Iron Promoted Ring Opening and Ring Closing Cascade (ROCC) Reaction of Ortho-Carboxy-Isoxazoles Leading to Isoindolinone Derivatives

Article abstract of DOI:10.1002/ejoc.202100716

An efficient and convenient route for the synthesis of various functionalized 3-alkylidene isoindolin-1-ones is presented. The synthesis involves the ring opening and ring closing cascade (ROCC) reaction of ortho-carboxy-isoxazole using Fe/NH₄Cl. This is the first report for the synthesis of 3-alkylidene isoindolin-1-one using Fe/NH₄Cl.

Full text of DOI:10.1002/ejoc.202100716

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Iron Promoted Ring Opening and Ring Closing Cascade (ROCC)
Reaction of Ortho-Carboxy-Isoxazole leading to Isoindolinone
Derivatives
Authors: Ramakrishna Gudipati, Vankudoth Jayaram, Dinesh
Bhoot, Satyanarayana Yennam, Manoranjan Behera, Karri
Raghavulu, and Keloth Basavaiah
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100716
Link to VoR: https://doi.org/10.1002/ejoc.202100716
01/2020

10.1002/ejoc.202100716
European Journal of Organic Chemistry
Iron Promoted Ring Opening and Ring Closing Cascade (ROCC)
Reaction of Ortho-Carboxy-Isoxazole leading to Isoindolinone
Derivatives
Ramakrishna Gudipati[a,b], Vankudoth Jayaram[a], Karri Raghavulu[a, b] , Dinesh Bhoot[a], Keloth
Basavaiah[b], Satyanarayana Yennam[a], Manoranjan Behera*[a]
Abstract: An efficient and convenient route for the synthesis of
various functionalized 3-alkylidene isoindolin-1-ones is presented.
The synthesis involves the ring opening and ring Closing Cascade
(ROCC) reaction of ortho-carboxy-isoxazole using Fe/NH4Cl. This is
the first report for the synthesis of 3-alkylidene isoindolin-1-one using
Fe/NH4Cl.
Introduction
N-containing heterocycles are highly demanded structural motifs and
they are found in nature with a numerous biological activities.[1]
Among the vast family of N-containing heterocycles, isoindolinones
(Fig 1) such as, chileninc, pictonamine2, lennoxamine, D4 dopamine
receptor ligand (S)-PD 172938, Pagoclone (Cl-1043) and
Pazinaclone (DN-2327) are very important boiological active
compounds.[3-6] Due to their great significance, many powerful
synthetic methodologies have been reported for the synthesis of
alkylidene Isoindolin-1-ones in last decades.These methods mainly
involved the traditional condensation reaction of phthalimides with
stabilized phosphoranes[7] or addition of organometallic reagents
followed by dehydration of the resulting 3-hydroxyphthalimidines[8].
Also, the Horner condensation of 3-(diphenylphosphinoyl)isoindolin-
1-ones with aldehydes,[9] ortho lithiation–anionic cyclization of N-
Figure 1. Selected examples of biologically active compounds
with the isoindolin-1-one skeleton.
acyl-2-bromobenzamides,[10] electrophilic cyclizations of 2-
alkynylbenzamides[11] (Scheme 1) and metal-catalyzed cascade
the relatively labile N-O bond, which is easy to cleave into
reactions[12] are reported in literature. However, most of these
heterocyclic compounds.[14] There are many examples found in the
procedures suffer from one or more drawbacks such as the use of
literature where isoxazoles have been employed as the starting
expensive metal reagents or palladium catalyzed reactions,
materials.[15-17] Recently, many research groups used isoxazoles as
availability of starting materials like alkyne ketone. So, there is an
substrates to react with alkynes in the presence of gold[18]
,
urgent need to develop new method for the synthesis of isoindoline
using less expensive regents.
[20]
platinum[19], Zn(OTf)2
and Tf2NH as catalysts[21], affording various
nitrogen containing heterocycles.The application of iron salts as
catalysts in organic synthesis has attracted much attention[22] owing
to their environmentally benign, low cost, and the abundance of
elemental iron.[23] However, it is still a challenge to form other
heterocycles from isoxazoles catalyzed by iron salts. There are few
examples reported for prepration of N-heterocycles using iron salts
as catalysts. For example, domino transformation of isoxazoles to 2,4-
dicarbonylpyrroles under Fe/Ni relay catalysis has been reported by
Khlebnikove and co-workers.24 The same group have also reported Fe(II)-
Catalyzed isomerization of 4-vinylisoxazoles into pyrroles25 and
Fe(II)/Au(I) relay catalyzed propargylisoxazole to pyridine
isomerization: access to 6-halonicotinates.26 Chen et al. has
reported iron-mediated Ring-Opening and Rearrangement Cascade
synthesis of polysubstituted pyrroles from 4-alkenylisoxazoles. 27
Isoxazoles have recently emerged as valuable precursors for
the synthesis of various other scaffolds.[13] One of the key structural
elements of isoxazole which attracts attention of synthetic chemist is
[a] R. Gudipati, V. Jayaram, K. Raghavulu, Dinesh Bhoot, S.
Yennam, Dr. M. Behera, Chemistry Services, Aragen Life Sciences
(Formerly known as GVK Biosciences),
Plot No. 125 (part)&126, IDA, Mallapur, Hyderabad, Telangana,
India, 500076.
E-mail: Manoranjan.Behera@aragen.com
[b] R. Gudipati, K. Raghavulu, Dr.K. Basavaiah
Department of Inorganic & Analytical Chemistry, Andhra
University, Waltair Junction, Visakhapatnam, Andhra
Pradesh, India, 530003.
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
Recently we have reported Fe/NH4Cl mediated conversion of
isoxazole to substituted pyridine derivatives via ROCC
mechanism.[28] In our continuous effort to prepare natural product
hybrids [29], we were interested to prepare few isoindoline derivatives.
Here in we report, the preparation of alkylidene Isoindolinone
derivatives from ortho-carboxy isoxazole via ROCC mechanism.
the 2-carboxy isoxazole derivatives 5a-5x with moderate to good
yields (Table1) (60-92%).
Table1: Various Ortho-Carboxy-Isoxazoles Prepareda
aYields of isolated products in parenthesis
With our previous work based on isoxazole opening, we started to
explore the ring opening ring closing cascade reaction of 5 with Fe/
NH4Cl condition. Initially we conducted the optimization reaction by
using Fe (10 equiv) and NH4Cl (6 equiv.) in EtOH: H2O (2:1) at 120
0C for 24 h and we observed the N-cyclized product 6 as a single
(Z)-isomer 6 in 45% yield The structure was ascertained by NMR
spectroscopy 2D conformation (Table 2, entry 1). Further reducing
the temperature to 90 0C and reaction time to 16 h led to the
improvement of the product yield (Table 2, entry 2). Then
decreasing the amount of catalyst loading Fe (5 equiv) and NH4Cl (3
equiv) resulted the product formation with improved yield to 89%
(Table 2, entry 3). When the reactions were performed in other
solvents such as MeOH (Table 2, entry 4), IPA (Table 2, entry 5),
DMF (Table 2, entry 6), Dioxane (Table 2, entry 7), yield of the
product could not be further improved. Notably, EtOH was most
favourable reaction media. In a similar manner, presence of EtOH
(Table 2 entry 8) and H2O (Table 2 entry 9) was critical for the
product formation.When the reaction was performed in the absence
of NH4Cl (Table 2, entry 10) very less product formation was
observed. Similarly, without Fe (Table 2, entry 11) the reaction gave
poor yield. The lowering of catalyst loading and reaction time (Table
2, entries 12-15) resulted in reduction of the product yield. No
improvement was found by switching of solvent and with the addition
of AcOH (Table 2, entries 16-17). The reaction was failed with the
use of other catalyst Fe and NH4OAc (Table 2, entry 18). Therefore,
the optimum reaction conditions for the transformation was found to
be taking 5 equiv of Fe, 3 equiv NH4Cl in EtOH: H2O (2:1) ration and
refluxing the reaction mixture at 90 oC for 16 h which gave 89% yield
(Table 2, Entry 3).
Scheme 1. Synthetic strategies toward the isoindolin-1-ones
framework
Results and discussion
We initiated our studies with 2-carboxy isoxazoles 5a as model
substrate, which was easily prepared from the commercially
available methyl 2-formylbenzoate via a three steps[30] synthetic
sequence (Scheme 2).
Scheme 2: Synthesis of Ortho-Carboxy-Isoxazoles
The reaction involved the condensation of hydroxylamine with
methyl 2-formylbenzoate to give oxime derivatives 2a-2b which upon
treatment with N-chlorosuccinimide gave the methyl 2-
(chloro(hydroxyimino)methyl) benzoate 2c-2d. The key 3+2
cycloaddition reaction was performed with substituted acetylenes to
afford various methyl 2-(isoxazol-3-yl) benzoate derivatives 4a-4x.
This was employed for basic hydrolysis without purification to afford
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
Based on the literature31, a plausible mechanism is proposed in
Scheme 3. The reaction starts with iron coordinating wth isoxaole
ring through N atom to form the interemediate 8a which undergo
reductive ring opening of isoxazole ring to give the enaminone
interemdiate 8b. The lone pair of nitrogen in enaminone
intermediate 8b picks up H+ ion in acidic medium (NH4Cl in H2O)
to form the intermediate 8c which picks up a second H+ to
facilitate the cleavage of Fe in the mechansism cycle and give the
2-(3-hydroxy-1-imino-3-phenylallyl) benzoic acid 8d. The
intermediate 8d undergoes intramolecular rearrangement to give
the
more
stable
2-(1-amino-3-oxo-3-phenylprop-1-en-1-yl)
benzoic acid 8e. The nucleophilic attack of nitrogen loan pair
towards the carbonyl function gave the ring closure intermediate 8C.
Finally, elimination of water takes place to afford the desired product
the 3-alkylidene isoindolin-1-one 6.
Scheme 3: Plausible Mechanism for the Formation of 3-alkylidene Isoindolin-1-ones
With the optimized conditions in hand, we then focused on studying
the scope of the different substitution in the isoxazole derivatives in
the ring opening and ring closing cascade reaction and the results
are described below (Table 3). Electron donating groups on
para/ortho position such as methoxy, methyl, could be well tolerated
and their corresponding products 6b-6e were obtained in
comparable yield (74-83%). On the other hand, aryl having electron
withdrawing group (-CN, COOH, Phenyl or –CF3) at the para /meta
position (6f-6j) gave moderate to good yield (51-84%). Interestingly,
halogen- substituted isoxazole could also be applied in this
methodology to give the products 6k-6n and 6u in good yields (77-
82%). It was found that hetero aromatics such as 2-methyl-1H-
imidazol-5-yle, 3-pyridyl, were also found to be good substrates to
furnish 6o, 6p (53-65%) yield. In addition, aliphatic side chain also
afforded 6q-6s in synthetically yields (56-64%). It is noteworthy to
mention here that ortho-carboxy-isoxazoles having NO2 group
substitution on phenyl ring was also engaged in ROCC mechanism
to give isoindoline derivative 6t with amine functionality in 56% yield.
Subsequently, if the R1 having chloro substitution and the targeted
products 6v-6x were obtained in moderate to good yields (76-85%).
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
Table 2: Optimization of the Reaction Conditions for the Synthesis of 3-alkylidene Isoindolinone 6
Catalyst
(x eq)
Entry
Temp
Time(h)
Solvent
Yield a
NH4Cl (eq)
1
Fe (10)
6
120
0C
24
EtOH/H2O(2:1)
45
2
3
4
Fe (10)
Fe( 5)
Fe (5)
6
3
3
90 0C
16
16
16
EtOH/H2O(2:1)
EtOH/H2O(2:1)
MeOH/H2O(2:1)
67
89
55
90 0C
90 0C
5
6
Fe(5)
Fe(5)
3
3
90 0C
90 0C
16
16
IPA/H2O(2:1)
DMF/H2O(2:1)
80
30
7
Fe(5)
3
90 0C
16
Dioxane /H2O
(2:1)
34
8
Fe(5)
Fe (5)
Fe (5)
-
3
3
-
90 0C
90 0C
90 0C
90 0C
90 0C
90 0C
90 0C
90 0C
90 0C
90 0C
16
16
16
16
16
4
H2O
63
12
8
9
EtOH
10
11
12
13
14
15
16
17
18
EtOH/H2O(2:1)
EtOH/H2O(2:1)
EtOH/H2O(2:1)
EtOH/H2O(2:1)
EtOH/H2O(2:1)
EtOH/H2O(2:1)
AcOH
3
1
3
3
3
-
5
Fe(2)
Fe (5)
Fe (5)
Fe(5)
Fe (5)
Zn (5)
20
15
32
64
30
0
8
12
16
16
16
-
AcOH
Fe(5) NH4OAc 90 0C
EtOH/H2O(2:1)
0
a Yields based on LC-MS analysis
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
Table 3. Scope of substituted 3-alkylidene Isoindolin-1-ones
aGeneral conditions: 5 (1 eq), Iron (5 eq) and NH4Cl (3 eq ), EtOH:H2O (2:1 mL), 90 0C, 16 h. b Yields of isolated products.
Conclusion:
General Procedure for the Ring-opening and Ring Closing
In conclusion, we have developed a simple and facile synthesis of
isoindolinones from easily accessible or commercially available
starting materials. The key features of this methodology involve
Fe/NH4Cl, mediated Reductive Ring Opening and Ring Closing
cascade (ROCC) mechanism of ortho-carboxy-Isoxazole This
general method affords a reasonably broad substrate scope and
good functional group compatibility, allowing for the introduction of
functionalized organic molecules. We believe that this methodology
Cascade (ROCC) of Ortho-Carboxy-Isoxazole (5a-5x). A solution
of methyl 2-(isoxazol-3-yl) benzoate 4a-4x (1.79 mmol) in EtOH
(10mL) and added 20% NaOH (5.37 mmol) at 0 0C and the RM was
stirred at RT for 2-4 h. TLC analysis in 100 % EtOAc/Pet-ether
showed completion of the reaction. Then RM was evaporated and
solid was dissolved in water. The aqueous solution was extracted
with ethyl acetate and discard. Then the aqueous layer was taken
0
into the RB flask and acidified with Conc.HCl at 0 C, solid formed,
will be of interest to the synthetic/medicinal chemists and may find
applications in the pharmaceutical industry.
filtered the solid and dried under vacuum to give the pure
compounds 5a-5x (60-92%) yield.
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
7.53(d, 1H, J = 7.6 Hz), 7.42-7.40 (d, 2H, J = 6 Hz), 7.38-7.28(m,
2H), 6.61(s, 1H). LC-MS (ESI+): m/z (M+H)+ found 334.18.
2-(5-(2-fluorophenyl)isoxazol-3-yl)benzoic acid (5k). Rf = 0.10
(EtOAc 100). Off-white solid (419 mg, 88%). M.p. 156-159 oC. 1H
NMR (400 MHz, CDCl3): δ 8.10-8.00(m, 2H), 7.66-7.56 (m, 3H),
7.45-7.41(t, 1H), 7.31-7.30 (d, 2H, J = 7.6 Hz), 7.22-7.17(t, 1H),
7.31-6.88-6.87 (d, 1H, J = 3.6 Hz). LC-MS (ESI+): m/z (M+H)+ found
284.26.
2-(5-phenylisoxazol-3-yl)benzoic acid (5a). Rf = 0.10 (EtOAc 100).
1
Off-white solid (437 mg, 92%). M.p. 144-147 oC. H NMR (400 MHz,
CDCl3): 8.08-8.07 (d, 1H, J = 7.0 Hz), 7.83-7.80 (dd, 2H, J = 8 & 7.2
Hz), 7.66-7.55 (m, 3H), 7.49-7.44 (m, 3H), 6.68(s, 1H). LC-MS
(ESI+): m/z (M+H)+ found 266.27.
2-(5-(4-methoxyphenyl)isoxazol-3-yl)benzoic acid (5b) Rf = 0.10
(EtOAc 100). Off-white solid (466 mg, 89%). M.p. 180-183 oC. 1H
NMR (400 MHz, CDCl3): δ 8.07-8.05(d, 1H, J = 7.6 Hz), 7.75-7.73(d,
2H, J = 8.8 Hz), 7.64-7.53 (m,3H), 6.99-6.96 (d, 2H, J = 8.8 Hz),
6.55(s, 1H), 3.87(s,3H). LC-MS (ESI+): m/z (M+H)+ found 296.27.
2-(5-(p-tolyl)isoxazol-3-yl)benzoic acid (5c) Rf = 0.10 (EtOAc
100).Off-white solid (427 mg, 90%). M.p. 152-155oC. 1H NMR (500
MHz, CDCl3): δ 8.08-8.06 (d, 1H, J = 7.5 Hz), 7.71-7.70(d, 2H, J = 8
Hz), 7.64-7.63 (t, 2H), 7.58-7.56 (d, 1H, J = 7.5 Hz), 7.78(s, 2H),
6.62(s, 1H), 2.41 (s,3H). LC-MS (ESI+): m/z (M+H)+ found 280.26.
2-(5-(2-methoxyphenyl)isoxazol-3-yl)benzoic acid (5d). Rf = 0.10
(EtOAc 100), Off-white solid (420 mg, 88%). M.p. 175-178 oC. 1H
NMR (400 MHz, CDCl3): δ 8.07-8.05(d, 1H, J = 7.6 Hz), 8.01-7.99 (d,
2H, J = 6.8 Hz), 7.64-7.63 (d, 2H, J = 4 Hz), 7.56-7.52 (m, 1H), 7.42-
7.38(m, 1H), 7.09-7.06(t, 1H), 7.00-6.98(d, 1H, J = 8.8 Hz), 6.94(s,
1H), 3.91 (s,3H). LC-MS (ESI+): m/z (M+H)+ found 296.27.
2-(5-(2,4-difluorophenyl)isoxazol-3-yl)benzoic acid(5l): Rf = 0.10
(EtOAc 100). Off-white solid (406 mg, 85%). M.p. 159-162 oC.1H
NMR (500 MHz, CDCl3): δ 8.07-8.06(d, 1H, J = 7.5 Hz), 8.01-
7.96(dd, 1H, J = 8.5 Hz), 7.66-7.55 (m, 3H), 7.05-7.01(m, 1H),6.96-
6.91(m, 1H), 6.80-6.79(d, 2H, J = 3.5 Hz). LC-MS (ESI+): m/z
(M+H)+ found 301.9.
2-(5-(2,6-difluorophenyl)isoxazol-3-yl)benzoic acid (5m) Rf = 0.10
(EtOAc 100). Off-white solid (391 mg, 82%). M.p. 191-194 oC.1H
NMR (400 MHz, CDCl3): δ 8.10-8.08(d, 1H, J = 8 Hz), 7.68-7.65(d,
2H, J = 13.2 Hz), 7.59-7.51(m, 1H), 7.44-7.37(m, 1H), 7.07-7.03(t,
2H), 6.87(s, 1H). LC-MS (ESI+): m/z (M+H)+ found 302.3.
2-(5-(3-fluorophenyl)isoxazol-3-yl)benzoic acid (5n): Rf = 0.10
(EtOAc 100). Off-white solid (400 mg, 84%). M.p. 176-179 oC.1H
NMR (400 MHz, CDCl3): δ 8.08-8.06(d, 1H, J = 7.6 Hz), 7.67-7.55(m,
4H), 7.52-7.49 (d, 1H, J = 9.2 Hz), 7.47-7.41(m, 1H), 7.16-7.12(m,
1H), 6.69 (s, 1H). LC-MS (ESI+): m/z (M+H)+ found 284.20.
2-(5-(2-methyl-1H-imidazol-4-yl)isoxazol-3-yl)benzoic acid (5o):
Rf = 0.10 (EtOAc 100). Off-white solid (309 mg, 65%). M.p. 159-162
oC.1H NMR (500 MHz, DMSO-d6): δ 13.4(bs, 1H), 8.66-8.61 (t, 1H),
8.02-7.99(t, 1H), 7.91-7.89(d, 1H, J = 7.5 Hz), 7.72-7.58(m, 3H),
7.23-7.21(t, 1H), 3.96( d, 3H, J = 2 Hz). LC-MS (ESI+): m/z (M+H)+
found 270.09.
2-(5-(o-tolyl)isoxazol-3-yl)benzoic acid (5e). Rf = 0.10 (EtOAc
1
100), Off-white solid (414 mg, 87%). M.p. 164-167 oC. H NMR (400
MHz, CDCl3): δ 8.10-8.08(d, 1H, J = 8 Hz), 7.75 (d, 1H, J = 2 Hz),
7.66 (d, 2H, J = 3.6 Hz),7.60-7.57 (m, 1H), 7.35-7.28 (m, 3H), 6.58(s,
1H), 2.52 (s, 3H). LC-MS (ESI+): m/z (M+H)+ found 280.30.
2-(5-(4-cyanophenyl)isoxazol-3-yl)benzoic acid (5f). Rf = 0.10
(EtOAc 100). Off-white solid (333mg, 70%). M.p. 172-175 oC.1H
NMR (500 MHz, CDCl3): δ 8.10-8.08 (d, 1H, J = 8.5 Hz), 7.93-7.91(d,
2H, J = 8.5 Hz), 7.78-7.76(d, 2H, J = 8.5 Hz), 7.67-7.66 (t, 1H), 7.62-
7.58 (m, 2H), 6.80 (s, 1H). LC-MS (ESI+): m/z (M+H)+ found 291.25
2-(5-(pyridin-3-yl)isoxazol-3-yl)benzoic acid (5p): Rf
= 0.10
(EtOAc 100). Off-white solid (365 mg, 77%). M.p. 226-229 oC.1H
NMR (500 MHz, CDCl3): δ 9.1(s, 1H), 8.67(s, 1H), 8.20-8.19(d, 1H, J
= 8 Hz), 8.11-8.10(d, 1H, J = 7 Hz), 7.67-7.60 (m, 3H), 7.48-7.46(d,
1H, J = 7.5Hz), 6.89 (s, 1H). LC-MS (ESI+): m/z (M+H)+ found
267.26.
2-(5-(4-carboxyphenyl)isoxazol-3-yl)benzoic acid (5g). Rf = 0.30
(MeOH/DCM 10:90). Off-white solid (344 mg, 72%). M.p. 207-210
oC.1H NMR (400 MHz, DMSO-d6): δ 13.17 (bs, 2H), 8.11-8.09 (d, 2H,
J = 8.8 Hz), 8.05-8.03 (d, 2H, J = 8.8 Hz), 7.90-7.88 (dd, 1H, J = 8 &
8 Hz), 7.70-7.62 (m, 3H), 7.40 (s, 1H). LC-MS (ESI+): m/z (M+H)+
found 310.
2-(5-(tetrahydro-2H-pyran-2-yl)isoxazol-3-yl)benzoic acid (5q):
Rf = 0.10 (EtOAc 100). Semi solid (299 mg, 63%).1H NMR (500 MHz,
CDCl3): δ 8.05-8.04(d, 1H, J = 7.5 Hz), 7.63-7.53(dd, 1H, J = 8.5&15
Hz), 7.56-7.53(t, 2H), 6.36(s, 1H), 4.36-4.60 (dd, 1H, J = 2&10.5 Hz),
4.11-4.09 (d, 1H, J = 11.5Hz), 3.66(t, 1H), 2.08-2.05(d, 1H, J =
13.5Hz), 1.98-1.97(d, 1H, J = 3.5Hz), 1.81-1.6 (m, 4H). LC-MS
(ESI+): m/z (M+H)+ found 274.34.
2-(5-([1,1'-biphenyl]-4-yl)isoxazol-3-yl)benzoic acid (5h). Rf
=
o
0.10 (EtOAc 100). Off-white solid (384 mg, 80%). M.p. 183-186 C.
1H NMR (400 MHz, CDCl3): δ 8.09-8.07 (d, 1H, J = 7.6 Hz), 7.89-
7.87(d, 2H, J = 8 Hz), 7.72-7.55 (m, 7H), 7.49-7.45(t, 2H), 7.39-
7.37(m, 1H), 6.71(s, 1H). LC-MS (ESI+): m/z (M+H)+ found 342.31.
2-(5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)benzoic acid (5i). Rf
= 0.10 (EtOAc 100). Off-white solid (365 mg, 76%). M.p.181-184oC.
1H NMR (400 MHz, CDCl3): δ 8.10-8.08(d, 1H, J = 7.6 Hz), 7.93-7.91
(d, 2H, J = 8.4Hz), 7.74-7.72(d, 2H, J = 8.4 Hz), 7.69-7.57(m, 3H),
6.77(s, 1H). LC-MS (ESI+): m/z (M+H)+ found 334.26.
2-(5-(tetrahydrofuran-3-yl)isoxazol-3-yl)benzoic acid (5r): Rf
=
0.10 (EtOAc 100). Semi solid (450 mg, crude 82% purity as such for
used for next step LC-MS (ESI+): m/z (M+H)+ found 260.19.
2-(5-cyclopropylisoxazol-3-yl)benzoic acid (5s): Rf = 0.10 (EtOAc
1
100). Semi solid (282 mg, 60%). H NMR (500 MHz, CDCl3): δ 8.06
2-(5-(3-(trifluoromethyl)phenyl)isoxazol-3-yl)benzoic acid (5j). Rf
= 0.10 (EtOAc 100). Off-white solid (360mg, 75%). M.p.123-126
oC.1H NMR (400 MHz, CDCl3): δ 7.82(s, 1H), 7.73-7.68(t, 2H), 7.55-
(d, 1H, J=2), 7.63-7.59 (m, 1H), 7.55-7.52 (m, 2H), 6.09 (s, 1H),
2.10-2.07 (m, 1H), 1.12-1.06 (m, 4H). LC-MS (ESI+): m/z (M+H)+
found 230.19
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100716
European Journal of Organic Chemistry
2-(5-(4-nitrophenyl)isoxazol-3-yl)benzoic acid (5t): Rf = 0.10
(EtOAc 100). Off-white solid (339 mg, 71%). M.p. 227-230 oC.1H
NMR (400 MHz, CDCl3): δ 8.36-8.34 (d, 2H, J = 8.8 Hz), 8.11-8.10
(d, 1H, J = 7.2 Hz), 8.00-7.98(d, 2H, J = 8.8 Hz), 7.68-7.61(m, 3H),
6.86 (s, 1H). LC-MS (ESI+): m/z (M+H)+ found 311.26.
94.7, 55.4. HRMS (ESI+): m/z (M+H)+ calculated for C17 H14O3N
280.0968 , found 280.0962
(Z)-3-(2-oxo-2-(p-tolyl)ethylidene)isoindolin-1-one (6c). 149 mg
(79%), off-white solid M.p. 323-326 oC, Rf = 0.6 (EtOAc/Hexane
30:70).1H NMR (500 MHz, CDCl3): δ 10.62 (bs, 1H), 7.96-7.94(d, 2H,
J = 7.0 Hz), 7.90-7.90(d, 1H, J = 6.5Hz), 7.84-7.83(d, 1H, J = 6.5Hz),
7.70-7.63(m, 2H) 7.33-7.31(d, 2H, J = 6.5Hz), 6.87(s, 1H), 2.45(s,
3H). 13C NMR (125 MHz, CDCl3): δ 190.6, 169.0, 148.0, 143.8, 137.1,
135.8, 132.8, 131.8, 129.4, 129.3, 128.0, 124.1, 121.0, 94.8, 21.6.
HRMS (ESI+): m/z (M+H)+calculated for C17H14O2N 264.1019, found
264.1014.
2-(5-(2-chlorophenyl)isoxazol-3-yl)benzoic acid (5u): Rf = 0.10
(EtOAc 100). Off-white solid (391mg, 82%). M.p. 173-178 oC.1H
NMR (400 MHz, CDCl3): δ 8.10-8.02 (dd, 2H, J = 7.2 & 6.8 Hz),
7.66-7.59(m, 3H), 7.52-7.50 (d, 1H, J = 7.2 Hz), 7.42-7.38(t, 2H),
7.13(s, 1H). LC-MS (ESI+): m/z (M+H)+ found 300.23.
5-chloro-2-(5-phenylisoxazol-3-yl)benzoic acid (5v): Rf = 0.10
(EtOAc 100). Off-white solid (429 mg, 90%). M.p. 210-213 oC. 1H
NMR (400 MHz, CDCl3): δ 8.05(s, 1H), 7.82-7.80 (d, 2H, J = 6.8 Hz),
7.62-7.59 (d, 2H, J = 10.8 Hz), 7.48-7.46(d, 3H, J = 5.6 Hz), 7.67(s,
1H). LC-MS (ESI+): m/z (M+H)+ found 300.23.
(Z)-3-(2-(2-methoxyphenyl)-2-oxoethylidene)isoindolin-1-one
(6d). 140 mg (4%), off-white solid M.p. 138-141 oC, Rf = 0.6
(EtOAc/Hexane 30:70)1H NMR (400 MHz, CDCl3): δ 10.49 (bs, 1H),
7.89-7.88 (, 1H, J = 7.2 Hz), 7.76 -7.73 (t, 2H), 7.66-7.59 (m, 2H),
7.51-7.47 (t, 1H) 7.07-7.00(m, 2H), 6.94(s, 1H), 3.96 (s, 3H).13C
NMR (101MHz, CDCl3): δ 192.3, 169.1, 158.1, 146.4, 137.4, 133.5,
132.6, 131.5, 130.6, 129.3, 129.2, 124.0, 121.0, 120.9, 111.6, 100.2,
55.7. HRMS (ESI+): m/z (M+H)+ calculated for C17 H14O3N 280.0968 ,
found 280.0962.
5-chloro-2-(5-(4-methoxyphenyl)isoxazol-3-yl)benzoic acid (5w):
Rf = 0.10 (EtOAc 100). Off-white solid (422mg, 88%). M.p. 172-
175oC. 1H NMR (400 MHz, CDCl3): δ 8.03(s, 1H), 7.74-7.73 (d, 2H, J
= 8.5 Hz), 7.61-7.56 (dd, 2H, J = 17.5Hz), 6.99-6.97(d, 2H, J =
8.5Hz), 7.54(s, 1H), 3.87(s, 3H). LC-MS (ESI+): m/z (M+H)+ found
330.27.
(Z)-3-(2-oxo-2-(o-tolyl)ethylidene)isoindolin-1-one (6e).150 mg
(80%), off-white solid M.p. 148-151 oC, Rf = 0.6 (EtOAc/Hexane
30:70)1H NMR (500 MHz, CDCl3): δ 10.6 (bs, 1H), 7.92-7.91(d, 1H, J
= 2Hz), 7.88 -7.76 (d, 1H, J = 6 Hz), 7.68-7.62(m, 3H), 7.41-7.40(t,
5-chloro-2-(5-(p-tolyl)isoxazol-3-yl)benzoic acid (5x): Rf = 0.10
(EtOAc 100). Off-white solid (402 mg, 84%). M.p. 253-256 oC.1H
NMR (400 MHz, CDCl3): δ 7.72-7.70 (d, 2H, J = 8 Hz), 7.56-7.54 (d,
1H, J = 8.5Hz), 7.36-7.34(d, 3H, J = 8.5Hz), 7.09 (s, 1H), 2.37(s, 3H). 1H) 7.38-6.28(m, 2H), 6.6 (s, 1H), 2.53 (s, 3H). 13C NMR (125 MHz,
LC-MS (ESI+): m/z (M+H)+ found 314.26.
CDCl3): δ 195.5, 169.1, 147.7, 139.6, 137.4, 137.1, 132.9, 131.9,
131.7, 131.0, 129.2, 127.9, 125.7, 124.2, 121.1, 98.3, 20.5. HRMS
(ESI+): m/z (M+H)+calculated for C17H14O2N 264.1019,found
264.1014.
General Procedure for the synthesis isoindolin-1-one (6a-6x). A
mixture of Ortho-Carboxy-Isoxazole 5a-5x (0.75 mmol), Fe (3.77
mmol), NH4Cl (2.26 mmol) in EtOH (5mL) and water (2.5 mL) was
stirred at 90 0C for 16h, then the reaction mixture cooled to room
temperature, passed through celite pad and diluted with water and
extracted with EtOAc (2 x 25 mL). The combined organic layers
were dried (Na2SO4) and the solvent was evaporated under reduced
pressure. The crude product was purified by combi-flash column
chromatography (60-120 mesh Silica gel, EtOAc in pet ether) to give
the corresponding ROCC products 6a-6x.
(Z)-4-(2-(3-oxoisoindolin-1-ylidene)acetyl)benzonitrile (6f). 96 mg
(51%), off-white solid M.p. 271-274 oC, Rf = 0.6 (EtOAc/Hexane
30:70)1H NMR (400 MHz, CDCl3): δ 10.56(bs, 1H), 8.13-8.11(d, 2H,
J = 8.4 Hz), 7.94-7.81(m, 4H), 7.77-7.66(m, 2H), 6.81(s, 1H). 13C
NMR (101MHz, CDCl3): δ 189.3, 168.9, 150.0, 141.6, 136.7, 133.1,
132.5, 132.4, 129.9, 129.1, 128.3, 127.8, 124.4, 121.2, 117.9, 116.0,
93.8. LC-MS (ESI+): m/z (M+H)+ found 275.27.
(Z)-3-(2-oxo-2-phenylethylidene)isoindolin-1-one(6a). 167 mg
(89%), off-white solid M.p. 160-163 oC, Rf = 0.6 (EtOAc/Hexane
30:70). 1H NMR (500 MHz, CDCl3): δ 10.60 (bs, 1H), 8.05-8.03 (d,
2H, J = 7.0 Hz), 7.91 (d, 1H, J = 6.5Hz), 7.87(d, 1H, J = 6.5Hz),
7.68-7.50 (m, 3H) 7.59 (t, 2H), 6.88(s, 1H). 13C NMR (125 MHz,
CDCl3): δ 191.07, 169.08, 148.4, 138.4, 137.1, 133.0, 132.9, 131.9,
129.3, 128.7, 124.2, 121.1, 94.7, HRMS (ESI+): m/z (M+H)
+calculated for C16H12O2N 250.0862, found 250.0858.
(Z)-4-(2-(3-oxoisoindolin-1-ylidene)acetyl)benzoic acid (6g). 105
o
mg (56%), off-white solid M.p. 330-333 C, Rf = 0.6 (EtOAc/Hexane
30:70)1H NMR (400 MHz, DMSO-D6): δ 13.3(bs,1H), 10.96 (bs, 1H),
8.38-8.36(d, 1H, J = 7.6 Hz), 8.30-8.28 (d, 2H, J = 8.4 Hz) 8.12-8.10
(d, 2H, J = 8.4 Hz), 7.87 -7.81 (q, 2H), 7.76-7.72 (t, 1H), 7.43(s, 1H).
13C NMR (101MHz, DMSO-d6): δ 189.2, 168.8, 166.7, 148.1, 140.9,
137.1, 134.5, 133.3, 132.2, 129.5, 128.4, 128.12, 123.4, 122.6, 95.6.
LC-MS (ESI+): m/z (M+H)+ found 294.30.
(Z)-3-(2-(4-methoxyphenyl)-2-oxoethylidene)isoindolin-1-one
(6b). 164 mg (87%), pale yellow solid M.p. 161-164 oC, Rf = 0.6
(EtOAc/Hexane 30:70)1H NMR (500 MHz, CDCl3): δ 10.63 (bs, 1H),
(Z)-3-(2-([1,1'-biphenyl]-4-yl)-2-oxoethylidene)isoindolin-1-one
(6h). 158 mg (83%), off-white solid M.p.209-212 oC Rf = 0.6
(EtOAc/Hexane 30:70).1H NMR (500 MHz, CDCl3): δ 10.64 (bs, 1H),
8.05 -8.04(d, 2H, J = 9 Hz), 7.92-7.90 (d, 1H, J = 7.5Hz), 7.84-7.82(d, 8.12-8.11(d, 2H, J = 8.5 Hz), 7.92 -7.85 (dd, 2H, J = 7.5 & 27 Hz),
1H, J = 7.5Hz), 7.70-7.62(m, 2H) 7.01-6.99(d, 2H, J = 8.5Hz), 6.86(s, 7.76-7.63 (m, 6H), 7.50-7.40 (m, 3H) 6.92 (s, 1H). 13C NMR (125
1H), 3.90(s, 3H). 13C NMR (101MHz, CDCl3): δ 189.4, 168.9, 163.5,
MHz, CDCl3): δ 190.5, 169.1, 148.3, 145.6, 139.7, 137.1, 137.1,
147.7, 137.1, 132.7, 131.7, 131.2, 130.2, 129.3, 124.1, 120.9, 113.9,
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
134.3, 132.9, 131.9, 129.3, 128.9, 128.6, 128.3, 127.3, 127.2, 124.2,
121.1, 94.8. LC-MS (ESI+): m/z (M+H)+ found 326.24.
130.4, 129.2, 124.3, 123.6, 121.1, 120.0, 114.9, 94.2. LC-MS (ESI+):
m/z (M+H)+ found 268.16.
(Z)-3-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethylidene)isoindolin-1-
one (6i). 160 mg (84%), off-white solid M.p.230-233 oC, Rf = 0.6
(EtOAc/Hexane 30:70)1H NMR (400 MHz, CDCl3): δ 10.57 (bs, 1H),
8.14-8.12(d, 2H, J = 8 Hz), 7.93 -7.91 (d, 1H, J = 6.8 Hz), 7.86-
7.84(d, 1H, J = 8 Hz), 7.79-7.77 (d, 2H, J = 8 Hz) 7.73-7.65(m, 2H),
6.84(s, 1H). 13C NMR (101MHz, CDCl3): δ 189.9, 169.0, 149.5,
141.2, 136.8, 134.3, 134.0, 133.0, 132.3, 129.2, 128.2, 125.7, 125.7,
124.9, 124.4, 121.2, 94.1. LC-MS (ESI+): m/z (M+H)+ found 318.23.
(Z)-3-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethylidene)isoindolin-1-
(Z)-3-(2-(2-methyl-1H-imidazol-5-yl)-2-oxoethylidene) isoindolin-
o
1-one(6o).100 mg (53%), off-white solid M.p. 221-223 C, Rf = 0.6
(EtOAc/Hexane 30:70). 1H NMR (400 MHz, CDCl3): δ 10.44 (bs, 1H),
7.91-7.81(dd, 3H, J = 7.6 & 32 Hz), 7.71-7.62(m, 3H), 6.59(s, 1H),
4.01(s, 3H). 13C NMR (101MHz, CDCl3): δ 181.2, 168.8, 147.4,
136.8, 132.8, 131.8, 129.1, 124.1, 121.1, 96.1, 34.9. HRMS (ESI+):
m/z (M+H)+ calculated for C14H12O2 N3 254.0924, found 254.0918.
(Z)-3-(2-oxo-2-(pyridin-3-yl)ethylidene)isoindolin-1-one(6p). 122
o
mg (65%), off-white solid M.p. 160-163 C, Rf = 0.6 (EtOAc/Hexane
o
one (6j).150 mg (78%), off-white solid M.p. 171-174 C, Rf = 0.6
30:70)1H NMR (400 MHz, CDCl3): δ 10.58 (bs, 1H), 9.28(s, 1H),
8.82-8.79(t, 1H), 8.33-8.31(d, 1H, J = 8Hz),7.93-7.91(d, 1H, J =
5.6Hz), 7.86-7.85(d, 1H, J = 7.2 Hz), 7.73-7.65 (m, 2H), 7.50-7.46 (q,
1H), 6.84(s, 1H). 13C NMR (101MHz, CDCl3): δ 189.4, 169.0, 153.2,
149.4, 149.1, 136.8, 135.4, 133.7, 133.1, 132.3, 129.1, 124.3, 123.7,
121.2, 94.0. HRMS (ESI+): m/z (M+H)+ calculated for C15 H11 O2
N2 = 251.0815, found 251.0810.
(EtOAc/Hexane 30:70)1H NMR (500 MHz, CDCl3): δ 10.58 (bs, 1H),
8.27(s, 1H), 8.23-8.22(d, 1H, J = 7.5 Hz), 7.93-7.84(m, 3H), 7.73 -
7.65 (m, 3H), 6.85(s, 1H). 13C NMR (125 MHz, CDCl3): δ 189.5,
169.0, 149.5, 138.9, 136.9, 133.1, 132.3, 131.4, 131.2, 129.4, 129.3,
129.2, 129.2, 124.8, 124.4, 121.3, 93.9. HRMS (ESI+): m/z (M+H)+
calculated for C17H11O2NF3 318.0736, found 318.0727.
(Z)-3-(2-(2-fluorophenyl)-2-oxoethylidene)isoindolin-1-one (6k).
Z)-3-(2-oxo-2-(tetrahydro-2H-pyran-2-yl)ethylidene)isoindolin-1-
one(6q).110 mg (59%), off-white solid M.p.127-129 oC, Rf = 0.6
(EtOAc/Hexane 30:70).1H NMR (400 MHz, CDCl3): δ 10.30 (bs, 1H),
7.88-7.86 (dd, 1H, J = 2 & 6.4 Hz), 7.79-7.77(d, 1H, J = 1.2 & 6 Hz),
154 mg (82%), off-white solid M.p.120-123 oC, Rf
= 0.6
(EtOAc/Hexane 30:70)1H NMR (400 MHz, CDCl3): δ 10.49 (bs, 1H),
7.93-7.90(m, 2H), 7.82 -7.80 (d, 1H, J = 6.8 Hz), 7.70-7.64(m, 2H),
7.56-7.54 (d, 1H, J = 8 Hz) 7.30-7.28(d, 1H, J = 7.6 Hz), 7.21-7.16(m, 7.66-7.59(m, 2H), 6.59 (s, 1H), 4.15-4.11(dd, 1H, J = 1.2 & 11.6 Hz),
1H), 6.86(d, 1H, J = 8 Hz). 13C NMR (101MHz, CDCl3): δ 188.6,
169.1, 162.4, 159.9, 148.3, 137.1, 134.4, 132.9, 132.0, 131.0, 129.2,
127.1, 124.7, 121.3, 116.7, 98.8. HRMS (ESI+): m/z (M+H)+
calculated for C16 H11O2NF 268.0768, found 268.0764.
3.95-3.92 (dd, 1H, J = 2.4 & 10.8Hz), 3.59-3.52(dd, 1H, J = 2.8 &
11.6 Hz), 2.02 -1.93(m, 2H), 1.69-1.51(m, 4H). 13C NMR (101 MHz,
CDCl3): δ 201.0, 169.0, 148.1,137.1, 132.8, 131.8, 129.2, 124.1,
123.5, 121.4, 93.9, 82.3, 68.3, 25.5, 23.1. HRMS (ESI+): m/z (M+H)+
calculated forC15 H16 O3 N 258.1124, found 258.1119.
(Z)-3-(2-(2,4-difluorophenyl)-2-oxoethylidene)isoindolin-1-one
(6l). 146 mg (77%), off-white solid M.p. 318-321 oC, Rf = 0.6
(EtOAc/Hexane 30:70)1H NMR (500 MHz, CDCl3): δ 10.47 (bs, 1H),
7.99-7.97(dd, 1H, J = 2 & 8.5 Hz), 7.92 -7.90 (d, 1H, J = 1 Hz), 7.82-
7.80(d, 1H, J = 7 Hz), 7.70-7.65 (m, 2H), 7.03-6.00 (t, 1H), 6.94 -
6.90 (m, 1H), 6.82 (d, 1H, J = 7 Hz). 13C NMR (125MHz, CDCl3): δ
187.0, 169.1, 166.7, 162.9, 160.9, 148.7, 137.0, 132.9, 132.1, 129.1,
124.2, 123.4, 121.3, 112.4, 104.9, 98.3. LC-MS (ESI+): m/z (M+H)+
found 286.19.
Z)-3-(2-oxo-2-(tetrahydrofuran-3-yl)ethylidene)isoindolin-1-
one(6r). 120 mg (64%), off-white solid M.p. 90-92 oC, Rf = 0.6
(EtOAc/Hexane 30:70)1H NMR (400 MHz, CDCl3): δ 10.28 (bs, 1H),
7.89-7.88 (d, 1H, J = 2 Hz), 7.74 -7.73 (d, 1H, J = 5.2 Hz), 7.68-
7.61(m, 2H), 6.16(s, 1H), 4.05-4.01(m, 3H), 3.86-3.81 (m, 1H), 3.39-
3.32(m, 1H), 2.26-2.18(m, 2H). 13C NMR (101 MHz, CDCl3): δ 200.8,
168.8, 147.6, 136.7, 132.8, 132.0, 129.3, 124.2, 121.1, 96.7, 69.9,
68.4, 51.7, 29.4. HRMS (ESI+): m/z (M+H)+ calculated for C14 H14 O3
N 244.0968, found 244.0964.
(Z)-3-(2-(2,6-difluorophenyl)-2-oxoethylidene)isoindolin-1-
o
one(6m). 150 mg (79%), off-white solid M.p. 188-191 C, Rf = 0.6
(Z)-3-(2-cyclopropyl-2-oxoethylidene)isoindolin-1-one (6s) .106
o
(EtOAc/Hexane 30:70)1H NMR (400 MHz, CDCl3): δ 10.37 (bs, 1H),
7.91-7.90(d, 1H, J = 6 Hz), 7.76 -7.74 (d, 3H, J = 5.6 Hz), 7.67-7.65
(t, 1H), 7.47-7.40 (m, 2H), 6.48(s, 1H). 13C NMR (101MHz, CDCl3): δ
186.6, 169.0, 161.5, 159.0, 148.4, 136.8, 134.2, 133.0, 132.6, 129.1,
124.3, 123.5, 121.4, 118.7, 112.3, 99.5. LC-MS (ESI+): m/z (M+H)+
found 286.19.
mg (57%), off-white solid M.p. 149-52 C, Rf = 0.6 (EtOAc/Hexane
1
30:70). H NMR (500 MHz, CDCl3): δ 10.31 (bs, 1H), 7.88-7.86 (d,
1H, J = 7 Hz), 7.74-7.72(d, 1H, J = 7.5 Hz), 7.66-7.59 (m, 2H), 6.82
(s, 1H), 2.10-2.05 (m, 1H), 1.18-1.17(q, 2H), 1.01-0.99 (q, 2H). 13C
NMR (125 MHz, CDCl3): δ 200.9, 168.8, 145.5, 137.0, 132.7, 131.6,
129.5, 124.1, 120.9, 98.3, 22.4, 11.59. LC-MS (ESI+): m/z (M+H)+
found 214.18
(Z)-3-(2-(3-fluorophenyl)-2-oxoethylidene)isoindolin-1-one(6n).
150 mg (80%), off-white solid M.p. 189-192oC, Rf
=
0.6
(Z)-3-(2-(4-aminophenyl)-2-oxoethylidene)isoindolin-1-
one(6t).100 mg (56%), off-white solid M.p. 218-221 oC, Rf = 0.6
(EtOAc/Hexane 30:70). 1H NMR (400 MHz, DMSO-D6): δ 10.82 (bs,
1H), 8.32-8.30 (d, 1H, J = 7.6 Hz), 7.97-7.95 (d, 2H, J = 8.8 Hz),
7.84-7.81(m, 2H), 7.79 -7.77(dd, 1H), 7.29(s, 1H), 6.65-6.63(d, 2H, J
= 8.8 Hz), 6.21(s, 2H). 13C NMR (101MHz, DMSO-d6): δ 187.4,
(EtOAc/Hexane 30:70).1H NMR (500 MHz, CDCl3): δ 10.57 (bs, 1H),
7.93-7.92(d, 1H, J = 7 Hz), 7.85 -7.82 (t, 2H), 7.73-7.66(m, 3H),
7.53-7.50 (t, 1H) 7.32-6.03(m, 1H), 6.81(s, 1H). 13C NMR (101MHz,
CDCl3): δ 189.6, 168.9, 164.1, 149.0, 140.5, 136.9, 133.0, 132.1,
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
[3] (a) T. R. Belliotti, W. A. Brink, S. R. Kesten, J. R. Rubin, D. J. Wustrow,
K. T. Zoski, S. Z. Whetzel, A. E. Corbin, T. A. Pugsley, T. G. Heffner, L.
D. Wise, Bioorg. Med. Chem. Lett. 1998, 8, 1499. (b) S. K. Ray, M. M.
Sadhu, R. G. Biswas, R. A. Unhale, V. K. Singh, Org. Lett. 2019, 21,
417.
168.3, 159.5, 154.0, 145.3, 137.3, 132.9, 131.5, 130.8, 129.8, 128.5,
125.6, 123.2, 122.2, 112.7, 112.5, 96.3. HRMS (ESI+): m/z (M+H)+
calculated forC16 H13 O2 N2 265.0971, found 265.0964.
(Z)-3-(2-(2-chlorophenyl)-2-oxoethylidene)isoindolin-1-one(6u).
o
1
153 mg (81%), off-white solid M.p. 163-166 C. H NMR (500 MHz,
CDCl3): δ 10.31 (bs, 1H), 7.92-7.90 (d, 1H, J = 6.5 Hz), 7.76-7.75 (d,
1H, J = 6.5 Hz), 7.68-7.63 (m, 3H), 7.47-7.36 (m, 3H), 6.64(s, 1H).
13C NMR (125 MHz, CDCl3): δ 192.8, 169.0, 147.9, 139.6, 136.9,
133.0, 132.1, 131.9, 131.2, 130.5, 129.6, 129.2, 127.1, 124.3, 121.3,
[4] (a) N. Kanamitsu, T. Osaki, Y. Itsuji, M. Yoshimura, M.; H. Tsujimoto, M.
Soga, Chem. Pharm. Bull. 2007, 55, 1682. (b) A. Suneja, V. Bisai, V. K.
Singh, J. Org. Chem. 2016, 81, 4779.
[5] (a) A. Couture, E. Deniau, P. Grandclaudon, C. Hoarau, Tetrahedron
2000, 56, 1491. (b) T. Yao, Z. Guo, X. Liang, L. Qi, J. Org. Chem. 2018,
83, 13370.
98.7.
HRMS (ESI+): m/z (M+H)+ calculated for C16H11O2NCl
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1273.
284.0472, found 284.0467
(Z)-6-chloro-3-(2-oxo-2-phenylethylidene)isoindolin-1-
one(6v).160 mg (85%), off-white solid M.p. 208-210 oC, Rf = 0.6
(EtOAc/Hexane 30:70). 1H NMR (400 MHz, CDCl3): δ 10.64 (bs, 1H),
8.04-8.02 (d, 1H, J = 7.6 Hz), 7.88 (s, 1H), 7.78-7.76 (d, 1H, J = 8
Hz), 7.66-7.59 (m, 2H), 7.55-7.51 (t, 2H), 6.86 (s, 1H). 13C NMR (125
MHz, CDCl3): δ 190.9, 167.6, 147.3, 138.2, 138.2, 135.2, 133.1,
133.0, 130.9, 128.7, 127.9, 124.5, 122.3, 95.2. HRMS (ESI+): m/z
(M+H)+ calculated for C16H11O2N Cl 284.0472, found 284.0465.
(Z)-6-chloro-3-(2-(4-methoxyphenyl)-2-oxoethylidene)isoindolin-
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o
1-one(6w).156 mg (82%), off-white solid M.p.218-221 C, Rf = 0.6
(EtOAc/Hexane 30:70). 1H NMR (500 MHz, DMSO-d6): δ 10.98 (bs,
1H), 8.40-8.38 (d, 1H, J = 8 Hz), 8.21-8.19(d, 2H, J = 8.5 Hz), 7.90-
7.87(t, 2H), 7.42(s, 1H), 7.11-7.10 (d, 2H, J = 8.5 Hz), 3.88(s, 3H).
13C NMR (125 MHz, CDCl3): δ 188.2, 167.3, 163.3, 145.7, 136.5,
135.9, 133.0, 130.7, 130.6, 124.3, 123.2, 114.0, 96.6, 55.6. HRMS
(ESI+): m/z (M+H)+ calculated for C17H13O3NCl 314.0578, found
314.0569.
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(Z)-6-chloro-3-(2-oxo-2-(p-tolyl)ethylidene)isoindolin-1-one (6x).
144 mg (76%), off-white solid M.p. 226-229 oC, Rf
= 0.6
(EtOAc/Hexane 30:70)1H NMR (500 MHz, CDCl3): δ 10.65 (bs, 1H),
7.94-7.84(m, 4H), 7.76-7.32 (m, 2H), 6.85 (s, 1H), 2.45 (s, 3H).13C
NMR (125 MHz, CDCl3): δ 190.4, 167.5, 146.9, 144.1, 138.1, 135.6,
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(ESI+): m/z (M+H)+ found 298.25
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Conflicts of interest
There are no conflicts to declare.
Acknowledgments:
G. Ramakrishna is grateful to Aragen Life Sciences (Formerly known
as GVK Biosciences) for giving the opportunity to pursue the Ph. D.
work as per Higher Education Policy of the Organization. Help from
the analytical department is highly appreciated. We thank Dr
Somesh Sharma for his invaluable support and encouragement.
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10.1002/ejoc.202100716
European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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COMMUNICATION
Ramakrishna Gudipati[a,b] , Vankudoth Jayaram[a], K.Raghavulu[a,b], Dinesh Bhoot[a], K.Basavaiah[b],
Satyanarayana Yennam[a] , Manoranjan Behera[a*]
An efficient and convenient route for the synthesis of various functionalized 3-alkylidene isoindolin-1-ones is presented. The synthesis
involves the ring opening and ring Closing Cascade (ROCC) reaction of ortho-carboxy-isoxazole using Fe/NH4Cl. This is the first report for the
synthesis of 3-alkylidene isoindolin-1-one using Fe/NH4Cl.
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