KOtBu-mediated synthesis of dimethylisoindolin-1-ones and dimethyl-5-phenylisoindolin-1-ones: Selective C-C coupling of an unreactive tertiary sp3 C-H bond

Article abstract of DOI:10.1021/jo402776u

A new reaction for the synthesis of dimethylisoindolinones has been presented from 2-halo-N-isopropyl-N-alkylbenzamide substrates and KO ^tBu by the selective C-C coupling of an unreactive tertiary sp ³ C-H bond. The reaction manifest

Full text of DOI:10.1021/jo402776u

Article
pubs.acs.org/joc
KOtBu-Mediated Synthesis of Dimethylisoindolin-1-ones and
Dimethyl-5-phenylisoindolin-1-ones: Selective C−C Coupling of an
Unreactive Tertiary sp3 C−H Bond
Bhagat Singh Bhakuni, Abhimanyu Yadav, Shailesh Kumar, Saket Patel, Shubham Sharma,
and Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, Indore By-pass Road, Bhauri, Bhopal,
Madhya Pradesh, India 462 066
S
* Supporting Information
ABSTRACT: A new reaction for the synthesis of dimethylisoindolinones has been presented from 2-halo-N-isopropyl-N-
alkylbenzamide substrates and KOtBu by the selective C−C coupling of an unreactive tertiary sp3 C−H bond. The reaction
manifested an excellent selectivity toward a tertiary sp3 C−H bond over primary or sec C−H bond. Moreover, biaryl C−C
coupling along with alkyl−aryl C−C coupling can be achieved in one pot using dihalobenzamides for the synthesis of biaryl 5-
phenylisoindolin-1-ones. It seems that the reaction proceeds via a radical pathway in which the aryl radical translocates via 1,5-
hydrogen atom transfer (HAT), forming a tertiary alkyl carbon-centered radical. The generated tertiary alkyl radical could attack
the benzamide ring in a 5-exo/endo-trig manner followed by the release of an electron and a proton, leading to a five-membered
isoindolinone ring. HAT seems to be responsible for the selective functionalization of the tertiary alkyl group over primary and
secondary C−H bonds.
The isoindolin-1-one core is present in a broad range of
biologically relevant molecules having a wide range of medicinal
properties such as anti-inflammatory, antihypertensive, anti-
ulcer, and antileukemic.6 As a result, several synthetic routes
have been developed for the preparation of isoindolinones such
as Grignard or lithiation procedures, reduction of phthalalde-
hyde, and transition-metal-catalyzed constructions.7,8 Nonethe-
less, there is only one report on the synthesis of
dimethylisoindolin-1-one 1 bearing a quaternary carbon center
in the ring in which 2-isoindoline-1,3-dione is converted into
indolinone by the reaction of zinc, followed by the addition of
potassium amide base and methyl iodide.9 On the other hand,
several methods on the coupling of activated alkyl C−H bonds
with aniline rings have been studied for the synthesis of
INTRODUCTION
■
Selective functionalization of unreactive tertiary alkyl C−H
bonds for carbon−carbon coupling reactions is highly desirable
for the synthesis of organic molecules bearing a quaternary
carbon center. For the functionalization of a C−H bond, a
transition-metal catalyst, particularly palladium, is often
employed for carbon−carbon coupling reactions. Transition-
metal-free approaches are also being studied for the
construction of carbon−carbon bonds as an alternative.
Recently, the use of potassium tert-butoxide reagent for the
promotion of carbon−carbon bond formation has aroused
interest in synthetic chemistry due to its ready availability and
nontoxicity. KOtBu-mediated inter- and intramolecular sp2−sp2
and activated sp3−sp2 carbon−carbon coupling reactions have
been reported in recent times.1−4 Herein, we present the
KOtBu-mediated synthesis of isoindolin-1-ones from 2-halo-N-
isopropyl-N-alkylbenzamide substrates by the selective C−C
coupling of an unreactive tertiary sp3 C−H bond, which has not
been reported by any method (Scheme 1). The only recent
report is on Ni-catalyzed synthesis of isoindolinones.5 None-
theless, the reaction was noted to be unselective toward
secondary and tertiary alkyl C−H bonds.
oxindole, a moiety closely related to isoindolin-1-one.10
A
method which is transition metal free and requires readily
accessible substrates and reagents would be highly desirable for
the synthesis of isoindolinones. N,N-Diisopropylamide is used
as an ortho directing and protecting group for acids for ortho-
Received: December 27, 2013
Published: March 5, 2014
© 2014 American Chemical Society
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Scheme 1. C−C Coupling in 2-Halo-N,N-dialkylbenzamide
metalation reactions and is noted to be unreactive even in the
presence of a strong base such as t-BuLi.11 Palladium-catalyzed
C−H functionalization in carboxamide has been reported;
however, Pd shows selectivity toward the methyl group over a
tertiary C−H bond (Scheme 1, eq 1).12 Here, selective
formation of a tertiary alkyl−aryl carbon−carbon bond is
realized while studying intermolecular biaryl coupling in 2-iodo-
N,N-diisopropylbenzamide (Scheme 2).13 The presented
reaction shows excellent selectivity toward a tertiary C−H
bond over primary methyl and secondary ethyl C−H bonds
(Scheme 1, eq 2). Moreover, arylation of the benzamide ring
could be achieved along with alkylation in one pot from 4-
chloro-2-iodobenzamides (Scheme 1, eq 3).
reaction conditions. We have also studied the memory of
positions in the reaction by using 2-iodo-N-isopropyl-N,3-
dimethylbenzamide and 2-iodo-N-isopropyl-N,5-dimethylben-
zamide substrates (entries 2 and 3, Table 1). Both substrates
gave nearly the same ratio (64:36 vs 70:30) of isomers 3a and
3b, which suggests that the memory of the positions is not the
determining factor for the selective formation of regioisomers
in this study. Next, selectivity toward an ethyl vs an isopropyl
group was studied (entries 5−7, Table 1). To our delight, the
tertiary isopropyl C−H bond showed reactivity over the ethyl
C−H bond in the C−C coupling reaction and dimethylisoin-
dolinones 5−7 were obtained in good yields. Interestingly,
benzamides having a cyclohexyl substitutent (entries 8 and 9,
Table 1) also underwent C−C coupling reactions and 2′-
methylspiro[cyclohexane-1,1′-isoindolin]-3′-ones 9 and 10
were obtained selectively in 94 and 93% yields, respectively.
After this, N,N-dialkylbenzamides having only primary or
secondary C−H bonds were studied in the reaction (entry 10,
Table 1). N,N-Diethyl-2-iodobenzamide gave a 26% yield of
C−C coupled product 10 and the reaction was observed to be
sluggish. N,N-Dimethyl-2-iodobenzamide substrate did not
produce even traces of C−C coupled product, which
demonstrated the selectivity of this reaction toward a tertiary
C−H bond. Next, N-methyl-N-benzylic-2-iodobenzamide
substrates were used in KOtBu-mediated alkyl−aryl C−C
coupling (entries 11−13, Table 1). The reaction showed
selectivity toward the benzylic C−H bond and benzylic
isoindolinones 11−13 were obtained as major products. In
the end, selectivity toward aromatic versus isopropyl C−H
bonds was evaluated by using N-isopropyl-N-phenyl-2-
iodobenzamide substrate. Unfortunately, the reaction was
selective toward sp2 C−H bonds and yielded a 70:30 ratio of
phenanthridinone 14b, an sp2−sp2 C−C coupled product, and
indolinone 14a, an sp3−sp2 C−C coupled product, respectively.
Next, benzamide ring substituted substrates were investigated
in the KOtBu-mediated reaction (entries 2−4 and 6−9, Table 1,
and Table 2). Various functional groups such as nitro, chloro,
methyl, methoxy, and dimethoxy have shown compatibility
with the reaction conditions. A substrate with the chloro
substituent para to the amide functionality gave the single
regioisomers 4, 6, 9, and 15 (entries 4, 6, 9, Table 1, and entry
1, Table 2). A 3-nitrobenzamide substrate also gave one
regioisomer, 16, as the major product (entry 2, Table 2). 2-
Chloro-N,N-diisopropyl-5-nitrobenzamide failed to provide a
C−C coupled product and yielded a hydroxylated product, 2-
hydroxy-N,N-diisopropyl-5-nitrobenzamide (see the Experi-
mental Section). Next, dimethoxybenzamide substrate also
afforded the single regioisomer 17 (entry 3, Table 2). On the
other hand, methyl-substituted benzamides (entries 2 and 3,
Table 1, and entry 4, Table 2) gave the two regioisomers 3a,b
RESULTS AND DISCUSSION
■
We started optimizing the reaction conditions using 2-iodo-
N,N-diisopropylbenzamide in various solvents using KOtBu
(Scheme 2). Optimization of the reaction conditions is
Scheme 2. Optimization of Reaction Conditions
presented in the Supporting Information (Table S1, page S2;
for the crystal structure of isoindolinone 1, see Figure S126,
page S131). Potassium tert-butoxide alone was noted to be
ineffective in benzene; however, it yielded 86% of isoindolinone
1 in DMSO and 10% substrate was recovered. Addition of a
catalytic amount (5 mol %) of vitamin E, a phenolic natural
product, to the reaction mixture not only led to the complete
conversion of the substrate into isoindolinone 1 but also
reduced the reaction time from 12 to 3 h. 2-Bromo- and 2-
chloro-N,N-diisopropylbenzamide substrates were found to be
less reactive in DMSO; however, they gave a good yield of 1 in
benzene in the presence of the radical initiator azomethylvaler-
onitrile (AMVN).
After screening for various reaction conditions, we decided to
use vitamin E as an additive in DMSO for iodo substrates and
AMVN as a radical initiator in benzene for bromo- and
chlorobenzamides. Various N-alkyl-substituted 2-halobenza-
mides were explored to study the selectivity in the KOtBu-
mediated alkyl−aryl coupling reactions (Table 1). We began
with N-methyl-N-isopropyl substrates (entries 1−4, Table 1)
and noticed that the reaction showed excellent selectivity
toward a tertiary isopropyl C−H bond over a methyl C−H
bond, as 1−4 were obtained exclusively under the optimized
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Table 1. Coupling of N-Alkyl-Substituted Arylbenzamides
a
Isolated yields. Isoindolinones were obtained from iodo substrates by using KOtBu (3 equiv) and vitamin E (5 mol %) in DMSO (procedure A).
b
c
Two regioisomers were obtained, and both were isolated. Isoindolinone 7 was obtained from the bromo substrate using KOtBu (3 equiv) and
AMVN (10 mol %) in benzene (procedure B).
and 18a,b, respectively. Similarly, 5-methoxy-substituted
benzamide reacted to give the two regioisomers 19a,b (entry
5, Table 2). After exploring benzene-based substrates, we tested
different aryl N,N-diisopropylcarboxamides under the reaction
conditions (entry 7, Table 1, and entries 6−8, Table 2). To our
delight, not only naphthyl and pyridyl amides but also
ferrocenylamide showed amenability to the reaction conditions
and produced the respective novel ferrocenylisoindolinone 21
quantitatively. The structure of ferrocenylisoindolinone 21 has
also been established by an X-ray single-crystal structure study
(see the Supporting Information, Figure S127, page S132).14
After exploring the tertiary sp3 C−H bond coupling reaction,
we envisioned synthesizing isoindolinones containing a biaryl
core in a single pot (Scheme 3). Biaryl cores are privileged
structures having numerous applications in pharmaceuticals,
agrochemicals, and materials.15
with benzene only occurred in the presence of AMVN initiator
under the harsh reaction conditions. The formation of 5-
phenylisoindolinone 23 was not observed under the vitamin E
catalyzed reaction conditions. 5-Phenylisoindolinone 23 has
also been characterized by an X-ray single-crystal structure
study (see the Supporting Information, Figure S128, page
S133). It is worth noting that the reaction proceeds in a
sequential manner: first the intramolecular alkyl−aryl C−C
coupled product isoindolinone 1 was formed, followed by sp2−
sp2 biaryl coupling of 1 with benzene leading to biaryl 23.16
A plausible mechanism is depicted in Scheme 4, and detailed
vitamin E catalyzed and AMVN-mediated mechanisms are
presented in the Supporting Information (pages S2−S3). On
the basis of the regioselective tertiary sp3 C−H bond
functionalization over methyl or ethyl substituents in this
study and KOtBu-mediated biaryl coupling reactions,1−3 it is
reasonable to assume that the reaction proceeds via a radical
pathway. It seems that the electron transfer from KOtBu to 2-
iodobenzamamide leads to the radical anion I, as in the
presence of vitamin E the rate of reaction increases
considerably, which is a good one-electron donor in the radical
chain reactions.17 Radical anion I may produce phenyl radical II
For this purpose, readily accessible 4-chloro-2-iodo-N,N-
dialkylbenzamides were exploited in the KOtBu-mediated
reaction. In the presence of excess KOtBu, the reaction yielded
the desired biaryls, 5-phenylisoindolin-1-ones 23−26, in 86−
89% yields in one pot on heating for a longer period of time.
The coupling of 4-chloro-2-iodo-N,N-diisopropylbenzamide
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a
Table 2. Coupling of 2-Iodo-N,N-diisopropylarylamides
a
The reaction was carried out on a 1 mmol scale using 2-halobenzamide substrates. Procedure A was applied for iodo substrates and procedure B
b
was applied for bromo susbstrates. The formation of a single isomer was noted and established by GC-MS analysis of the crude reaction mixture.
c
d
Two regioisomers were obtained, and both were isolated. The combined yield for both isomers is presented, and the isomers were not separated.
Scheme 3. Synthesis of 5-Phenylisoindolinones
selectivity toward a tertiary C−H bond. The alkyl radical III
would attack the benzamide ring in a 5-exo/endo-trig manner,
leading to the cyclohexadienyl radical IV. Abstraction of a
proton from radical IV would give radical anion V. Finally
radical anion V donates an electron to the 2-iodobenzamide
substrate, leading to the radical anion I and thus completing the
radical chain reaction with the concomitant release of
isoindolinone 1. Biaryl isoindolinone 23 could be realized by
the coupling of 5-chloro-2-isopropyl-3,3-dimethylisoindolin-1-
one 15 with benzene (see the proposed mechanism in the
Supporting Information, page S4).1,2c
SUMMARY
■
upon the release of iodide. 1,5-Hydrogen atom transfer reaction
led to the tertiary alkyl radical III. This seems to be the key step
in this transformation and could be the reason for the excellent
In conclusion, a transition-metal-free selective carbon−carbon
coupling of an unreactive tertiary alkyl C−H bond has been
achieved, which has not been reported earlier by any method.
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Scheme 4. Proposed Mechanism for sp3-C−H Coupling
Potassium tert-butoxide mediated coupling of a tertiary sp3 C−
H bond was successfully employed with a series of 2-
halobenzamides such as ferrocene-, pyridine-, and naphtha-
lene-derived substrates to furnish diversified isoindolinones.
The presented methodology enables the construction of
biologically relevant isoindolinone and biarylisoindolinone
organic molecules from monohalo- and dihalobenzamides,
respectively, in a single pot. Further application and under-
standing of the reaction, particularly the enantioselective
version, are currently in progress in our laboratory.
Scheme 5. Synthesis of 2-Halo Tertiary Benzamides
EXPERIMENTAL SECTION
■
General Experimental Details. All NMR experiments were
carried out on a 400 MHz spectrometer. CDCl3 and NMR chemical
shifts are reported in ppm referenced to the solvent peaks of CDCl3
(7.26 ppm for 1H and 77.16 ( 0.06) ppm for 13C, respectively). High-
resolution mass analysis was performed on a quadrupole time of flight
(Q-TOF) mass spectrometer equipped with an ESI source (positive).
DMF and DMSO with seal septa and 1,10-phenanthroline were used
as received. Benzene and mesitylene were dried over calcium hydride
and freshly distilled before use. Potassium tert-butoxide (98% purity)
was used as purchased and stored in a desiccator. Silica gel (100−200
mesh size) was used for column chromatography. TLC analysis of
reaction mixtures was performed using silica gel plates. Isoindolinones
1,9 5,18 8,19 10,5 11a,20 11b,21 13,22 14a,23 and 14b10i are known, and
the rest of the isoindolinones are unknown. Substituted benzoyl
chlorides were prepared from the respective benzoic acids by refluxing
with excess thionyl chloride and otherwise prepared according to the
reported procedure. Excess thionyl chloride was removed under
vacuum, and the resulting residue was used for amide preparation
without further purification. Substrates: 2-iodo-N,N-diisopropylbenza-
mide (substrate for 1),24 2-iodo-N-phenylethylbenzamide13a (pre-
cursor for 2-iodo-N-methyl-N-phenylethylbenzamide), N,N-diethyl-2-
iodobenzamide25 (substrate for 10), 4-chloro-2-iodo-N,N-diisopropyl-
benzamide26 (substrate for 15), 2-bromo-N,N-diisopropyl-4,5-dime-
thoxybenzamide7 (substrate for 17), 2-iodo-N,N-diisopropyl-3-meth-
ylbenzamide27 (substrate for 18a,b), 2-bromo-N,N-diisopropyl-5-
methoxybenzamide28 (substrate for 19), 2-iodo-N,N-diisopropylferro-
cenecarboxamide11b (substrate for 21), and 2-hydroxy-N,N-diisoprop-
yl-5-nitrobenzamide29 are also known, and analytical data correlate
well with the reported values.
triethylamine (203 mg, 2.0 mmol) in DCM (10 mL) using a dropping
funnel at 0 °C. After complete addition, the reaction mixture was
stirred for 5 h. After this 10% HCl aqueous solution (40 mL) was
added to the reaction mixture. The resulting solution was extracted
with DCM (20 mL × 3), and the DCM layer was washed with water
(30 mL) and dried over Na2SO4. The organic layer was concentrated
on a rotary evaporator under vacuum. A white solid was obtained.
1
Yield: 298 mg, 90%. H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0
Hz, 1H), 7.33 (t, J = 7.53 Hz, 1H), 7.13 (dd, J = 7.54 Hz, J = 1.54 Hz,
1H), 7.01 (dt, J = 7.74 Hz, J = 1.54 Hz, 1H), 3.61−3.45 (m, 2H), 1.58
(d, J = 6.87 Hz, 3H), 1.55 (d, J = 6.87 Hz, 3H), 1.25 (d, J = 6.70 Hz,
3H), 1.05 (d, J = 6.70 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
169.9, 144.1, 139.3, 129.5, 128.2, 125.9, 92.3, 51.3, 46.1, 20.8, 20.7,
20.1. LRMS: m/z 332.0, calculated for C13H18INO + H+ 332.1.
General Procedures for the Synthesis of Isoindolinones.
Isoindolinones were synthesized from 2-iodobenzamides by following
procedure A. 2-Bromo and 2-chloro substrates were converted into
products by following procedure B.
Procedure A for the Synthesis of 2-Isopropyl-3,3-dimethylisoin-
dolin-1-one (1). A sealed tube (25 mL) containing 2 mL of dry
DMSO was charged with 2-iodo-N,N-diisopropylbenzamide (464 mg,
1.4 mmol), vitamin E (30 mg, 0.07 mmol), and KOtBu (474 mg, 4.2
mmol) under N2. The resulting reaction mixture was refluxed for 3 h
at 100 °C. The progress of the reaction was monitored by TLC. After
completion of the reaction, water (110 mL) was added. The resulting
brownish white solution was stirred for 30 min and extracted with
ethyl acetate (20 mL × 3), dried over Na2SO4, and concentrated under
vacuum. The resulting white crystalline solid was purified by flash
column chromatography. Yield: 278 mg, 98%.
General Procedures for the Synthesis of 2-Halo Tertiary
Benzamides. Substrates for isoindolinones 1−22 (except 13) were
prepared by following Scheme 5. The substrate for 13 was prepared by
using NaH and methyl iodide. The 2-halo tertiary benzamides
Procedure B. In a 15 mL capacity sealed tube containing 5 mL of
benzene, the substrate (304 mg, 1 mmol), AMVN (25 mg, 0.1 mmol,
10 mol %), and potassium tert-butoxide (358 mg, 3.1 mmol, 3 equiv)
were heated to 100 °C. The progress of the reaction was monitored by
TLC. The reaction mixture was refluxed for 3 h at 100 °C. After
completion of the reaction, water (100 mL) was added to the resulting
brownish white solid and the mixture was stirred for 30 min. The
resulting solution was extracted with ethyl acetate (20 mL × 3) and
1
substrates show E/Z rotational isomerism, as observed in H and 13C
NMR spectra.
General Procedures for Amide Synthesis: Synthesis of 2-
Iodo-N,N-diisopropylbenzamide Substrate for 1). To a stirred
solution of 2-iodobenzoyl chloride (266 mg, 1.0 mmol) in DCM (10
mL) were added dropwise diisopropylamine (152 mg, 1.5 mmol) and
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dried over Na2SO4. The organic layer was concentrated on a rotary
evaporator under vacuum. The resulting crude reaction mixture was
purified by column chromatography using hexane/ethyl acetate (8/2)
on silica to give the desired isoindolinone 1. Yield: 176 mg, 87%.
2-Isopropyl-3,3-dimethylisoindolin-1-one (1) from 2-Iodo-N,N-
benzamide substrate. 1H NMR of 3a,b (400 MHz, CDCl3): ratio
64:36, δ 7.67 (d), 7.61 (t), 7.32 (d), 7.27 (t), 3.01 (s), 3.00 (s), 2.49
(s), 2.40 (s), 1.50 (s), 1.41 (s). 13C NMR (100 MHz, CDCl3): δ 167.4,
167.2, 148.9, 148.4, 137.93, 137.92, 132.4, 131.7, 131.5, 131.0, 128.0,
123.8, 121.3, 120.4, 62.9, 61.9, 25.0, 23.9, 23.5. 22.5, 21.3, 18.7.
4-Chloro-2-iodo-N-isopropyl-N-methylbenzamide (Substrate for
4 and 24). 4-Chloro-2-iodo-N-isopropyl-N-methylbenzamide was
prepared using 4-chloro-2-iodobenzoyl chloride and N-methyl-N-
isopropylamine. Yield: 95%. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J
= 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.07 (q, J = 4.0 Hz, 2H),
4.99−4.92 (m, 1H), 3.62−3.55 (m, 1H), 2.93 (s, 3H), 2.60 (s, 3H),
1.23−1.18 (m, 9H), 1.04 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 169.6, 169.5, 141.72, 141.70, 138.8, 138.5, 134.8, 134.7,
128.8, 128.6, 127.6, 127.1, 92.7, 92.5, 50.1, 44.4, 25.8, 20.6, 20.2.
HRMS: m/z 336.9739, calculated for C11H13NOICl 336.9730.
5-Chloro-2,3,3-trimethylisoindolin-1-one (4) from 4-Chloro-N-
methyl-2-iodo-N-isopropylbenzamide. Compound 4 was prepared
by following procedure A. White solid. Yield: 0.192 g (92%). 1H NMR
(400 MHz, CDCl3): δ 7.73 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz,
2H), 3.0 (s, 3H), 1.44 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 178.9,
153.1, 137.8, 129.4, 128.6, 124.9, 121.3, 61.9, 24.8, 24.0. HRMS: m/z
209.0592, calculated for C11H12NOCl 209.0607.
1
diisopropylbenzamide. H NMR (400 MHz, CDCl3): δ 7.69 (d, J =
8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.26 (d,
J = 8.0 Hz, 1H), 3.59−3.55 (m, 1H), 1.48 (d, J = 8.0 Hz, 6H), 1.39 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 167.2, 151.3, 132.0, 131.2,
127.8, 123.1, 120.6, 63.3, 44.5, 25.4, 20.5. LRMS: m/z 204.1, calculated
for C13H17O N + H+ 204.1.
2-Iodo-N-isopropyl-N-methylbenzamide (Substrate for 2). 2-
Iodo-N-isopropyl-N-methylbenzamide was prepared using 2-iodoben-
zoyl chloride and N-methyl-N-isopropylamine, which gave a white
semisolid. Yield: 93%. 1H NMR (400 MHz, CDCl3): δ 7.82−7.78 (m,
2H), 7.38−7.34 (m, 2H), 7.19−7.14 (m, 2H), 7.07−7.01 (m, 2H),
5.02 (m, 1H), 3.64 (m, 1H), 2.97 (s, 3H), 2.64 (s, 3H), 1.26−1.05(s,
12H). 13C NMR (100 MHz, CDCl3): δ 170.4, 170.3, 143.3, 141.7,
139.4, 139.1, 129.9, 128.5, 128.2, 126.8, 126.4, 92.5, 92.3, 50.0, 44.1,
29.6, 25.7, 20.6, 20.2. HRMS: m/z 303.0094, calculated for
C11H14INO 303.0120.
2,3,3-Trimethylisoindolin-1-one (2). Compound 2 was prepared by
following procedure A, which gave a white solid. Yield: 156 mg, 90%.
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.24 Hz, 1H) 7.51 (t, J =
7.24 Hz, 1H) 7.43−7.38 (m, 2H) 3.01 (s, 3H) 1.43 (s, 6H). 13 C NMR
(400 MHz, CDCl3) δ167.2, 151.5, 131.4, 130.91, 128.0, 123.6, 120.6,
62.1, 24.9, 23.9. HRMS: m/z 175.0968, calculated for C11H13NO
175.0997.
N-Ethyl-2-iodo-N-isopropylbenzamide (Substrate for 5). N-Ethyl-
2-iodo-N-isopropylbenzamide was prepared using 2-iodobenzoyl
1
chloride and N-ethyl-N-isopropylamine. Yield: 70%. H NMR (400
MHz, CDCl3): δ 7.79 (t, J = 7.81 Hz, 2H), 7.37−7.33 (m, 2H), 7.22−
7.14 (m, 2H), 7.05−7.01 (m, 2H), 3.64−3.53 (m, 3H), 3.32−3.02 (m,
3H), 1.34−1.23 (m, 12H), 1.06−0.98 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 170.5, 170.0, 143.4, 139.3, 139.1, 129.8, 129.7, 128.2, 128.1,
127.2, 126.3, 92.9, 92.5, 50.5, 46.2, 39.3, 35.4, 21.24, 21.19, 16.3, 14.4.
HRMS: m/z 317.0255, calculated for C12H16INO 317.0277.
2-Iodo-N-isopropyl-N,3-dimethylbenzamide (Substrate for 3). 2-
Iodo-N-isopropyl-N,3-dimethylbenzamide was prepared using 2-iodo-
3-methylbenzoyl chloride and N-methyl-N-isopropylamine. A white
1
2-Ethyl-3,3-dimethylisoindolin-1-one (5) from N-Ethyl-2-iodo-N-
solid was obtained. Yield: 92%. H NMR (400 MHz, CDCl3): δ 7.24
isopropylbenzamide. Compound 5 was prepared by following
(t, J = 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 2H) 6.93(d, J = 8.0 Hz, 2H),
5.06−5.00 (m, 1H), 3.69−3.63 (m, 1H), 2.96 (s, 3H), 2.62 (s, 3H),
2.45 (d, J = 4.0 Hz, 6H), 1.24 (d, J = 4.0 Hz, 6H), 1.20 (d, J = 4.0 Hz,
3H), 1.05 (d, J = 4.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.0,
170.9, 144.4, 142.9, 142.6, 129.3, 128.6, 128.3, 129.2, 123.9, 123.6,
99.4, 99.1, 49.9, 44.0, 25.6, 20.6, 20.2, 19.5, 18.7. HRMS: m/z
317.0274, calculated for C12H16INO 317.0277.
1
procedure C. White semisolid. Yield: 0.168 g (89%). H NMR (400
MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 6.0 Hz, 1H),
7.41 (m, 1H), 7.34 (m, 1H), 3.49 (q, J = 4.0 Hz, 2H), 1.46 (s, 6H),
1.28 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 167.4, 151.6,
131.4, 128.5, 127.9, 123.4, 120.6, 62.8, 33.4, 26.0, 14.7. HRMS: m/z
190.1249, calculated for C12H15NO + H+ 190.1232.
4-Chloro-N-ethyl-2-iodo-N-isopropylbenzamide (Substrate for 6
and 25). 4-Chloro-N-ethyl-2-iodo-N-isopropylbenzamide was pre-
pared using 4-chloro-2-iodobenzoyl chloride and N-ethyl-N-isopropyl-
amine. Yield: 85%. 1H NMR (400 MHz, CDCl3): δ 7.83 (dd, J = 7.11
Hz, J = 1.85 Hz, 2H), 7.38−7.34 (d, J = 7.31 Hz, 2H), 7.16−7.08 (m,
2H), 3.63−3.53 (m, 3H), 3.33−3.02 (m, 3H), 1.35−1.27 (m, 12H),
1.07−1.00 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 169.7, 169.1,
141.9, 141.8, 138.8, 138.5, 134.6, 134.5, 128.6, 128.5, 127.9, 127.0,
93.1, 92.7, 50.5, 46.4, 39.4, 35.5, 21.23, 21.20, 16.3, 14.3. HRMS: m/z
350.9876, calculated for C12H15ClINO 350.9887.
2,3,3,4-Tetramethylisoindolin-1-one (3a) from 2-Iodo-N-isoprop-
yl-N,3-dimethylbenzamide. Following general procedure A, a white
solid was obtained, which was purified by column chromatography
hexane/EtOAc (8/2) on silica gel. This gave two fractions: first
fraction, white solid 3a; second fraction, white solid 3b. Yield for 3a:
1
0.132 g (70%). H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz,
1H), 7.32 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 3.0 (s, 3H),
2.50 (s, 3H), 1.50 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 167.2,
148.4, 133.9, 131.7, 131.6, 128.0, 121.3, 62.8, 23.5, 22.5, 18.7. HRMS:
m/z 189.1134, calculated for C12H15NO 189.1154.
5-Chloro-2-ethyl-3,3-dimethylisoindolin-1-one (6) from 4-
Chloro-N-ethyl-2-iodo-N-isopropylbenzamide. Compound 6 was
prepared by following procedure A. White solid. Yield: 0.205 g
(92%). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.37 (dd, J = 8.0,
1.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 3.48 (q, J = 4.0 Hz, 2H), 1.46
(m, 6H), 1.28 (t, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
166.3, 153.2, 137.7, 129.6, 128.5, 124.8, 121.3, 62.6, 34.1, 25.9, 14.7.
HRMS: m/z 224.0833, calculated for C12H14ClNO + H+ 224.0842.
2-Bromo-N-ethyl-N-isopropylnicotinamide (Substrate for com-
2,3,3,6-Tetramethylisoindolin-1-one (3b) from 2-Iodo-N-isoprop-
yl-N,3-dimethylbenzamide. Second fraction. Yield: 0.038 g (20%). 1H
NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.32 (d, J = 8.0 Hz, 1H),
7.27 (d, J = 8.0 Hz, 1H), 3.00 (s, 3H), 2.41 (s, 3H), 1.41 (s, 6H). 13C
NMR (100 MHz, CDCl3): δ 167.4, 148.9, 137.9, 132.4, 131.0, 123.8,
120.4, 61.9, 25.0, 23.9, 21.3. HRMS: m/z 189.1147, calculated for
C12H15NO 189.1154.
2-Iodo-N-isopropyl-N,5-dimethylbenzamide (Substrate for 3a,b).
This substrate was prepared from 2-iodo-4-methylbenzoyl chloride
1
1
pound 7). White semisolid. Yield: 85%. H NMR (400 MHz,
and N-methyl-N-isopropylamine. Yield: 87%. H NMR (400 MHz,
CDCl3): δ 8.38−8.37 (m, 2H), 7.62−7.54 (m, 2H), 7.28−7.25 (m,
2H), 4.72−3.02 (m, 6H), 1.30−1.22 (m, 12H), 1.05−0.96 (m, 6H).
13C NMR (100 MHz, CDCl3): δ 166.4, 165.7, 149.64, 1.64.0, 147.2,
147.0, 136.5, 136.0, 133.6, 133.4, 122.6, 122.4, 50.6, 46.4, 39.1, 35.5,
21.3, 20.9, 20.4, 20.0, 16.3, 14.3. HRMS: m/z 270.0361, calculated for
C11H15BrN2O 270.0368.
6-Ethyl-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one
(7). Compound 7 was prepared by following procedure B. White
semisolid. Yield: 0.143 g (75%). 1H NMR (400 MHz, CDCl3): δ 8.62
(dd, J = 4.8, 1.35 Hz, 1H), 8.02 (dd, J = 7.6, 1.35 Hz, 1H), 7.30−7.26
(m, 1H), 3.49 (q, J = 7.0 Hz, 2H), 1.48 (s, 6H), 1.27 (t, J = 7.3 Hz,
CDCl3): δ 7.60 (t, J = 8.0 Hz, 2H), 6.94 (t, J = 4.0 Hz, 2H), 4.96 (m,
1H), 3.62 (m, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.24 (s, 6H), 1.21 (d,
J = 4.0 Hz, 6H), 1.16 (d, J = 4.0 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 170.4, 170.3, 143.2, 143.1, 139.0, 138.8, 138.7, 138.5,
130.92, 130.90, 127.6, 127.1, 88.4, 88.1, 49.9, 44.0, 29.6, 25.6, 21.0,
20.9, 20.6, 20.3. HRMS: m/z: 317.0251, calculated for C12H16INO
317.0276.
2,3,3,4-Tetramethylisoindolin-1-one (3a) and 2,3,3,6-Tetrame-
thylisoindolin-1-one (3b). The ratio of 3a and 3b is 64:36, obtained
from 2-iodo-N-isopropyl-N,5-dimethylbenzamide substrate. This is
similar to the ratio obtained from 2-iodo-N-isopropyl-N,3-dimethyl-
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3H). 13C NMR (100 MHz, CDCl3): δ 169.7, 165.6, 152.1, 131.7,
124.5, 123.1, 63.9, 34.1, 24.3, 14.6. HRMS: m/z 191.1208, calculated
for C11H14N2O + H+ 191.1184.
2-Ethyl-3-phenylisoindolin-1-one (11a) from N-Benzyl-N-ethyl-2-
iodobenzamide. Procedure A was followed for the synthesis of 11a,b.
A white solid was obtained, which was purified by column
chromatography with hexane/EtOAc (8/2) on silica gel. This gave
two fractions; first fraction, white solid 11a; second fraction, white
solid 11b. Yield of 11a: 161 mg (68%). 1H NMR (400 MHz, CDCl3):
δ 7.72 (d, J = 4.0 Hz, 1H), 7.47−7.41 (m, 2H), 7.38 (dd, J = 8.0, 3.0
Hz, 2H), 7.34−7.29 (m, 3H), 7.26−7.24 (m, 2H), 3.54−3.45 (m, 1H),
3.13−3.05 (m, 1H), 1.03 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 167.6, 148.9, 138.6, 132.6, 130.7, 129.5, 128.50, 128.47,
126.2, 123.2, 122.6, 91.4, 34.3, 14.3. HRMS: m/z 238.1233 calculated
for C16H15NO + H+ 238.1232.
N-Cyclohexyl-2-iodo-N-methylbenzamide (Substrate for 8). N-
Cyclohexyl-2-iodo-N-methylbenzamide was prepared using 2-iodo-
benzoyl chloride and N-cyclohexyl-N-methylamine. Yellowish solid.
Yield: 98%. 1H NMR (400 MHz, CDCl3): δ 7.78−7.73 (m, 2H),
7.33−7.28 (m, 2H), 7.13−7.08 (m, 2H), 7.02−6.96 (m, 2H), 4.58−
4.50 (m, 1H), 3.11−3.03 (m, 1H), 2.94 (s, 3H), 2.61 (s, 3H), 1.92−
1.39 (m, 20H). 13C NMR (100 MHz, CDCl3): δ 170.6, 170.3, 143.5,
143.4, 139.3, 139.1, 129.84, 129.82, 128.5 128.2, 126.8, 126.3, 92.5,
92.4, 58.5, 52.4, 31.0, 30.9, 30.7, 27.1, 25.7, 25.6, 25.4, 25.1. HRMS:
m/z 343.0420, calculated for C14H18INO 343.0433.
2-Benzyl-3-methylisoindolin-1-one (11b). Second fraction. Yield:
1
2′-Methylspiro[cyclohexane-1,1′-isoindolin]-3′-one (8). Com-
24 mg (10%). H NMR (400 MHz, CDCl3): δ 7.88 (d, J = 8.0 Hz,
pound 8 was prepared by following procedure A. White semisolid.
1H), 7.52 (t, J = 4.0 Hz, 1H), 7.45 (t, J = 6.0 Hz, 1H), 7.35 (d, J = 8.0
Hz, 2H), 7.28 (t, J = 8.0 Hz, 4H), 5.32 (d, J = 12.0 Hz, 1H), 4.37 (q, J
= 4.0 Hz, 1H), 4.24, (d, J = 12.0 Hz, 1H), 1.41 (d, J = 8.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 168.1, 147.0, 137.3, 131.7, 131.5, 128.7,
128.1, 128.0, 127.6, 123.9, 121.9, 55.0, 43.7, 18.0. HRMS: m/z
236.1073, calculated for C16H15NO − H+ 236.1075.
1
Yield: 202 mg (94%). H NMR (400 MHz, CDCl3): δ 7.82 (d, J =
3.69, 1H), 7.72 (d, J = 3.69, 1H), 7.45−7.37 (m, 2H), 2.96 (s, 3H),
13
1.94−1.82 (m, 8H), 1.38−1.36 (m, 2H).
C NMR (400 MHz,
CDCl3): δ 167.5, 150.6, 130.6, 127.8, 123.8, 123.4, 114.1, 64.4, 32.9,
24.7, 24.3, 22.4. LRMS: m/z 216.2, calculated for C14H17ON + H+
216.1.
2-Iodo-N-(2-methoxybenzyl)-N-methylbenzamide (Substrate for
12). 2-Iodo-N-(2-methoxybenzyl)-N-methylbenzamide was prepared
using 2-iodobenzoyl chloride and 1-(2-methoxyphenyl)-N-methylme-
4-Chloro-N-cyclohexyl-2-iodo-N-methylbenzamide (Substrate for
9 and 26). 4-Chloro-N-cyclohexyl-2-iodo-N-methylbenzamide was
prepared using 4-chloro-2-iodobenzoyl chloride and N-cyclohexyl-N-
methylamine. Yield: 91%. 1H NMR (400 MHz, CDCl3): δ 7.80 (dd, J
= 12, 2 Hz, 2H), 7.33 (dt, J = 8, 2 Hz, 2H), 7.07 (q, J = 8 Hz, 2H),
2.96 (s, 3H), 2.64 (s, 3H), 1.96−0.99 (m, 22H). 13C NMR (100 MHz,
CDCl3): δ 169.7, 169.5, 142.0, 138.8, 138.5, 134.7, 128.8, 128.6, 127.6,
127.0, 92.7, 92.5, 58.6, 52.6, 31.0, 30.9, 30.7, 29.7, 29.2, 27.2, 25.6,
25.5, 25.4, 25.1. HRMS: m/z 378.0131, calculated for C14H17ClINO +
H+ 378.0122.
6′-Chloro-2′-methylspiro[cyclohexane-1,1′-isoindolin]-3′-one (9)
from 4-Chloro-N-cyclohexyl-2-iodo-N-methylbenzamide. Com-
pound 9 was prepared by following procedure A. White solid. Yield:
232 mg (93%). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 12.0 Hz,
1H), 7.75 (t, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 3.01 (s,
3H), 1.96−1.84 (m, 8H), 1.46−1.41 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 176.8, 152.0, 136.8, 128.4, 124.9, 123.9, 111.8, 64.3, 32.7,
24.6, 24.3, 22.4. HRMS: m/z 250.1006, calculated for C14H16ClON +
H+ 250.0999.
1
thanamine. Yield: 95%. H NMR (400 MHz, CDCl3): δ 7.80 (d, J =
7.97 Hz, 2H), 7.47−7.45 (m, 1H), 7.39−7.35 (m, 1H), 7.32−7.26 (m,
2H), 7.23−7.21 (m, 3H), 7.11 (d, J = 7.20 Hz 1H), 7.06−7.00 (m,
2H), 6.97−6.90 (m, 2H), 6.88 (d, J = 8.20 Hz, 1H), 6.81 (d, J = 8.20
Hz, 1H), 4.85−4.77 (m, 2H), 4.34 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H),
3.03 (s, 3H), 2.73 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 171.4,
170.8, 157.7, 157.3, 142.9, 142.6, 139.2, 139.1, 130.1, 130.03, 129.99,
128.9, 128.7, 128.5, 128.4, 128.1, 127.5, 127.2, 124.6, 124.0, 120.7,
120.5, 110.35, 110.31, 93.0, 92.3, 55.4, 55.1, 49.6, 44.7, 36.1, 32.6.
HRMS: m/z 381.0210, calculated for C16H16INO2 381.0226.
3-(2-Methoxyphenyl)-2-methylisoindolin-1-one (12) from 2-
Iodo-N-(2-methoxybenzyl)-N-methylbenzamide. Compound 12
was prepared by following procedure A. White solid. Yield: 0.152 g
(60%). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.0 Hz, 3H), 7.48
(t, J = 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 3H), 3.95 (s, 1H), 3.02 (s, 3H),
3.00 (s, 3H). 13C NMR (100 MHz, CDCl3) 171.0, 155.3, 151.7, 148.9,
143.3, 138.9, 133.8, 131.4, 126.8, 123.1, 119.0, 118.9, 112.4, 65.8, 39.8,
13.7. HRMS (APCI): m/z 254.1170, calculated for C16H15NO2 + H
253.1181.
N,N-Diethyl-2-iodobenzamide (Substrate for 10). N,N-Diethyl-2-
iodobenzamide was prepared using 2-iodobenzoyl chloride and
1
diethylamine. Yield: 93%. H NMR (400 MHz, CDCl3): δ 7.79 (d, J
2-Iodo-N-methyl-N-(1-phenylethyl)benzamide (Substrate for 13).
2-Iodo-N-methyl-N-(1-phenylethyl)benzamide was prepared by using
NaH and CH3I. 2-Iodo-N-phenylethylbenzamide (598 mg, 1.7 mmol)
was dissolved in dry DMF, to this was added NaH (280 mg, 7.0
mmol) portionwise at 0 °C, and the mixture was stirred for 30 min at
this temperature under N2. Methyl iodide (0.65 mL, 10 mmol) was
added dropwise at 0 °C under N2. After this, the reaction mixture was
stirred at room temperature for 4 h. The resulting reaction mixture was
slowly poured over ice and extracted with ethyl acetate (20 mL × 3),
and the extract was dried over Na2SO4 and concentrated under
vacuum. The resulting yellowish oil was purified by column
chromatography using hexane/ethyl acetate (8/2) on silica gel. The
resulted product was obtained as a thick liquid which solidified on
= 8.06 Hz, 1H), 7.35 (t, J = 7.63 Hz, 1H), 7.18 (dd, J = 7.63 Hz, J =
1.64 Hz, 1H), 7.03 (dt, J = 7.73 Hz, J = 1.64 Hz, 1H), 3.91−3.75 (m,
1H), 3.35−3.21 (m, 1H), 3.13−3.09 (m, 2H), 1.27 (t, J = 7.14 Hz,
13
3H), 1.04 (t, J = 7.14 Hz, 3H). C NMR (100 MHz, CDCl3): δ
170.1, 142.9, 139.2, 129.9, 128.2 126.9, 92.8, 42.8, 38.9, 13.9, 12.5.
LRMS: m/z 304.0, calculated for C11H14INO + H+ 304.0.
2-Ethyl-3-methylisoindolin-1-one (10) from N,N-Diethyl-2-iodo-
benzamide. Compound 10 was prepared by following procedure A.
White solid. Yield: 45 mg (26%). 1H NMR (400 MHz, CDCl3): δ 7.81
(d, J = 8.0 Hz, 1H), 7.51 (t, J = 6.0 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H),
7.40 (d, J = 8.0 Hz, 1H), 4.56 (q, J = 6.0 Hz, 1H), 3.98−3.94 (m, 1H),
3.32−3.28 (m, 1H), 1.46 (d, J = 8.0 Hz, 3H), 1.25 (t, J = 8.0 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 167.7, 146.9, 131.3, 128.1, 126.8,
1
standing. Yield: 85%. H NMR (400 MHz, CDCl3): δ 7.89−7.79 (m,
123.5, 121.8, 55.2, 34.6, 18.2, 13.8. LRMS: m/z 176.1, calculated for
C11H13NO + H+ 176.1.
1H), 7.51−7.25 (m, 6H), 7.22−7.02 (m, 2H), 6.24−4.73 (m, 1H),
2.94−2.45 (m 3H), 1.70−1.55 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ 171.2, 170.6, 143.0, 142.9, 140.2, 140.1, 139.5, 139.2, 130.1,
130.01, 128.7, 128.5, 128.2, 127.94, 127.87, 127.7, 127.5, 126.9, 126.7,
126.2, 93.3, 92.7, 56.72, 56.67, 50.42, 29.4, 27.7, 18.4. HRMS: m/z
365.0267, calculated for C16H16INO 365.0277.
N-Benzyl-N-ethyl-2-iodobenzamide (Substrate for 11a,b). N-
Benzyl-N-ethyl-2-iodobenzamide was prepared using 2-iodobenzoyl
chloride and N-benzyl-N-ethylamine. Yield: 95%. 1H NMR (400 MHz,
CDCl3): δ 7.80 (t, J = 7.19 Hz, 2H), 7.46 (d, J = 7.31 Hz, 2H), 7.39−
7.22 (m, 10H), 7.14 (d, J = 7.15 Hz, 2H), 7.09−6.99 (m, 2H), 5.07 (d,
J = 14.64 Hz, 1H), 4.51 (d, J = 14.64 Hz, 1H), 4.38−4.28 (m, 2H),
4.01−3.97 (m, 1H), 3.08−3.03 (m, 3H), 1.24 (t, J = 7.16 Hz, 3H),
1.01 (t, J = 7.11 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 170.7,
170.6, 142.6, 142.3, 139.4, 139.2, 136.9, 136.3, 130.1, 130.0, 128.8,
128.7, 128.5, 128.4, 128.2, 127.7, 127.5, 127.3, 127.2, 127.1, 92.9, 92.6,
51.5, 46.7, 42.2, 39.2, 13.3, 11.8. HRMS: m/z 365.0261, calculated for
C16H16INO 365.0277.
2,3-Dimethyl-3-phenylisoindolin-1-one (13). Compound 13 was
prepared by following procedure A. White semisolid. Yield: 166 mg
(70%). 1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 6.51, 1H), 7.41 (t,
J = 6.72, 2H), 7.32−7.27 (m, 3H), 7.17−7.13 (m, 3H), 2.87 (s, 3H),
1.84 (s, 3H). 13C NMR (400 MHz, CDCl3): δ 168.2, 151.9, 139.9,
131.9, 130.6, 128.9, 128.1, 127.9, 126.1, 123.7, 121.8, 67.2, 24.7, 22.5.
HRMS: m/z 238.1248, calculated for C16H15ON + H+ 238.1232.
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2-Iodo-N-isopropyl-N-phenylbenzamide (Substrate for 14). 2-
Iodo-N-isopropyl-N-phenylbenzamide was prepared using 2-iodoben-
zoyl chloride and N-benzyl-N-isopropylamine. Yield: 90%. H NMR
(400 MHz, CDCl3): δ 7.57 (d, J = 7.9 Hz, 1H), 7.23−7.21 (m, 5H),
7.04 (t, J = 7.4 Hz, 1H), 6.97 (dd, J = 7.4 Hz, J = 1.5 Hz, 1H), 6.74 (dt,
J = 7.9 Hz, J = 1.5 Hz, 1H), 5.21−5.12 (m, 1H), 1.20 (d, J = 6.7 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 169.8, 142.9, 138.9, 137.9,
130.4, 129.3, 128.5, 128.2, 128.0, 127.1, 93.6, 46.9, 20.9. HRMS: m/z
366.0365, calculated for C16H16INO + H+ 366.0355.
3,3-Dimethyl-2-phenylisoindolin-1-one (14a). Following proce-
dure A, a white solid was obtained, which was purified by column
chromatography hexane/EtOAc (8/2) on silica gel. This gave two
fractions: first fraction, white solid 14a; second fraction, white solid
14b. Yield for 14a: 63 mg (27%). 1H NMR (400 MHz, CDCl3): δ 7.91
(d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (m, 5H), 7.26 (d, J =
7.4 Hz, 2H), 1.50 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 167.7,
151.7, 135.8, 132.0, 130.5, 129.7, 129.4, 128.2, 128.1, 124.3, 120.9,
64.5, 26.8. LRMS: m/z 238.2, calculated for C16H15NO + H+ 238.1.
5-Isopropylphenanthridin-6(5H)-one (14b). Second fraction.
White solid. Yield for 14b: 152 mg (64%). 1H NMR (400 MHz,
CDCl3): δ 8.50 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.23 (d, J
= 8.0 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.56
(t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H),
5.62−5.31 (m, 1H), 1.69 (d, J = 7.0 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 162.0, 137.3, 133.5, 132.3, 128.9, 128.6, 127.8, 126.4, 123.6,
122.1, 121.4, 120.1, 115.9, 47.4, 19.9. LRMS: m/z 238.2, calculated for
C16H15NO + H+ 238.1.
2-Isopropyl-5,6-dimethoxy-3,3-dimethylisoindolin-1-one (17).
Compound 17 was prepared by following procedure B; the reaction
mixture was heated for 12 h. White semisolid. Yield: 177 mg (67%).
1H NMR (400 MHz, CDCl3): δ 7.23 (s, 1H), 6.75 (s, 1H), 3.93 (t,
3H), 3.90 (t, 3H), 3.64−3.57 (m, 1H), 1.52 (d, J = 8.0 Hz, 6H), 1.43
(s, 6H). 13C NMR (100 MHz, CDCl3): δ 167.4, 152.4, 149.5, 144.8,
124.2, 105.0, 102.9, 62.9, 56.23, 56.20, 44.6, 25.6, 20.58. HRMS: m/z
263.1493, calculated for C15H21NO3 263.1521.
2-Iodo-N,N-diisopropyl-3-methylbenzamide (Substrate for
18a,b). 2-Iodo-N,N-diisopropyl-3-methylbenzamide was prepared
using 2-iodo-3-methylbenzoyl chloride and diisopropylamine. White
solid. Yield: 90%. 1H NMR (400 MHz, CDCl3): δ 7.21 (t, J = 7.4 Hz,
1H), 7.14(d, J = 6.7 Hz, 1H), 6.89 (d, J = 6.9 Hz, 1H), 3.61−3.55 (m,
1H), 3.53−3.46 (m, 1H), 2.5 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.55
(d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.7 Hz, 3H),
13C NMR (100 MHz, CDCl3): δ 170.4, 145.3, 142.6, 128.9, 128.2,
1
123.0, 99.1, 51.1, 45.9, 28.8, 20.74, 20.70, 20.68, 19.9. GCMS: m/z
345.0, calculated for C14H20INO 345.1.
2-Isopropyl-3,3,4-trimethylisoindolin-1-one (18a). Following pro-
cedure A, a white solid was obtained which was purified by column
chromatography with hexane/EtOAc (8/2) on silica gel. This gave two
fractions: first fraction, white solid 18a; second fraction, white solid
18b. Yield: 174 mg (80%). 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J
= 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H),
3.66−3.59 (m, 1H), 2.47 (s, 3H), 1.55 (d, J = 8.0 Hz, 6H), 1.53 (s,
6H). 13C NMR (100 MHz, CDCl3): δ 167.2, 148.1, 133.7, 132.6,
131.5, 127.9, 120.9, 64.2, 44.3, 22.9, 20.5, 18.7. HRMS: m/z 218.1544,
calculated for C14H19ON + H+ 218.1545.
4-Chloro-2-iodo-N,N-diisopropylbenzamide (Substrate for 15). 4-
Chloro-2-iodo-N,N-diisopropylbenzamide was prepared using 4-
2-Isopropyl-3,3,6-trimethylisoindolin-1-one (18b). Second frac-
1
chloro-2-iodobenzoyl chloride and diisopropylamine. Yield: 90%. H
1
tion. White solid 18b. Yield: 39 mg (18%). H NMR (400 MHz,
NMR (400 MHz, CDCl3): δ 7.80 (d, J = 4.0 Hz, 1H), 7.32 (dd, J =
8.0, 2.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.45−3.56 (m, 2H), 1.56 (d,
J = 8.0 Hz, 3H), 1.53 (d, J = 8.0 Hz, 3H), 1.24 (d, J = 4.0 Hz, 3H),
1.04 (d, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 169.0,
142.7, 138.7, 134.2, 128.6, 126.5, 92.4, 51.3, 46.1, 20.8, 20.0. HRMS:
m/z 366.0146, calculated for C13H17INOCl + H+ 366.0122.
5-Chloro-2-isopropyl-3,3-dimethylisoindolin-1-one (15). Com-
pound 15 was prepared by following procedure A. White semisolid.
Yield: 228 mg (96%). 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0
Hz, 1H), 7.35 (dd, J = 2.0, 8.0 Hz, 1H), 7.30 (d, J = 3.0 Hz, 1H),
3.63−3.56 (m, 1H) 1.52 (d, J = 8.0 Hz, 6H), 1.44 (s, 6H). 13C NMR
(100 MHz, CDCl3): δ 166.2, 152.8, 137.5, 130.5, 128.5, 124.6, 121.2,
63.1, 44.7, 25.3, 20.4. HRMS: m/z 238.1017, calculated for
C13H16NOCl + H+ 238.0999.
CDCl3): δ 7.56 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz,
1H), 3.65−3.58 (m, 1H), 2.40 (s, 3H), 1.53 (d, J = 8.0 Hz, 6H), 1.44
(s, 6H). 13C NMR (100 MHz, CDCl3): δ 167.4, 137.8, 132.2, 131.4,
123.4, 120.3, 115.6, 55.6, 44.6, 25.5, 21.3, 20.5. HRMS: m/z 218.1526,
calculated for C14H19ON+ H+ 218.1545.
2-Bromo-N,N-diisopropyl-5-methoxybenzamide (Substrate for
19). 2-Bromo-N,N-diisopropyl-5-methoxybenzamide was prepared
using 2-bromo-5-methoxybenzoyl chloride and diisopropylamine.
1
White solid. Yield: 85%. H NMR (400 MHz, CDCl3): δ 7.39 (d, J
= 8.7 Hz, 1H), 6.72 (dd, J = 8.8, 2.9 Hz, 1H), 6.68 (d, J = 2.9 Hz, 1H),
3.75 (s, 3H), 3.64−3.54 (m, 1H), 3.52−3.43 (m, 1H), 1.55−1.52 (m,
6H), 1.21 (d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.67 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 167.9, 159.0, 140.8, 133.6, 115.6, 111.9, 109.2,
55.6, 51.15, 45.97, 20.9, 20.7, 20.5, 20.0. LRMS: m/z: 314.2, calculated
for C14H20BrNO2 + H+ 314.1.
2-Bromo-N,N-diisopropyl-3-nitrobenzamide (Substrate for 16). 2-
Bromo-N,N-diisopropyl-3-nitrobenzamide was prepared using 2-
bromo-3-nitrobenzoyl chloride and diisopropylamine. Yellowish
2-Isopropyl-6-methoxy-3,3-dimethylisoindolin-1-one (19a) and
2-Isopropyl-4-methoxy-3,3-dimethylisoindolin-1-one (19b) from 2-
Bromo-N,N-diisopropyl-5-methoxybenzamide. Procedure B was
followed. A white solid was obtained, which was purified by column
chromatography with hexane/EtOAc (8/2) on silica gel. This gave a
1
solid. Yield: 98%. H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.45
Hz, 1H), 7.47 (t, J = 7.76 Hz, 1H), 7.34 (d, J = 7.07 Hz, 1H), 3.57−
3.47 (m, 2H), 1.55 (t, J = 6.33, 6H), 1.24 (d, J = 6.69 Hz, 3H), 1.07 (d,
J = 6.69 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 166.2, 150.8, 143.1,
129.5, 128.7, 124.6, 111.2, 51.4, 46.4, 20.8, 20.7, 20.5, 19.9. HRMS: m/
z 328.0406, calculated for C13H17BrN2O3 328.0423.
2-Isopropyl-3,3-dimethyl-4-nitroisoindolin-1-one (16) from 2-
Bromo-N,N-diisopropyl-3-nitrobenzamide. Compound 16 was pre-
pared by following procedure B. Yellowish semisolid. Yield: 109 mg
(44%). 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J = 8.0, 1H), 8.12 (d,
J = 7.40, 1H), 7.61 (t, J = 8.0, 1H), 3.72−3.66 (m, 1H), 1.68 (s, 6H),
1.57 (d, J = 3.42, 6H). 13C NMR (400 MHz, CDCl3): δ 182.1, 143.6,
140.4, 140.3, 129.5, 127.8, 123.5, 66.2, 45.0, 22.5, 20.3. HRMS: m/z
248.1161, calculated for C13H16N2O3 248.1161.
2-Bromo-N,N-diisopropyl-4,5-dimethoxybenzamide (Substrate
for 17). 2-Bromo-N,N-diisopropyl-4,5-dimethoxybenzamide was pre-
pared from 2-bromo-4,5-dimethoxybenzoyl chloride and diisopropyl-
amine. Yield: 89%. 1H NMR (400 MHz, CDCl3): δ 6.94 (s, 1H), 6.61
(s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.62−3.56 (m, 1H), 3.49−3.42 (m,
1H), 1.51 (d, J = 6.8 Hz, 6H), 1.18 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.6
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 168.1, 149.3, 148.6, 132.2,
115.4, 109.3, 109.0, 56.19, 56.17, 51.2, 45.9, 21.0, 20.7, 20.5, 20.0.
LRMS: m/z 344.0, calculated for C15H22BrNO3 + H+ 344.0.
1
mixture of 19a and 19b. White solid. Yield: 158 mg (68%). H NMR
(400 MHz, CDCl3): δ 7.38−7.32 (m, 2H), 7.20 (d, J = 12.0 Hz, 2H),
7.04 (dd, J = 4.0, 8.0 Hz, 1H), 6.95 (dd, J = 4.0, 8.0 Hz, 1H), 3.88 (s,
3H), 3.80 (s, 3H), 3.65−3.58 (m, 2H), 1.54 (m, 6H), 1.52 (d, J = 4.0
Hz, 12H), 1.43 (s, 6H). 13C NMR (100 MHz, CDCl3) δ.157.2, 154.2,
135.0, 134.1, 134.0, 133.8, 129.3, 121.5, 119.5, 115.3, 112.9, 105.92,
105.9, 63.4, 63.0, 55.7, 55.4, 44.6, 44.2, 25.5, 22.8, 20.5. HRMS: m/z
233.1398, calculated for C14H19O2N 233.1416.
1-Bromo-N,N-diisopropyl-2-naphthamide (Substrate for 20).
This substrate was prepared by using 2-bromonaphthoyl chloride
1
and diisopropylamine. White solid. Yield: 89%. H NMR (400 MHz,
CDCl3): δ 8.29 (d, J = 8.4 Hz, 1H), 7.82 (dd, J = 8.4 Hz, J = 2.2 Hz,
2H), 7.61 (td, J = 7.1 Hz, J = 1.2 Hz, 1H), 7.55−7.51 (m, 1H), 7.26 (d,
J = 8.4 Hz, 1H), 3.68−3.60 (m, 1H), 3.58−3.49 (m, 1H), 1.64 (d, J =
6.8 Hz, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.05
(d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 168.6, 138.0,
133.7, 132.1, 128.5, 128.2, 127.9, 127.3, 127.0, 123.5, 118.9, 51.2, 46.0,
20.8, 20.72, 20.70, 20.2. HRMS: m/z 334.0781, calculated for
C17H20BrNO + H+ 334.0807.
2951
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The Journal of Organic Chemistry
Article
2-Isopropyl-3,3-dimethyl-2,3-dihydro-1H-benzo[f ]isoindol-1-one
(20a) from 3-Bromo-N,N-diisopropyl-2-naphthamide. Following
procedure B, a white solid was obtained, which was purified by
column chromatography with hexane/EtOAc (8/2) on silica gel. This
gave two fractions: first fraction, white solid 20a; second fraction,
white solid 20b. Yield obtained for 20a: 152 mg (60%). 1H NMR (400
MHz, CDCl3): δ 8.28 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0
Hz, 1H), 7.74 (s, 1H), 7.56−7.48 (m, 2H), 3.71−3.64 (m, 1H), 1.59
(d, J = 8.0 Hz, 6H), 1.56 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
167.0, 146.9, 135.1, 133.1, 130.3, 129.5, 128.0, 127.3, 126.1, 123.3,
119.4, 63.4, 44.8, 26.2, 20.6. HRMS: m/z 253.1459, calculated for
C17H19ON 253.1467.
152.0, 144.7, 140.8, 130.9, 128.9, 127.9, 127.5, 127.2, 123.6, 119.4,
63.3, 44.7, 25.6, 20.5. HRMS: m/z 280.1715, calculated for C19H21ON
+ H+ 280.1701.
2-Methyl-3,3-dimethyl-5-phenylisoindolin-1-one (24) from 4-
Chloro-N-methyl-2-iodo-N-isopropylbenzamide. Compound 24
was prepared by following procedure C. White solid. Yield: 216 mg
1
(86%). H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.0 Hz, 1H),
7.64−7.57 (s, 4H), 7.46 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H),
3.04 (s, 3H), 1.49 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 178.4,
152.2, 147.9, 128.9, 128.0, 127.5, 127.3, 123.9, 119.5, 100.0, 99.1, 62.2,
25.0, 24.0. HRMS: m/z 251.1295, calculated for C17H17NO 251.1310.
2-Ethyl-3,3-dimethyl-5-phenylisoindolin-1-one (25) from 4-
Chloro-N-ethyl-2-iodo-N-isopropylbenzamide. Compound 25 was
prepared by following procedure C. White solid. Yield: 236 mg, 89%.
1H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 1H), 7.61 (t, J =
2-Isopropyl-1,1-dimethyl-1H-benzo[e]isoindol-3(2H)-one (20b).
1
Yield: 86 mg (34%). H NMR (400 MHz, CDCl3): δ 8.04 (d, J =
8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.87 (q, J = 8.0 Hz, 2H), 7.63−
7.56 (m, 2H), 3.80−3.72 (m, 1H), 1.72 (s, 6H), 1.61 (d, J = 8.0 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 167.4, 147.7, 135.8, 130.1,
130.0, 129.3, 126.9, 126.7, 126.69, 123.7, 119.8, 64.4, 44.5, 24.8, 20.7.
HRMS: m/z 253.1446, calculated for C17H19ON 253.1467.
8.0 Hz, 3H), 7.54 (s, 1H), 7.45 (t, J = 6.0 Hz, 2H), 7.38 (t, J = 6.0 Hz,
1H), 3.53 (t, J = 6.0 Hz, 2H), 1.52 (s, 6H), 1.32 (t, J = 6.0 Hz, 3H) .
13C NMR (100 MHz, CDCl3): δ 167.2, 152.3, 144.8, 140.7, 130.0,
128.9, 128.0, 127.5, 127.3, 123.8, 119.4, 62.9, 34.1, 26.1, 14.8. HRMS:
m/z 266.1553, calculated for C18H19NO + H+ 266.1545.
N,N-Diisopropyl-2-iodoferrocenecarboxamide (Substrate for 21).
This compound was prepared by following a literature procedure.12
2′-Methyl-6′-phenylspiro[cyclohexane-1,1′-isoindolin]-3′-one
(26) from 4-Chloro-N-cyclohexyl-2-iodo-N-methylbenzamide. Com-
pound 26 was prepared by following procedure C. White solid. Yield:
1
Yield: 95%. H NMR (400 MHz, CDCl3): δ 4.42 (s, 1H), 4.34 (s,
5H), 4.27 (s, 1H), 4.16 (s, 1H), 3.61 (s, 1H), 3.40 (s, 1H), 1.49 (s,
6H), 1.09 (s, 3H), 0.97 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
166.3, 73.6. 72.8, 67.6, 66.8, 50.8, 45.9, 40.5, 20.8. LRMS: m/z 440.0,
calculated for C17H22ONIFe + H+ 440.0.
1
215 mg (86%). H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.0 Hz,
2H), 7.65 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.47 (t, J
= 8.0 Hz, 2H), 7.39 (t, J = 8.0 Hz, 1H), 3.05 (s, 3H), 2.01−1.88 (s,
8H), 1.52−1.47 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 175.5,
151.3, 144.0, 130.6, 129.0, 127.9, 127.6, 127.3, 124.0, 122.4, 100.0,
64.4, 32.9, 24.8, 24.3, 22.6. HRMS: m/z 291.1611, calculated for
C20H21NO 291.1623.
Ferrocenylisoindolinone (21). Compound 21 was prepared by
1
following procedure A. Orange solid. Yield: 300 mg (96%). H NMR
(400 MHz, CDCl3): δ 4.59 (s, 1H), 4.25−4.20 (m, 7H), 3.48 (s, 1H),
1.72 (s, 3H), 1.51 (d, J = 4.0 Hz, 3H), 1.47 (d, J = 4.0 Hz, 3H), 1.29
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.5, 104.3, 70.7, 69.6, 60.7,
60.1, 45.0, 28.7, 27.2, 20.7, 20.6. HRMS: m/z 311.0963, calculated for
C17H21ONFe 311.0973.
2-Chloro-N,N-diisopropyl-5-nitrobenzamide. 1H NMR (400 MHz,
CDCl3): δ 8.13 (dd, J = 8.0, 2.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H),
7.55 (d, J = 8.0 Hz, 1H), 3.59−3.48 (m, 2H), 1.55 (dd, J = 8.0, 2.0 Hz,
6H), 1.22 (d, J = 8.0 Hz, 1H), 1.10 (d, J = 8.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 164.9, 146.7, 139.2, 137.2, 130.9, 124.2, 121.9, 51.5,
46.4, 20.5, 20.1. HRMS: 284.0904, calculated for C13H17ClN2O3
284.0928.
2-Bromo-N,N-diisopropylnicotinamide (Substrate for 22). 2-
Bromo-N,N-diisopropylnicotinamide was prepared using 2-bromoni-
1
cotinoyl chloride and diisopropylamine. White solid. Yield: 95%. H
NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.53 (dd, J = 7.52 Hz, J =
1.71 Hz, 1H), 7.27−7.24 (m, 1H), 3.58−3.47 (m, 2H), 1.54 (t, J = 6.5
Hz, 6H), 1.23 (d, J = 6.57 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 165.5, 149.3, 147.0, 135.5, 134.2, 122.6, 51.3,
46.2, 20.9, 20.6, 20.5, 19.9. HRMS: m/z 284.0507, calculated for
C12H17BrN2O 284.0524.
2-Hydroxy-N,N-diisopropyl-5-nitrobenzamide. This compound
was prepared by following procedure B; a white solid was obtained.
1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 8.0, 2.0 Hz, 1H), 7.03
(d, J = 8.0 Hz, 1H), 3.88 (s, 2H), 1.40 (d, J = 8.0 Hz, 12H). HRMS:
m/z 267.1323, calculated for C13H18N2O4 + H+ 267.1345.
6-Isopropyl-7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
one (22). Compound 22 was prepared by following procedure B.
Yellowish semisolid. Yield: 162 mg (79%). 1H NMR (400 MHz,
CDCl3): δ 8.66 (dd, J = 5.0, 1.4 Hz, 1H), 8.03 (dd, J = 7.6, 1.4 Hz,
1H), 7.34−7.31 (m, 1H), 3.75−3.64 (m, 1H), 1.55 (d, J = 6.8 Hz,
6H), 1.52 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 169.4, 165.4,
151.9, 131.5, 125.5, 123.1, 64.5, 44.9, 23.8, 20.5. HRMS: m/z
205.1357, calculated for C12H16N2O + H+ 205.1341.
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables, figures, and CIF files giving details for the optimization
of reaction conditions, mechanistic details, NMR spectra,
HRMS spectra of unknown compounds, and crystallographic
data (CCDC file 968215 for 21, 968216 for 23, 968217 for 1).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Typical Procedure for the Synthesis of 5-Phenylisoindolin-1-
ones. 2-Isopropyl-3,3-dimethyl-5-phenylisoindolin-1-one (23)
from 4-Chloro-2-iodo-N,N-diisopropylbenzamide (Procedure
C). In a 15 mL capacity sealed tube containing 5 mL of benzene, 4-
chloro-2-iodo-N,N-diisopropylbenzamide (511 mg, 1.4 mmol),
AMVN (35 mg, 0.14 mmol, 10 mol %), and potassium tert-butoxide
(818 mg, 7.3 mmol) were heated to 100 °C. The progress of the
reaction was monitored by TLC. The reaction mixture was refluxed for
28 h at 100 °C. After completion of the reaction, water (100 mL) was
added to the resulting brownish white solid and the mixture was
stirred for 30 min. The resulting solution was extracted with ethyl
acetate (20 mL × 3), and the extract was dried over Na2SO4. The
organic layer was concentrated on a rotary evaporator under vacuum.
The resulting crude reaction mixture was purified by column
chromatography using hexane/ethyl acetate (8/2) on silica to give
the desired 2-isopropyl-3,3-dimethyl-5-phenylisoindolin-1-one (23).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for S.K.: sangitkumar@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.K. thanks the DST New Delhi, DRDO New Delhi, DAE-
BRNS Mumbai, and IISER Bhopal for generous funding. A.Y.
acknowledges the UGC-CSIR for a fellowship. S.K. acknowl-
edges Dr. Sanjit Konar and Ms. Anusha Upadhyay for single-
crystal data collection and C. D. Prasad for proofreading.
1
White solid. Yield: 340 mg (87%). H NMR (400 MHz, CDCl3): δ
7.83 (d, J = 8.0 Hz, 1H), 7.62−7.58 (m, 3H), 7.50 (s, 1H), 7.45 (t, J =
8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 1H), 3.69−3.62 (m, 1H), 1.56 (d, J =
8.0 Hz, 6H), 1.51 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 167.1,
2952
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The Journal of Organic Chemistry
Article
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Kusano, S.; Sakata, H.; Nagasaka, T. Tetrahedron Lett. 1999, 40, 2169.
(f) Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R. Tetrahedron 1999,
55, 12361. (g) Kundu, N. G.; Khan, M. W. Tetrahedron 2000, 56,
4777. (h) Lu, C.; Dubrovisky, A. V.; Larock, R. C. J. Org. Chem. 2012,
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(9) Beak, P.; Kerrick, S. T.; Gallagher, D. J. J. Am. Chem. Soc. 1993,
115, 10628.
(10) Synthesis of oxindoles by the coupling of an activated C−H
bond with an aniline ring: (a) Beckwith, A. L. J.; Bowry, V. W.;
Bowman, W. R.; Mann, E.; Parr, J.; Storey, J. M. D. Angew. Chem., Int.
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