semiꢀsolid;
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Yield 40% (26 mg); H NMR (CDCl3): δ 9.65 (s, 1H), 7.62 (d, J= 8.1 Hz, 1H), 7.12 (d, J=8.2
Hz, 1H), 6.23 (s, 1H), 4.01 (6H), 3.83 (s, 3H).
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Methyl (E)-3-benzamidoacrylate (8a)8:White solid; Yield 87% (44 mg); H NMR (CDCl3): δ
8.45 (s, 1H), 8.30ꢀ8.23 (m, 1H), 7.88 (d, J = 7.1 Hz, 2H), 7.62 (dt, J = 5.6, 1.2 Hz, 1H), 7.52 (t, J
= 7.84 Hz, 2H), 5.68 (d, J = 14.2 Hz, 1H), 3.77 (s, 3H); HRMS(ESI) m/z calcd for C11H12NO3
[M+H]+ 206.0817, found 206.0811.
Methyl (E)-3-(2,6-difluorobenzamido)acrylate (8b): Yellowish semi solid; Yield 43% (25
mg); 1H NMR (CDCl3): δ8.24ꢀ8.17 (m ,1H), 7.96 (s, 1H), 7.54ꢀ7.46 (m, 1H), 7.06ꢀ7.02 (m, 2H),
5.67 (d, J = 14 Hz, 1H), 3.78 (s, 3H);13C NMR(CDCl3): δ 166.5, 137.3, 124.3, 112.6, 112.3,
107.0, 97.9, 51.5; HRMS(ESI) m/z calcd for C11H10F2NO3 [M+H]+ 242.0629, found
242.0622;IR (KBr): 3274, 1731, 1465, 1273, 680 cmꢀ1.
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Methyl (E)-3-(2-ethoxybenzamido)acrylate (8c): Yellow semiꢀsolid; Yield 59% (37 mg); H
NMR (CDCl3): δ 10.25 (s, 1H), 8.36ꢀ8.25 (m, 2H), 7.55 (dt, J = 8.5, 4.6 Hz, 1H), 7.15 (t, J = 7.9
Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 5.55 (d, J = 14.2 Hz, 1H), 4.30 (d, J = 6.9 Hz, 2H), 3.78 (s,
3H), 1.62 (t, J = 4.9 Hz, 3H); 13C NMR (CDCl3): δ 167.8, 157.2, 138.3, 134.4, 132.9, 121.7,
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119.4, 112.5, 101.4, 65.1, 51.4, 14.7; HRMS (ESI) m/z calcd for C13H16NO4 [M+H]+ 250.1079
found 250.0177; IR (KBr): 3299, 1732, 744 cmꢀ1.
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Methyl (E)-3-(2,4-difluorobenzamido)acrylate (8d): Yellowish semiꢀsolid; Yield 42% (27
mg);1H NMR (CDCl3): δ 8.19ꢀ8.14 (m, 1H), 7.81 (d, J = 16.4 Hz, 1H), 7.13 (t, J = 8.7 Hz, 1H),
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6.80 (d, J = 16.4 Hz, 1H), 6.60 (s, 1H), 5.90 (s, 1H), 3.86 (s, 3H); C NMR (CDCl3): δ 165.4,
164.3, 136.5, 136.1, 134.6, 131.8, 131.2, 120.6, 114.0, 52.6; HRMS (ESI) m/z calcd for
C11H10F2NO3 [M+H]+ 242.0629, found 242.0630.
Methyl (Z)-3-benzamidoacrylate (9a)7:Creame solid;Yield60% (31 mg); H NMR (CDCl3):
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δ11.5 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.80 (m, 1H), 7.61 (m, 1H), 7.53 (m, 2H), 5.31 (d, J = 8.8
Hz, 1H), 3.81 (s, 3H); HRMS(ESI) m/z calcd for C11H12NO3 [M+H]+ 206.0817, found 206.0818.
Computational Methods:
The quantum chemical calculations were employed with Gaussian09 suite of programs.13 The
Density Functional Theory (DFT)14 was used for the geometry optimizations and frequency
calculations for all the structures using B3LYP15 functional and 6–311+G(d,p) basis set. To
model the palladium complexes, the effective core potentials with standard doubleꢀ
ζ valence
basis set (LanL2DZ)16 were applied on palladium atom. The transition states were confirmed to
have only one imaginary frequency. The energy values discussed in the manuscript are based on
the
free energy (∆G) changes.
ASSOCIATED CONTENT
Supporting Information
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Copies of H and C NMR spectra for all new compounds. Cartesian coordinates and absolute
energies of the optimized geometries and transition state. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
*Eꢀmail: jlaha@niper.ac.in, pvbharatam@niper.ac.in.
Note
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The financial support from the Department of Science and Technology, New Delhi, India is
greatly appreciated.
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