Application of Isocyanides as Amide Surrogates in the Synthesis of Diverse Isoindolin-1-one Derivatives by a Palladium-Catalyzed Tandem Carboxamidation/Hydroamidation Reaction

Article abstract of DOI:10.1002/ejoc.201600999

The rapid synthesis of the isoindolinone skeleton has been accomplished by a palladium-catalyzed one-pot tandem process, which consists of an isocyanide insertion/hydration (carboxamidation) and 5-exo-dig cycloisomerization (hydroamidation) reaction seque

Full text of DOI:10.1002/ejoc.201600999

A Journal of
Accepted Article
Title: Application of isocyanides as an amide surrogate for the synthesis of diver-
se isoindolin-1-one derivatives via Palladium-catalyzed tandem Carboxamida-
tion/Hydroamidation reaction
Authors: Ramdas S Pathare; Shivani Sharma; Sathish Elagandhula; Vaishali Sai-
ni; Devesh Sawant; Monika Yadav; Ashoke Sharon; Shahnawaz Khan; Ram T
Pardasani
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600999
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600999
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European Journal of Organic Chemistry
10.1002/ejoc.201600999
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Application of isocyanides as an amide surrogate for the
synthesis of diverse isoindolin-1-one derivatives via Palladium-
catalyzed tandem Carboxamidation/Hydroamidation reaction
Ramdas S Pathare,a Shivani Sharma,a Sathish Elagandhula,b Vaishali Saini,b Devesh M
Sawant,b* Monika Yadav,c Ashoke Sharon,c Shahnawaz Khan,d* Ram T Pardasania*
Abstract Rapid synthesis of the isoindolinone skeleton has been
accomplished using Palladium-catalyzed one-pot tandem process
consisting isocyanide insertion-hydration (carboxamidation) followed
by 5-exo-dig cyclo-isomerization (hydroamidation) reaction in good
to excellent yield. This is an example of sequential C-C/C-O/C- N
bond formation. Preliminary mechanistic studies suggest that
carboxamidation
is
Palladium-dependent
process,
while
hydroamidation is mediated solely by base and is driven by
electrophilicity of alkynes.
Figure 1: Selected examples of biological relevant Isoindolin-
1-ones.
Introduction
Isoindolin-1-one is a structural motif that exists in an array of
naturally occurring and pharmacologically interesting
substances such as stachybotrin C,[10] fumaridine[11] and
lennoxamine,[12] pagoclone,[13] zopiclone,[14] AKS-186,[15]
pictonamine,[16] and pazinaclone[17] (Figure 1). Besides it also
has a noteworthy biological profile like HIV-1 inhibiting,[18,19]
anti-hypertensive,[20] antileukemic,[21] antimicrobial,[22] anti-
inflammatory,[23] antihyperglycemic activity,[24] and TACE
inhibiting activities.[25] Consequently, substantial synthetic
methodologies have been developed for the preparation of
isoindolinone derivatives[26,27] such as tandem
Isocyanide is
a
modern artist of current synthetic
architectures. Its stability and compatibility with a spectrum of
reagents offers an incredible opportunity to design tandem
processes for the rapid and efficient generation of complex
molecules.[1] Isocyanide, structurally and functionally
analogous to carbon monoxide, inherits unique reactivity by
virtue of its ambivalent nature at carbon and transforms itself
into an amide functional group.[2] This ability had been
elegantly exploited in Ugi and Passerini multicomponent
reactions.[3] Isocyanides also introduce an additional diversity
in the molecular framework. Recently, isocyanides have been
used to generate benzamides using
Pd-catalyzed
carboxamidation from readily available aryl halides.[4] This
has prompted us to opening of new opportunities to utilize
isocyanides as “amide surrogates”. Similarly, alkynes
represent an attractive and diverse building blocks for the
construction of complex molecular structures.[5] In this
context, metal-catalyzed isocyanide insertion[6,7] and
intramolecular cyclization of alkynes[8,9] offer incredible
opportunities for the construction of an array of heterocycles
via tandem C-C or C-X bond formation.
Scheme 1: Pd-catalyzed tandem isocyanide insertion strategy toward
isoindolin-1-ones from 1-halo-2-alkynylbenzenes
elimination–cyclization– Suzuki coupling sequence reported
by Couture and coworkers,[27] Heck–Suzuki–Miyaura domino
reactions of ynamides and arylboronic acids,[28] reaction of
phosphorous ylides with phthalimide derivatives,[29] a Pd-
[a]
[b]
Department of Chemistry, SCSP, Central University of Rajasthan,
Bandarsindri, Kishangarh – 305817, Rajasthan, India
Email- rtpardasani@curaj.ac.in
http://www.curaj.ac.in
catalyzed
oxidative
cyclization–alkoxycarbonylation
Department of Pharmacy, SCSP, Central University of Rajasthan,
Bandarsindri, Kishangarh – 305817, Rajasthan, India
Email- dms@curaj.ac.in
http://www.curaj.ac.in
Department of Chemistry, Birla Institute of Technology, Mesra,
Ranchi – 835215, Jharkhand, India
Email-asharon@bitmesra.ac.in
Department of Chemistry, University of Rajasthan, JLN Marg, Jaipur
– 302004, Rajasthan, India
sequence published by Kondo et al,[30] one-pot Sonogashira
coupling-carbonylation–hydroamination
reactions
of
dihalides,[31] an Ullman coupling-heteroannulation of 2-
bromobenzamides and terminal alkynes,[32] intramolecular
[c]
[d]
Email- khancdri@gmail.com
www.uniraj.ac.in
Supporting information for this article is given via a link at the end of the
document.
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European Journal of Organic Chemistry
10.1002/ejoc.201600999
FULL PAPER
the most effective (entries 5, 14-17). Solvent studies revealed
that the combination of DMF/H2O in the ratio 9:1
Scheme 2: The design of tandem carboxamidation-
hydroamidation.
Heck
reactions
of
enamides,[33]
a
Pd-catalyzed
aminocarbonylation approach for the synthesis of fluorinated
isoindolinones[34] and intramolecular cyclization of acyl radicals
on to an azide group.[35] Majorities of the existing methods go
through certain limitations with respect to the yield, substrate
scope, extra-dry conditions, or dependency over complex
precursors, which are generated through multi-step syntheses.
Thus, they are not suitable for the preparation of compound
libraries and hence there is a considerable scope for the
advancements. Thus in continuation to our studies on the
development of novel synthetic pathways for the preparation of
bioactive heterocycles,[36] herein, we report a novel and efficient
regio- and stereo-selective synthetic route to isoindolinones
through a sequential one-pot Pd-catalyzed isocyanide insertion
(C-C bond formation), hydration of imine intermediate (C-O bond
formation) and 5-exo-dig cyclo-isomerization (C-N bond
formation, Scheme 1 and 2).
Figure 2: ORTEP diagram (50% probability) for the X-ray crystal structure of
the compound 3cb with an atom numbering scheme showing C8-C9 exo-
double bond with E-configuration (CCDC 1472755). [37]
produced maximum yield of 3aa (entries 5, 18-20). The reaction
failed to initiate in extra dry DMF (entry 18). The catalytic
efficiency of Pd(OAc)2 remain unperturbed despite of reducing it
to 3 mol% (entry 21), however its further reduction to 1 mol%
furnished poor yield (entry 22). At lower temperature, the
reaction produced poor conversions and most of the starting
material was recovered, while raising the temperature had
detrimental effects on the reaction producing multiple spots. In
general, 3.0 mol% of Pd(OAc)2, 3.0 mol% of XantPhos, 2.0 equiv
Cs2CO3 as the base at 100 °C in DMF/H2O (9:1) was considered
as the best optimal condition and produced the excellent result
with 89% isolated yield of 3aa (entry 21).
Once the condition for tandem C-C/C-O/C-N cross-coupling
reaction sequences was optimized, we next investigated the
scope and limitation of this reaction by employing various ortho-
haloarylalkynes 1 and isocyanides (Scheme 3). The nature of R2
substituent attached to triple bond had a major impact on the
success of the reaction. Electron withdrawing substituents on
arenes at R2 increased the efficiency of the reactions to produce
3 in good to excellent yield (in 3af, 3ag, 3bc and 3be). The
reactions involving electron donating substituents on arenes at
R2 were sluggish and produced title compounds in diminished
yield (3ac, 3ad and 3ah). In contrast, alkyl- and alkenyl-
substituents at R2 failed to produce the cyclized product 3 and
instead furnished amide intermediate 2 as the only product.
Thus, electron withdrawing nature of R2 favors hydroamidation
by decreasing the electron density on the proximal end of the
triple bond. Interestingly, good yields were obtained when R2
was naphthalene (in 3bd) and heteroaryl group (in 3ea, 3ga and
3gb). Interestingly, in all cases E-isomers were established as a
major product and was confirmed by 1H NMR and X-ray
crystallographic analysis.(refer supporting information for further
details).[38]
Results and Discussion
We envisaged isocyanide as an amide surrogate that can be
elegantly exploited to generate 2-alkynylbenzamide 2 in situ
from ortho-haloarylalkynes 1, and subsequently cyclized to
either isoindole 3 or isoquinolone 4 in a one-pot tandem
sequence of carboxamidation and hydroamidation (Scheme 2).
We embarked our studies by investigating the sequential
isocyanide insertion and hydroamidation of 1aa using 5 mol % of
Pd(OAc)2/dppf as a catalyst system and 2.0 equivalents of
Cs2CO3 as a base at 100 °C in DMF/H2O (refer table 1 for
details). To our delight, the desired product 3aa was isolated in
30% yield (entry 1). The isoindole 3aa was fully characterized by
1H, 13C NMR and mass spectroscopic data. Further, X-ray
crystallographic analysis of compound 3cb unequivocally
confirmed the formation of regioisomer 3 and not 4 (refer Fig 2
and Scheme 3). Initial screening of catalyst and ligand
suggested that Pd(OAc)2 along with XantPhos afforded the
maximum yield (entries 1-10). The reaction failed to initiate in
the absence of catalyst, ligand or base (entries 11-13). Thus all
three components were critical for the success of tandem
reaction. Among various bases screened, Cs2CO3 proved to be
In order to gain the mechanistic insights, we first performed the
reaction in presence of TEMPO and Galvinoxyl (Scheme 4A). It
was observed that the radical scavengers had negligible effects
on tandem reaction. Hence a non-radical path is playing a role in
the formation of 3aa. To study the effect of reactants on
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European Journal of Organic Chemistry
10.1002/ejoc.201600999
FULL PAPER
the.tandem reaction, we designed control experiments to
dichotomize the tandem reaction into two discrete sets of
18.
19.
20.
21.
22.
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (3)
Pd(OAc)2 (1)
XantPhos
(5)
Cs2CO3
(2)
DMF
trace
35
XantPhos
(5)
Cs2CO3
(2)
DMSO/H2O
Dioxane
DMF/H2Oc
DMF/H2O
Table 1. Reaction Optimization for Isoindolin-1-one formation.a
XantPhos
(5)
Cs2CO3
(2)
trace
89d,e
30
XantPhos
(3)
Cs2CO3
(2)
XantPhos
(1)
Cs2CO3
(2)
[a]
Reaction condition: all reaction were performed in sealed tube on 0.3
t
mmol scale using 1a (1.0 equiv), BuNC (1.5 equiv), Pd(OAc)2 (3 mol
Entry
1.
Catalyst
(mol %)
Ligand
(mol %)
Base
(mol %)
Solvent
Yieldb
(%)
%), and ligand (3 mol %) and base (2.0 equiv) in 0.1 mL of H2O in 1.0
mL of solvent at 100 oC for 4h.
[b]
[c]
[d]
[e]
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
dppf (5)
Cs2CO3
(2)
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2Oc
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
30
40
45
55
90
trace
10
25
35
45
n.r.
n.r.
n.r.
30
32
45
8
Isolated yield.
n.r. – no reaction.
Among various compositions tried 9:1 ratio of DMF/ H2O produced best
results.
Reaction failed to initiate at 50 oC, 70 oC, and furnished poor yields at
2.
PPh3 (5)
Pcy3 (5)
Cs2CO3
(2)
3.
Cs2CO3
(2)
higher temperatures.
Among various combinations tried, 2 equivalents of Cs2CO3 and 1.5
equivalents of tBuNC produced optimum yield.
4.
X-Phos (5)
Cs2CO3
(2)
5.
XantPhos
(5)
Cs2CO3
(2)
carboxamidation and hydroamidation (Scheme 4B-C). For the
first step of carboxamidation, both catalyst/ligand and base (1.0
equiv) were crucial for the formation of both 6 and 2a (Scheme
4B)[39] In contrast, the second step, hydroamidation of 2e, was a
palladium-independent process and was solely mediated by
base [1.0 equiv. of Cs2CO3] to furnish 3aa (Scheme 4C). To
further understand the nature of reaction intermediates, we
treated substrate 1aa under the reported condition in the
absence of isocyanide. The failure to formation of 7 clearly
excludes hydration of 1aa to 7 and subsequent isocyanide
insertion and cyclization as a possible mechanism[39b] (Scheme
4D). The intermolecular competition experiments revealed
arenes bearing electron deficient group 1bc were preferentially
converted to their corresponding product 3bc as a sole product
with no formation of 3bb (Scheme 5A). In addition, competition
between substrates bearing aryl group on the distal end of triple
bond against substrates bearing alkyl and alkenyl group showed
preference to the aryl substituent to furnish 3aa exclusively
(Scheme 5B-C). The failure of substrates bearing alkenyl and
alkyl substituents (R2) to participate in competition with their aryl
counterparts substantiates the fact that the electrophilicity of
alkyne is the driving force for the tandem reaction.
6.
Pd(dppf)2Cl2
(5)
XantPhos
(5)
Cs2CO3
(2)
7.
PdCl2 (5)
XantPhos
(5)
Cs2CO3
(2)
8.
Pd(PPh3)2Cl2
(5)
XantPhos
(5)
Cs2CO3
(2)
9.
Pd2(dba)3 (5)
XantPhos
(5)
Cs2CO3
(2)
10.
11.
12.
13.
14.
15.
16.
17.
Pd(CH3CN)2Cl2
(5)
XantPhos
(5)
Cs2CO3
(2)
-
XantPhos
(5)
Cs2CO3
(2)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
-
Cs2CO3
(2)
XantPhos
(5)
-
XantPhos
(5)
K2CO3
(2)
Based on experimental investigations and previous
mechanistic insights,[4,40,41] a plausible mechanistic discourse
is proposed in figure 3. The catalytically active species 8 on
XantPhos
(5)
Dabco
(2)
oxidative addition forms
a
complex 9. Subsequently,
XantPhos
(5)
CsF (2)
coordination and migratory insertion of isocyanide furnishes
intermediate 11. Addition of water to C=N bond of 11 in the
presence of base and β-hydride elimination gives 2 that
further undergoes base-mediated hydroamidation to generate
the title compounds 3.
XantPhos
(5)
KtOBu
(2)
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European Journal of Organic Chemistry
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It is interesting to note that ortho-haloarylalkynes 1 were
synthesized from Pd-catalyzed Sonogashira reaction. Conditions
employed for the synthesis of 1 and subsequent reactions
thereof are very similar. Thus, we developed a Pd-catalyzed
one-pot self-
Scheme 4: Control experiments.
Scheme
3:
Pd-catalyzed
reaction
of
1-bromo-2-
(phenylethynyl)benzene derivatives with isonitriles.
relay protocol for the synthesis of 3aa from 2-
bromoiodobenzenes (Scheme 6).[42]
Scheme 5: Intermolecular Competition Experiment.
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European Journal of Organic Chemistry
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A 10 mL schlenk tube equipped with a stir-bar was charged with 1-
bromo-2-(phenylethynyl)benzene (0.1 g, 0.388 mmol) and DMF/H2O (1.0
mL, 9:1) as a solvent. The reaction tube was purged with argon. Then
after 5-10 min tert-butylisocyanide (0.048 g, 0.583 mmol), Cs2CO3 (0.253
g, 0.78 mmol), XantPhos (0.007 g, 0.01 mmol) and Pd(OAc)2 (0.003 g,
0.01 mmol) was added to the reaction mixture followed by argon purging.
The mixture was stirred at 100oC for 4 hrs. After cooling to room
temperature, the reaction mixture was passed through celite bed and
washed with EtOAc. The reaction mixture was diluted with EtOAc, which
was washed with water and brine successively, dried over anhydrous
sodium sulphate, filtered, and concentrated in vacuo. Purification by silica
gel (100-200 mesh) chromatography (EtOAc: Hexane) to yield the
desired product.
3-benzylidene-2-(tert-butyl)isoindolin-1-one
(3aa)
(known
compound).38 Brown Oil (97 mg, 90%); 1H NMR (δ ppm) (500 MHz,
CDCl3), E (major): 7.74 (d, J = 7.5 Hz, 1H), 7.45-7.39 (m, 5H), 7.33 (t, J =
7.4 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.02 (s, 1H), 6.85 (d, J = 7.9 Hz, 1H),
1.86 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 167.92, 137.43,
136.35, 135.48, 131.10, 131.03, 129.54, 128.80, 128.69, 127.68, 123.11,
122.66, 114.56, 57.62, 30.61; HRMS (ESI) calcd. for C19H20NO ([M + H]+)
278.1545, found, 278.1552. Product contains E- and Z-isomer in the ratio
of 92:8.
2-(tert-butyl)-3-(3-chloro-4-fluorobenzylidene)isoindolin-1-one (3ab).
Pale yellow oil (90 mg, 85%); 1H NMR (δ ppm) (500 MHz, CDCl3), E
(major): 7.75 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 6.95 Hz, 1H), 7.38 (t, J =
7.4 Hz, 1H), 7.29-7.20 (m, 3H), 6.86 (s, 1H), 6.83 (d, J = 7.9 Hz, 1H),
1.85 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 167.82, 158.58 (JC-F
=
Figure 3: Plausible mechanism.
248.75 Hz), 138.39, 135.04, 133.46 (JC-F = 3.75 Hz), 131.72, 131.37,
131.04, 129.56 (JC-F = 7.5 Hz), 129.13, 122.92, 121.38 (JC-F = 18.75 Hz),
117.11, 116.94, 111.54, 57.71, 30.53; 19F NMR (470.385 MHz, CDCl3): -
116.42; HRMS (ESI) calcd for C19H18ClFNO ([M + H]+) 330.1061, found,
330.1071. Product contains E- and Z-isomer in the ratio of 95:5
Conclusions
2-(tert-butyl)-3-(2-methoxybenzylidene)isoindolin-1-one (3ac). Yellow
oil (77 mg, 72%); 1H NMR (δ ppm) (500 MHz, CDCl3), E (major): 7.73 (d,
J = 7.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.21-7.18 (m,
1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00-6.98 (m, 2H), 6.89 (s, 1H), 3.85 (s, 3H),
1.87 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 167.86, 157.56,
140.36, 136.65, 135.59, 132.79, 131.54, 131.06, 131.04, 129.49, 128.54,
128.43, 124.78, 122.84, 122.61, 120.45, 111.77, 110.78, 57.57, 55.63,
30.66; HRMS (ESI) calcd for C20H22NO2 ([M + H]+) 308.1650, found,
308.1656. Product contains E- and Z-isomer in the ratio of 87:13. Despite
repeated drying on high vacuum, a significant solvent peak is observed in
1H and 13C NMR spectra. The isolated yield has been modified from 78%
to 72 %.
In conclusion, we have reported application of isocyanide as an
amide surrogate for the synthesis of isoindolinones. An efficient
method based on Pd(OAc)2/XantPhos has been developed to
synthesize isoindolin-1-ones derivatives. The methodology
demonstrated wide substrate scope and applications. The reaction
was operationally simple and avoid using toxic carbon monoxide
and acid chloride, which require an inert/ dry conditions.
Mechanistic investigations revealed that carboxamidation indeed
depends on both catalyst/ ligand and base, in contrast
hydroamidation was Pd-independent process and mediated by
base. Electrophilicity of the alkyne was the driving force for
hydroamidation and lack of electrophilic assistance led to
formation of amides 2a-2d. Interestingly, isocyanides also
furnished an additional diversity in the title compound. Here, we
also developed a one pot protocol for straightforward synthesis
of valuable isoindolin-1-one derivatives from simple and easily
available precursors.
2-(tert-butyl)-3-(3-methoxybenzylidene)isoindolin-1-one (3ad). Pale
yellow oil (86 mg, 76%); 1H NMR (δ ppm) (500 MHz, CDCl3), E (major):
7.73 (d, J = 7.5 Hz, 1H), 7.36-7.32 (m, 2H), 7.21-7.18 (m, 1H), 6.99-6.91
(m, 5H), 3.83 (s, 3H), 1.86 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3):
167.91, 159.90, 137.67, 137.47, 135.41, 131.16, 130.99, 129.87, 128.73,
123.29, 122.63, 121.89, 114.53, 114.33, 113.58, 57.62, 55.35, 30.60;
HRMS (ESI) calcd for C20H22NO2 ([M + H]+) 308.1650, found, 308.1656.
Product contains E- and Z-isomer in the ratio of 93:7.
2-(tert-butyl)-3-(3-chlorobenzylidene)isoindolin-1-one
(3ae).
Colourless oil (98 mg, 92%); 1H NMR (δ ppm) (500 MHz, CDCl3), E
(major): 7.74 (d, J = 7.5 Hz, 1H), 7.41 (s, 1H), 7.37-7.35 (m, 3H), 7.29-
7.28 (m, 1H), 7.23-7.20 (m, 1H), 6.90 (s, 1H), 6.85 (d, J = 7.9 Hz, 1H),
1.85 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 167.86, 138.22,
138.12, 135.17, 134.63, 131.30, 131.03, 130.07, 129.63, 129.01, 127.85,
127.78, 123.04, 122.82, 112.57, 57.69, 30.55; HRMS (ESI) calcd for
C19H19ClNO ([M + H]+) 312.1155, found, 312.1146. Product contains E-
and Z-isomer in the ratio of 92:8.
4-((2-(tert-butyl)-3-oxoisoindolin-1-ylidene)methyl)benzonitrile (3af).
Colourless oil (88 mg, 82%); 1H NMR (δ ppm) (500 MHz, CDCl3), E
(major): 7.76-7.72 (m, 3H), 7.54 (d, J = 8 Hz, 2H), 7.39 (t, J = 7.4Hz, 1H),
7.23 (t, J = 7.5 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J = 7.9 Hz, 1H), 1.85 (s,
9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 167.80, 141.53, 138.77,
134.88, 132.53, 131.38, 131.06, 130.58, 129.42, 123.06, 122.77, 118.76,
111.77, 111.32, 57.84, 30.53; HRMS (ESI) calcd for C20H19N2O ([M + H]-
+) 303.1497, found. 303.1488. Product contains E- and Z-isomer in the
Scheme 6: Development of one-pot self-relay protocol.
Experimental Section
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European Journal of Organic Chemistry
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FULL PAPER
ratio of 92:8. Despite repeated drying on high vacuum, a significant
solvent peak is observed in 1H and 13C NMR spectra. The isolated yield
has been modified from 87% to 82 %.
contains E- and Z-isomer in the ratio of 69:31. Despite repeated drying
on high vaccum, a significant solvent peak is observed in 1H and 13C
NMR spectra. The isolated yield has been modified from 88 % to 81 %.
2-(tert-butyl)-3-(4-fluorobenzylidene)isoindolin-1-one
(3ag).
3-(4-(trifluoromethyl)benzylidene)-2-(2,4,4-trimethylpentan-2-
Colourless oil (87 mg, 82%); 1H NMR (δ ppm) (500 MHz, CDCl3), E
(major): 7.74 (d, J = 7.5 Hz, 1H), 7.40- 7.34 (m, 3H), 7.20 (t, J = 7.8 Hz,
1H), 7.13 (t, J = 8.6 Hz, 2H), 6.94 (s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 1.85
(s, 9H); Z (minor): 7.80 (d, J =7.6 Hz, 1H), 7.67 (d, J = 7.75 Hz, 1H), 7.55
(t, J = 7.45 Hz, 1H), 7.43 (t, J = 7.45 Hz, 1H), 7.40-7.34 (m, 2H), 7.08 (t, J
= 8.6 Hz, 2H), 6.62 (s, 1H), 1.42 (s, 9H); 13C NMR (δ ppm) (125 MHz,
CDCl3) (Mixture of E and Z): 167.88, 163.31, 161.34, 139.34, 137.78,
135.30, 132.22 (JC-F = 3.75 Hz), 131.89, 131.30, 131.24 (JC-F = 7.5 Hz),
131.04, 128.84, 128.30 122.88 (JC-F = 12.5 Hz), 118.53, 115.96, 115.79,
115.63, 114.11, 113.24, 109.66, 60.01, 57.65, 30.58, 29.41; 19F NMR
(470.385 MHz, CDCl3): -114.06; HRMS (ESI) calcd for C19H19FNO ([M +
H]+) 296.1450, found 296.1442, found 296.1430. Product contains E- and
Z-isomer in the ratio of 80:20.
yl)isoindolin-1-one (3be). Pale yellow oil (97 mg, 79%); 1H NMR (δ
ppm) (500 MHz, CDCl3), E (major): 7.75 (d, J = 7.5 Hz, 1H), 7.69 (d, J =
7.9 Hz, 2H), 7.52 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.21 (t, J =
7.8 Hz, 1H), 7.00 (s, 1H), 6.79 (d, J = 7.9 Hz, 1H), 2.08 (s, 2H), 1.94 (s,
6H), 1.03 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 168.43, 140.37,
139.03, 135.12, 131.35, 131.05, 130.03, 129.92 (JC-F = 5.0 Hz), 129.14,
125.77 (JC-F = 3.75 Hz), 122.92 (JC-F = 12.5 Hz), 118.86, 113.24, 64.08,
61.55, 51.95, 50.67, 32.09, 31.27; 19F NMR (470.385 MHz, CDCl3): -
62.37; HRMS (ESI) calcd for C24H27F3NO ([M + H]+) 402.2044, found,
402.2035. Product contains E- and Z-isomer in the ratio of 93:7.
3-benzylidene-2-(tert-butyl)-6-methylisoindolin-1-one (3ca). Pale
yellow oil (97 mg, 84%); 1H NMR (δ ppm) (500 MHz,CDCl3), E (major):
7.52 (s, 1H), 7.44-7.37 (m, 5H), 6.98 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H),
6.71 (d, J = 8.0 Hz, 1H), 2.35 (s, 3H), 1.85 (s, 9H); 13C NMR (δ ppm)
(125 MHz, CDCl3): 168.06, 139.01, 137.47, 136.52, 132.95, 132.15,
131.25, 129.61, 128.74, 128.56, 122.92, 122.77, 113.76, 57.56, 30.62,
21.38; HRMS (ESI) calcd for C20H22NO ([M + H]+) 292.1701, found
292.1710. Product contains E- and Z-isomer in the ratio of 88:12.
2-(tert-butyl)-3-(4-methoxybenzylidene)isoindolin-1-one (3ah) (known
compound).38 Yellow oil (69 mg, 65%); 1H NMR (δ ppm) (500 MHz,
CDCl3), E (major): 7.73 (d, J = 7.5 Hz, 1H), 7.35-7.30 (m, 3H), 7.19 (t, J =
8.0 Hz, 1H), 6.97-6.93 (m, 4H), 3.88 (s, 3H), 1.85 (s, 9H); 13C NMR (δ
ppm) (125 MHz, CDCl3): 167.87, 159.14, 137.12 , 135.50, 131.07,
130.97, 130.76, 128.56, 128.43, 123.03, 122.63, 114.50, 114.17, 57.57,
55.37, 30.63; HRMS (ESI) calcd for C20H22NO2 ([M + H]+) 308.1650,
found 308.1654. Product contains E- and Z-isomer in the ratio of 79:21.
3-benzylidene-6-methyl-2-(2, 4, 4-trimethylpentan-2-yl)isoindolin-1-
one (3cb). Yellow oil (89 mg, 70%); 1H NMR (δ ppm) (500 MHz, CDCl3),
E (major): 7.52 (s, 1H), 7.44-7.37 (m, 5H), 7.01 (s, 1H), 6.96 (dd, J = 1.0,
8.0 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 2.35 (s, 3H), 2.07 (s, 2H), 1.93 (s,
6H), 1.02 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 168.63, 138.96,
138.23, 136.67, 133.04, 132.19, 131.26, 12956, 128.79, 127.60, 123.03,
122.82, 114.60, 61.31, 51.94, 32.19, 31.27, 21.36; HRMS (ESI) calcd for
C24H30NO ([M + H]+) 348.2327, Found, 348.2325. Product contains E-
and Z-isomer in the ratio of >99:<1.
3-benzylidene-2-(2,4,4-trimethylpentan-2-yl)isoindolin-1-one (3ba).
Brown oil (114 mg, 88%); 1H NMR (δ ppm) (500 MHz, CDCl3), E (major):
7.74-7.72 (m, 1H), 7.45-7.37 (m, 5H), 7.35-7.32 (m, 1H), 7.18-7.15 (m,
1H), 7.08 (s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 2.09 (s, 2H), 1.94 (s, 6H), 1.03
(s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 168.49, 138.15, 136.50,
135.53, 131.10, 131.02, 129.49, 128.85, 128.64, 127.71, 123.19, 122.70,
115.39, 61.40, 51.98, 32.14, 32.08, 31.27; HRMS (ESI) calcd for
C23H28NO ([M + H]+) 334.2171, found 334.2180. Product contains E- and
Z-isomer in the ratio of 94:6.
7-benzylidene-6-(tert-butyl)-6, 7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
one (3da). Yellow oil (71 mg, 66%); 1H NMR (δ ppm) (500 MHz, CDCl3),
E (major): 8.56 (d, J = 5.9 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.69 (d, J =
7.0 Hz, 2H), 7.44 - 7.27 (m, 4H ), 7.07 (s, 1H), 1.87 (s, 9H); 13C NMR ;
165.80, 154.77, 152.57, 135.78, 134.58, 130.72, 130.45, 129.65, 128.60,
127.72, 127.61, 124.11, 123.46, 123.22, 118.01, 58.05, 30.73, 29.29;
HRMS (ESI) calcd for C18H19N2O ([M + H]+) 279.1497, found 279.1491.
Product contains E- and Z-isomer in the ratio of 87:13.
3-(4-methylbenzylidene)-2-(2,4,4-trimethylpentan-2-yl)isoindolin-1-
one (3bb). Yellow oil (91 mg, 71%); 1H NMR (δ ppm) (500 MHz, CDCl3),
E (major): 7.73 (d, J = 7.5, 1H), 7.35-7.31 (m, 1H), 7.28-7.23 (m, 4H),
7.19-7.16 (m, 1H), 7.04 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 2.44 (s, 3H),
2.07 (s, 2H), 1.93 (s, 6H), 1.02 (s, 9H), Z (minor) : 7.78 (d, J = 7.4 Hz,
1H), 7.66 (d, J = 7.8 Hz, 1H), 7.55-7.52 (m, 1H), 7.41 (t, J = 7.5 Hz, 1H),
7.35-7.16 (m, 4H), 6.72 (s, 1H), 2.38 (s, 3H), 1.78 (s, 2H), 1.42 (s, 6H),
0.80 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 168.47, 137.91,
137.52, 135.59, 133.37, 131.05, 129.53, 129.35, 128.55, 123.20, 122.66,
115.62, 61.35, 51.98, 32.17, 32.09, 31.27, 21.39; HRMS (ESI) calcd for
C24H30NO ([M + H]+) 348.2327, found 348.2335. Product contains E- and
Z-isomer in the ratio of 82:18.
2-(tert-butyl)-3-(thiophen-2-ylmethylene)isoindolin-1-one
(3ea).
1
Brown oil (87 mg, 81%); H NMR (δ ppm) (500 MHz, CDCl3), E (major):
7.73 (d, J = 7.5 Hz, 1H), 7.43-7.41 (m, 1H), 7.39-7.35 (m, 1H), 7.27 –
7.24 (m, 1H), 7.12-7.10 (m, 1H), 7.06-7.04 (m, 1H), 7.01 (d, J = 7.9 Hz,
1H), 6.82 (s, 1H), 1.84 (s, 9H), Z (minor): 7.79 (d, J = 7.6 Hz, 1H), 7.65 (d,
J = 7.8 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.43 – 7.41 (m, 1H), 7.39 – 7.35
(m, 1H), 7.12 – 7.10 (m, 1H), 7.06 – 7.04 (m, 1H), 6.66 (s, 1H), 1.51 (s,
9H); 13C NMR (Mixture of E/Z) ; 172.22,167.95, 141.64, 140.86, 140.04,
139.80, 137.87, 137.80, 135.16, 133.72, 131.90, 131.43, 130.82, 129.09,
128.37, 128.30, 127.64, 127.61, 127.48, 126.73, 126.67, 123.26, 122.91,
122.69, 122.61, 118.62, 105.79, 103.39, 60.35, 57.76, 30.55, 29.31.
HRMS (ESI) calcd for C17H18NOS ([M + H]+) 284.1109, found 284.1101.
Product contains E- and Z-isomer in the ratio of 72:28.
4-((3-oxo-2-(2,4,4-trimethylpentan-2-yl)isoindolin-1
ylidene)methyl)benzonitrile (3bc). Off white solid (95 mg, 75 %); 1H
NMR (δ ppm) (500 MHz, CDCl3), E (major): 7.76-7.72 (m, 3H), 7.53 (d, J
= 7.9 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H), 7.23-7.20 (m, 1H), 6.96 (s, 1H),
6.79 (d, J = 8.0 Hz, 1H), 2.07 (s, 2H), 1.93 (s, 6H), 1.02 (s, 9H); 13C NMR
(δ ppm) (125 MHz, CDCl3): 168.36, 141.66, 139.48, 134.94, 132.56,
131.38, 131.07, 130.55, 129.37, 123.11, 122.84, 118.72, 112.58, 112.53,
111.39, 61.66, 51.94, 32.05, 31.26; HRMS (ESI) calcd for C24H27N2O ([M
+ H]+) 359.2123, found 359.2130. Product contains E- and Z-isomer in
the ratio of 95:5.
3,7-di((E)-benzylidene)-2,6-di-tert-butyl-2,3,6,7-tetrahydropyrrolo[3,4-
f]isoindole-1,5-dione (3fa). Green solid (74 mg, 68%); 1H NMR (δ ppm)
(500 MHz, CDCl3), EE (major): 7.50 - 7.40 (m, 6H), 7.37 - 7.35 (m, 4H),
7.19 (s, 2H), 7.03 (s, 2H), 1.80 (s, 18H), EZ (minor): 8.01 (s, 1H), 7.50 -
7.40 (m, 7H), 7.37-7.35 (m, 4H), 7.08 (s, 1H), 6.75 (s, 1H), 1.88 (s, 9H),
1.36 (s, 9H). 13C NMR (δ ppm) (125 MHz, CDCl3): 166.87, 136.65,
135.55, 135.34, 133.58, 129.31, 129.07, 128.35, 117.80, 115.78, 57.93,
30.52; HRMS (ESI) calcd for C32H33N2O2 ([M + H]+) 477.2542, Found
477.2535. Product contains E- and Z-isomer in the ratio of 89:11. Despite
repeated drying on high vaccum, a significant solvent peak is observed in
1H and 13C NMR spectra. The isolated yield has been modified from
72 % to 68 %.
3-(naphthalen-2-ylmethylene)-2-(2,4,4-trimethylpentan-2-
1
yl)isoindolin-1-one (3bd). Reddish oil (101 mg, 81%); H NMR (δ ppm)
(500 MHz, CDCl3), E (major): 7.98 (d, J = 8.1 Hz, 1H), 7.92 (t, J = 8.6 Hz,
2H), 7.70 (d, J = 7.4 Hz, 1H), 7.75-7.44 (m, 4H), 7.27 (s, 1H), 7.24 (d, J =
8.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.45 (d, J = 7.9 Hz, 1H), 2.15 (s, 2H),
2.01(s, 6H), 1.08 (s, 9H), Z (minor): 8.02 (d, J = 7.9 Hz, 1H), 7.94-7.88 (m,
1H), 7.82-7.76 (m, 3H), 7.75-7.44 (m, 6H), 7.03 (s, 1H), 1.28-1.24 (m,
8H), 0.70 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3) (Mixture of E/Z):
171.22, 168.57, 138.84, 135.56, 133.93, 133.81, 132.09, 131.73, 131.19,
131.02, 128.64, 128.61, 128.40, 127.68, 126.64, 126.57, 126.44, 125.77,
125.46, 125.23, 123.35, 122.74, 122.69, 113.37, 108.09, 63.39, 61.50,
52.05, 50.27, 32.28, 32.20, 31.38, 31.21, 29.76, 29.63; HRMS (ESI)
calcd for C27H30NO ([M + H]+) 384.2327, found, 384.2318. Product
2-(tert-butyl)-3-(pyridin-2-ylmethylene)isoindolin-1-one (3ga). Yellow
Oil (79 mg, 73%); 1H NMR (δ ppm) (500 MHz, CDCl3), E (major): 8.73 (d,
J = 4.3 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H), 7.37 (t,
J = 7.4 Hz, 1H), 7.30 – 7.22 (m, 2H), 7.09 (d, J = 7.9 Hz, 1H), 6.98 (s,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600999
FULL PAPER
1H), 1.86 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 168.09, 155.34,
149.86, 139.62, 136.59, 135.04, 131.34, 131.04, 129.28, 125.31, 123.23,
122.75, 122.37, 113.29, 57.84, 30.59; HRMS (ESI) calcd for C18H19N2O
([M + H]+) 279.1497, Found, 279.1487. Product contains E- and Z-isomer
in the ratio of 91:9. Despite repeated drying on high vaccum, a significant
solvent peak is observed in 1H and 13C NMR spectra. The isolated yield
has been modified from 79 % to 73 %.
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(b) T. Vlaar, E. Ruijter, B. U. W. Maes, R. V. A. Orru, Angew. Chemie -
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132, 17378-17380.
3-(pyridin-2-ylmethylene)-2-(2, 4, 4-trimethylpentan-2-yl)isoindolin-1-
one (3gb). Colourless oil (99 mg, 77%); 1H NMR (δ ppm) (500 MHz,
CDCl3), E (major): 8.74 (d, J = 4.5 Hz, 1H), 7.75-7.72 (m, 2H), 7.45 (d, J
= 7.5Hz, 1H), 7.36 (t, J = 7.0 Hz, 1H), 7.30-7.28 (m, 1H), 7.23 (t, J = 7.0
Hz, 1H) 7.05 (d, J = 7.9 Hz, 1H), 7.02 (s, 1H), 2.10 (s, 2H), 1.94 (s, 6H),
1.03 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 168.60, 155.46,
149.91, 140.19, 136.56, 135.13, 131.34, 131.01, 129.23, 125.37,123.23,
122.79, 122.35, 114.12, 108.84, 61.67, 52.01, 32.10, 31.28; HRMS (ESI)
calcd for C22H27N2O ([M + H]+) 335.2123, found 335.2131. Product
contains E- and Z-isomer in the ratio of 92:8
[3] (a) A. Dömling, Chem. Rev. 2006, 106, 17–89. (b) A. Dömling, W. Wang,
K. Wang, chem. Rev. 2012, 112, 3083-3135 and references therein.
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Chem. Eur. J. 2016, 22, 5878-5882.
N-(tert-butyl)-2-(3,
3-dimethylbut-1-yn-1-yl)benzamide
(2a).
1
Colourless oil (90 mg, 83%); H NMR (δ ppm) (500 MHz, CDCl3): 7.93 -
7.91 (m, 1H), 7.44-7.42 (m, 1H), 7.34 - 7.33 (m, 2H), 7.08 (bs, 1H), 1.50
(s, 9H), 1.36 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 165.94,
136.45, 134.07, 129.85, 129.47, 128.03, 120.01, 104.85, 77.93, 51.87,
30.95, 28.93, 28.39; HRMS (ESI) calcd for C17H24NO ([M + H]+) 258.1858,
found 258.1851.
[5] (a) Y. Yamamoto, Chem. Soc. Rev. 2014, 43, 1575–1600. (b) A. Fusano,
T. Fukuyama, S. Nishitani, T. Inouye, I. Ryu, Org. Lett. 2010, 12, 2410–
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12051. (d) M. Leibeling, M. Pawliczek, D. Kratzert, D. Stalke, D. B. Werz,
Org. Lett. 2012, 14, 346–349.
N-(tert-butyl)-2-(hept-1-yn-1-yl)benzamide (2b). Colourless oil (87 mg,
70%); 1H NMR (δ ppm) (500 MHz, CDCl3): 8.02-8.00 (m, 1H), 7.46 - 7.44
(m, 2H), 7.37-7.35 (m, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.68 - 1.62 (m, 2H),
1.48 (s, 9H), 1.45 – 1.43 (m, 2H), 1.38 – 1.36 (m, 2H), 0.92 (t, J = 7.25
Hz, 3H); 13C NMR (δ ppm) (125 MHz, CDCl3): 165.50, 136.30, 133.61,
130.05, 129.63, 128.18, 120.07, 97.30, 79.46, 51.49, 31.23, 28.86, 28.27,
22.26, 19.65, 14.0; HRMS (ESI) calcd for C18H26NO ([M + H]+) 272.2014,
found 272.2006.
[6] For recent examples on palladium-catalyzed processes to synthesis of N-
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2-(3,
3-dimethylbut-1-yn-1-yl)-N-(2,
4,
4-trimethylpentan-2-
yl)benzamide (2c). Colourless oil (80 mg, 76%); 1H NMR (δ ppm) (500
MHz, CDCl3): 7.94 - 7.92 (m, 1H), 7.45 - 7.43 (m, 1H), 7.35 - 7.33 (m,
2H), 7.08 (bs, 1H), 1.95 (s, 2H), 1.55 (s, 6H), 1.37 (s, 9H), 1.02 (s, 9H);
13C NMR (δ ppm) (125 MHz, CDCl3): 165.61, 136.44, 134.28, 131.33,
129.79, 129.42, 128.03, 120.03, 104.91, 78.09, 55.79, 50.97, 31.77,
31.49, 30.96, 29.58, 28.41; HRMS (ESI) calcd for C21H32NO ([M + H]+)
314.2484, found 314.2491.
N-(tert-butyl)-2-(cyclohex-1-en-1-ylethynyl)benzamide (2d). Reddish
oil (105 mg, 80%); 1H NMR (δ ppm) (500 MHz, CDCl3): 7.99-7.97 (m, 1H),
7.46 - 7.44 (m, 1H), 7.37-7.35 (m, 2H), 7.23 (bs, 1H), 6.27 - 6.25 (m, 1H),
2.25 - 2.22 (m, 2H), 2.19 – 2.16 (m, 2H), 1.71-1.67 (m, 2H), 1.66 - 1.61
(m, 2H), 1.47 (s, 9H); 13C NMR (δ ppm) (125 MHz, CDCl3): 165.62,
136.63, 136.43, 133.40, 130.01, 129.64, 128.36, 120.21, 119.88, 97.51,
85.06, 51.63, 29.10, 28.86, 25.83, 22.24, 21.41; HRMS (ESI) calcd for
C19H24NO ([M + H]+) 282.1858, found 282.1865
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Acknowledgements
We are grateful to CSIR [Grant No. 02(0201)/14/EMR-II] and
DST [Grant No. SB/FT/CS-012/2014] for funds and fellowship
to SS and RSP respectively. SK is thankful to UGC for D. S.
Kothari postdoctoral fellowship. We acknowledge the help of
Dr Gopal K. (Department of Chemistry, SCSP, CURaj) for
scientific discussions.
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Keywords: 5-exo-dig cyclization • Insertion • Isoindolin-1-Ones •
Regioselectivity • Tandem Reaction
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66, 2414–2421.
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European Journal of Organic Chemistry
10.1002/ejoc.201600999
FULL PAPER
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This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600999
FULL PAPER
Ramdas S Pathare,a Shivani Sharma,a
Sathish Elagandhula,b Vaishali Saini,b
Devesh M Sawant,b* Monika Yadav,c
Ashoke Sharon,c Shahnawaz Khan,d*
Ram T Pardasania*
Text for Table of Contents
Page No.1 – Page No.9
Application of isocyanides as an
amide surrogate for the synthesis of
diverse isoindolin-1-one derivatives
via
Palladium-catalyzed
tandem
Carboxamidation/Hydroamidation
reaction
Palladium(II) catalyzed transformation of ortho-haloarylalkynes
into 2-alkynylbenzamide using isocyanide as amide surrogate
is described (carboxamidation). The 2-alkynylbenzamide, so
generated in-situ, was subsequently cyclized to isoindolinone by
hydroamidation of alkynes. Thus a simple precursor (ortho-
haloarylalkynes) could be transformed into
a
bioactive
heterocycle (isoindolinone). The efficacy of our protocol is the
formation of four new chemical bonds with excellent regio-
/stereo-control. This is the first report on the synthesis of
isoindolin-1-one via Pd-catalyzed isocyanide insertion/cyclization
process.
This article is protected by copyright. All rights reserved