Synthesis of 2-Acetylbenzonitriles and Their Reactivity in Tandem Reactions with Carbon and Hetero Nucleophiles: Easy Access to 3,3-Disubstituted Isoindolinones

Article abstract of DOI:10.1002/ejoc.201800240

2-Acetylbenzonitriles have been conveniently synthesized by the oxidation of the respective 2-ethylbenzonitriles, combining in a one-pot procedure radical bromination and hydrolysis reactions. The obtained ketones reacted under very mild conditions with c

Full text of DOI:10.1002/ejoc.201800240

A Journal of
Accepted Article
Title: Synthesis of 2-acetylbenzonitriles and reactivity in tandem
reactions with carbon- and hetero-nucleophiles: easy access to
3,3-disubstituted isoindolinones.
Authors: Antonia Di Mola, Miriam Di Martino, Vito Capaccio, Giovanni
Pierri, Laura Palombi, Consiglia Tedesco, and Antonio Massa
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800240
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
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Synthesis of 2-acetylbenzonitriles and reactivity in tandem
reactions with carbon- and hetero-nucleophiles: easy access to
3,3-disubstituted isoindolinones.
Antonia Di Mola,[a] Miriam Di Martino,[a] Vito Capaccio,[a] Giovanni Pierri,[a] Laura Palombi,[a] Consiglia
Tedesco[a] and Antonio Massa*.[a]
Abstract. The synthesis of 2-acetylbenzonitriles has been
conveniently achieved by oxidation of the respective 2-
ethylbenzonitriles, combining in one-pot procedures radical
bromination and hydrolysis reaction. The obtained ketones, reacted
under very mild conditions with carbon- and hetero-nucleophiles, led
to a wide range of 3,3-disubstituted isoindolinones in yields of 80 to
99% via a tandem process consisting of an addition step and a
subsequent Dimroth type rearrangement. Among the tested
nucleophiles, the addition of water in the presence of catalytic
amount of KOH allowed a convenient access to an unprecedented
variety of novel 3-hydroxy-3-methyl isoindolinones.
found in many pharmaceuticals and complex natural products,
like pagoclone, pazinaclone, PD-172938.[5] In comparison, the
synthesis
of
3,3-disubstituted
isoindolinones
with
a
tetrasubstituted carbon remain underdeveloped,[6] requiring
complex, multi-step pathways.[7] Even if the nucleophilic
additions to ketones have always been a major challenge in
organic synthesis because of the poorer electrophilic character
of the carbonyl group and because of competitive enolisation,[8]
the aim of the present work is to investigate the reactivity of 2-
acetylbenzonitriles as electrophiles in order to develop
convenient tandem synthesis of isoindolinones with
tetrasubstituted carbon (Scheme 1). To our knowledge, very few
applications of 2-acetylbenzonitriles have been reported in
literature. In 2012 and 2016 respectively Gotor[9a] and
Romano[9b] described a biocatalytic reduction for the synthesis of
benzyl alcohols and methylphthalides.[9]
Introduction
The interest of the chemical community towards “one-pot”
reactions increased rapidly over the past two decades. These
processes, which also include tandem reactions, are
characterized by a high level of atom and step economy.[1]
Tandem reactions are often used to prepare heterocycles of
high biopharmacological value.[2] To facilitate the reaction design,
the utilization of bifunctional building blocks in tandem reactions
has emerged as an important research area of organic
chemistry. However, most of the bifunctional compounds are not
easy to synthesize due to the difficulty of installing two or more
reactive sites into one molecule. Many 2-substituted
benzaldehydes belong to this class and have been widely used
in tandem reactions for the synthesis of heterocyclic compounds.
Particularly in recent years, one-pot cross aldol-initiated tandem
reactions of 2-formylbenzonitriles (2-cyanobenzaldehydes) have
become a powerful tool for the synthesis of several heterocyclic
compounds of great value. The reactions of 2-
cyanobenzaldehydes have been performed in the presence of a
wide range of catalytic systems and nucleophiles, to give, under
very mild conditions, 3-substituted isoindolinones.[3] Also
imidates and isobenzofuranones (phthalides) have been
obtained.[4] 3-Substituted isoindolinone scaffold, in particular, is
In addition, 2-acetylbenzonitrile itself is rather expensive
and it is not easy to synthesize. Few synthetic pathways are
available. They are not efficient and often require several steps
or employ cyanating agents like NaCN or CuCN in Sandmeyer’s
reactions.[9a,10] Acylation of arylzinc bromides using a cobalt
catalysis has also been reported to give 2-acetylbenzonitrile in
low yields.[11] Efficient synthesis of acetophenones has been
reported
via
palladium-catalyzed
arylation
of
vinyloxytrimethylsilane, but 2-acetylbenzonitrile was obtained
with low efficiency.[12]
Thus, in this work we have also evaluated alternative
approaches for the synthesis of 2-acetylbenzonitriles from
readily available and cheaper starting materials. In this context,
reactions of benzal bromides, obtained from methyl benzenes
and 2-tolunitriles by treatment with NBS and AIBN in CCl4, have
emerged as useful alternatives to give benzaldehydes and 2-
formylbenzonitriles under a variety of conditions (Scheme 1).[13]
One of the major advantage of the use of N-halosuccinimides is
that the byproduct succinimide can be easily recovered and
converted back to N-halosuccinimides to be reused.[14] However,
to our knowledge the transformation of the readily available 2-
ethylbenzonitriles into 2-acetylbenzonitriles has never been
investigated (Scheme 1).
[a]
Dipartimento di Chimica e Biologia "A. Zambelli", Università di
Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, (SA), Italy.
*E-mail address: amassa@unisa.it (A. Massa).
http://www.unisa.it/docenti/antoniomassa/index
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800240
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optimized conditions, the process was easily scaled-up with
unchanged efficiency (Entry 9). Higher amount of NBS or the
use of BPO instead of AIBN gave comparable results (Entries 10
and 11, respectively). Decomposition products (Entries 4 and 5)
or a slower reaction rate (Entry 12) were observed at other
CH3CN/H2O ratios. A slower reaction was also observed with
lower NBS amount (Entry 13).
Table 1. One-pot bromination/hydrolysis of 2-ethylbenzonitrile
Entry
Solvent (ratio)
NBS
(eq)
4
Time
(h)
48
Yield
(%)[a]
--
1
2
CCl4
CH3CN
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
4.5
4.5
3.5
2.5
24
1.5
1.5
1.5
4
--
58
3
H2O
4
CH3CN/H2O (1/9)
CH3CN/H2O (1/4)
CH3CN/H2O (4/1)
CH3CN/H2O (4/1)
CH3CN/H2O (4/1)
CH3CN/H2O (4/1)
CH3CN/H2O (4/1)
CH3CN/H2O (4/1)
CH3CN/H2O (5/1)
CH3CN/H2O (4/1)
69
5
62
6
82[b]
81[c]
55[d]
80
7
3
8
5
9[e]
10
11[f]
12
13
3
3.5
3.5
5
83
83
69
30[g]
Scheme 1. Previous works and current work
3.5
[a]
Yields refer to chromatographically pure compounds. [b] α-
Bromoethyl benzonitrile and α-bromo ketone were isolated
respectively in 5% and 10% yield. [c]α-Bromoethylbenzonitrile
and α-bromo ketone were isolated respectively in 12% and
4% yield. [d]α-Bromoethylbenzonitrile and α-bromo ketone
were isolated respectively in 5% and 38% yield. [e] Reaction
was scaled to 4 mmol. [f]0.1 eq of dibenzoyl peroxide (BPO)
was used instead of AIBN. [g]The main product was α-
bromoethylbenzonitrile
Results and Discussion
a) Synthesis of 2-acetylbenzonitriles
In contrast with the 2-tolunitriles,[13] the treatment of 2-
ethylbenzonitrile 1 with NBS and catalytic amount of AIBN in
CCl4 led to the complete disappearance of the starting material
only after a long reaction time and a 1/1 mixture of α-
bromoethylbenzonitrile and α,α-dibromoethylbenzonitrile was
obtained (Table 1, Entry 1). In acetonitrile the results were
disappointing too, since only the formation of α-
bromoethylbenzonitrile was observed (Entry 2). To improve the
reaction rate and the yield and in order to combine bromination
and hydrolysis in a single pot, the reaction was performed in
water, which is considered a convenient solvent for radical
reactions.[15] Pleasingly, the ketone 2a was obtained in moderate
yield in only 1.5 h, even if hydrolysis by-products were detected
(Entry 3). In order to minimize the side reactions, we carried out
the transformation in different CH3CN/H2O mixtures, increasing
progressively the amount of CH3CN at the same molar
concentration of the reactants (Entries 4-13). Very good yields
were obtained with a 4/1 ratio in 3-4h (Entries 6, 7). However,
the formation of α-bromo ketone became progressively more
evident as the reaction time increased (Entry 8). Under the
With the optimized one-pot procedure in hand, we turned
our attention to analyze the scope of the methodology in the
presence of substituted ethylbenzonitriles 3-5, 6 and 7. These
substrates were obtained as 95/5 mixtures of regioisomers in
good yields after nitration, reduction and acetylation or
Sandmeyer reactions of the substituted aniline 4 (Scheme 2).
The 2-ethyl-5-nitrobenzonitrile 3 was less reactive and a higher
amount of NBS was required (Table 2, Entries 2-5). Both 5-
chloro-2-ethylbenzonitrile 5a and 5-bromo-2-ethylbenzonitrile 5b
showed a reactivity comparable to 1a, giving the respective
ketones in good yields (Entries 6-8). 2-Ethylbenzonitriles with
electron-donating groups were also tested (Scheme 2b and 2c).
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10.1002/ejoc.201800240
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Scheme 2. Synthesis of substituted 2-ethylbenzonitriles
Intrigued by this multivalent behavior, in control
experiments we firstly treated the 2-acetylbenzonitrile with OH-
only (1 eq). Interestingly, under the conditions of Scheme 3, 3-
hydroxy-3-methyl isoindolinone 8a was isolated in a very good
80% yield, as the result of the addition of OH- to the ketone with
a subsequent cyclization at cyano group and rearrangement
process, according to the mechanism described in Scheme 3.
Even though hydroxide anion acts as nucleophile, in this case
the role of water is very important for the regeneration of the
anion (Scheme 3). The entire process can be indeed ascribed to
the formal addition of water to 2a. Accordingly, in another
experiment 2a was reacted in CH3CN/H2O (9/1) mixture in the
presence of catalytic amount of KOH. Nicely, the product 8a was
obtained in an excellent 93% yield, in 3h (Scheme 4). It is
noteworthy that 3-hydroxy-3-methyl isoindolinone is a known
compound and is reported to be an effective substrate for
asymmetric addition of nucleophiles like aryl boron reagents or
in Friedel-Crafts reactions in the presence of chiral metal
complexes or chiral phosphoric acids, leading to 3,3-
The acetamide 6 gave mainly electrophilic bromination on the
aromatic ring and in less extent the relative ketone: even after
long reaction time it was poorly reactive for the presence of the
free NH group[16] (Scheme 2b; Table 2, Entry 9). Conversely, the
N-methyl acetamide 7 reacted smoothly, leading to the desired
ketone in good yield (Scheme 2b and Entry 10). A similar
outcome was observed with the 2-ethylbenzonitrile 5c
substituted with the -OMe group. In this case, two new
acetylbenzonitriles were synthesized (Scheme 2c; Table 2,
Entries 11 and 12). Depending on the reaction conditions, the 2-
acetylbenzonitrile 2h with a tetrasubstituted aromatic ring was
isolated in good yield (Scheme 2c; Table 2, Entry 12).
b) Tandem reactions of 2-acetylbenzonitriles
The investigation of the reactivity of 2-acetylbenzonitriles
focused on the use of ready available carbon nucleophiles like
dimethyl malonate, nitromethane and malononitrile and hetero-
nucleophiles like primary amines. The hydroxide anion was also
tested with the aim to investigate possible competitive reactions
as the result of enolisation of 2-acetylbenzonitrile vs
deprotonation and addition of the used nucleophile and vs direct
addition of OH- to the ketone group.
disubstituted
isoindolinones.[17,18]
3-Hydroxy-3-methyl
isoindolinone has been used for the synthesis of 3-methyl
isoindolinone via reductive deoxygenation reactions.18a,b 3-
Hydroxy isoindolinones are also pharmacophores, found in
important drugs. [7d]
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Table 2. Synthesis of 2-acetylbenzonitriles
these compounds (Scheme 5).[18c] In comparison the
methodology herein developed is particularly convenient. All the
previously synthesized 2-acetylbenzonitriles 2a-2h, bearing both
electron-withdrawing or electron-donating groups, reacted
smoothly under the optimized conditions, furnishing an
unprecedented variety of substituted 3-hydroxy-3-methyl
isoindolinones (Scheme 4). All the substituted 3-hydroxy-3-
methyl isoindolinones were isolated in excellent yields also due
to the simple work-up and purification procedures (See
supporting information).
Entry CH3CN/
H2O
2
X
Y
NBS
(eq)
3.5
t (h)
Yield
(%)[a]
82
1
(4/1)
(4/1)
(4/1)
(1/1)
(1/4)
(4/1)
(4/1)
(4/1)
(4/1)
(4/1)
(4/1)
(4/1)
2a
2b
2b
2b
2b
2c
2c
2d
2e
2f
H
NO2
NO2
NO2
NO2
Cl
H
H
H
H
H
H
H
H
Br
H
H
Br
4
36
96
48
48
7
2
7.0
3.5
4.5
4.5
3.5
3.5
3.5
7.0
3.5
3.5
5.0
59
22[b]
19[b]
24[b]
67
3
4
5
6
7
Cl
4
70
8
Br
5.5
48-72
2
72
9
AcNH
AcNMe
MeO-
MeO-
14
10
11
12
70
18[c]
2g
3
2h
6
70
[a] Yields refer to chromatographically pure compounds.
[b] α-Bromoethylbenzonitrile was the main product.
[c] 2-bromo-6-ethyl-3-methoxybenzonitrile was the main product.
Scheme 4. Optimized synthesis of 3-hydroxy-3-methyl
isoindolinones.
Scheme 5. Literature synthetic approach to 3-hydroxy-3-methyl
isoindolinones.18c
Scheme 3. Conditions control experiment: 2a (0.2 mmol), KOH
(1 eq.), acetonitrile (2 mL), 2h.
In another control experiment 2-acetylbenzonitrile 2a was
simultaneously treated with 1 eq of OH- and dimethyl malonate.
In a first reaction, we observed a quantitative conversion and the
product 9a of the addition of dimethyl malonate was isolated
together with 8a in comparable yields (Scheme 6). The product
To our knowledge only one typical methodology has been
reported for the synthesis of 8a, by nucleophilic addition of
Grignard CH3MgBr[18a] or methyl lithium[18b] to phthalimide.
However, according to the literature, the addition of
organometallic reagents to phthalimides substituted on the
aromatic ring gives mixtures of regioisomeric isoindolinones
which are very difficult to separate, limiting the applications of
1
9a was characterized by H and 13C NMR, HRMS. The lactamic
structure and the presence of a tetrasubstituted carbon were
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
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unequivocally confirmed using X-ray diffraction (Figure 1). We
also determined X-ray diffraction structure of 8a, which has
never been reported (Figure 1). Then, the efforts of the research
were focused on the improvement of the chemoselectivity of the
process depicted in Scheme 6 (Table 3). As demonstrated
before, since the formation of 8a is favored by the presence of
water (Schemes 3 and 4), we performed the reaction of Scheme
6 under dry conditions. To our delight, the formation of 8a was
minimized and 9a was obtained with a good 75% yield (Table 3,
entry 2).
Table 3. Optimization of the tandem reaction.
Entry
1
Base / eq
KOH / 1
Solvent (M)[a]
CH3CN (0.17)
t (h)
48
Yield
(%)[b]
55c
2[d]
3[d]
4
KOH / 1
KOH / 0.3
K2CO3 / 1
K2CO3 / 1
K2CO3 / 0.3
CH3CN (0.17)
solvent free
CH3CN (3.0)
CH3CN (3.0)
CH3CN (3.0)
24
3
75[e]
80
48
18
48
88
5[f]
6[f]
87
Scheme 6. Competitive control experiment.
82
[a]Molar concentration of 2a. [b]Yields refer to chromatographically
pure compounds. [c] 8a was obtained in a 40% yield. [d]Performed
under dry conditions. [e] 8a was obtained in a 17% yield. [f] Reaction
performed at 50°C.
On the basis of the obtained results, a tandem mechanism
can proposed according to Scheme 8. The presence of the
cyano group in 2-position of the aromatic ring has the advantage
to drive the unfavorable addition reaction toward the formation of
the cyclic imidate. The presence of an acidic proton at the
position on the side chain of the imidate permits a further
Dimroth type rearrangement via deprotonation, ring opening and
intramolecular aza-Michael conjugated addition leading in this
case to 3,3-disubstituted isoindolinones. The proposed
mechanistic pathway can also be extended to the other carbon
nucleophiles, to the amines and the hydroxide anion as well.
.
9a
8a
Figure 1. The CIF files were deposited with the Cambridge
Crystallographic Data Centre, deposition numbers are CCDC
1587578-1587579.
The tandem reaction also occurred using catalytic amount of
KOH under solvent free and dry conditions with a very good
80% yield (Entry 3). Potassium carbonate can also be efficiently
used both in stoichiometric or catalytic amount under quasi
solvent free conditions, leading to 9a in high yields (Entries 4-6).
In these latter cases, the control of the dryness was not
necessary since the presence of OH- in the system is minimized.
Then, the scope of the reaction was briefly analyzed in the
presence of several nucleophiles using previously synthesized
2-acetylbenzonitriles (Scheme 7). In addition to dimethyl
malonate and OH-, other carbon- and hetero-nucleophiles were
employed. In all the cases, very high yields were obtained, even
employing K2CO3 as base, allowing the access to novel 3,3-
disubstituted isoindolinones of high biopharmaceutical potential
with a variety of functionalized side chains and substituents on
the aromatic ring.
Conclusions
In summary, a convenient one-pot methodology for the
synthesis of 2-acetylbenzonitriles has been developed by the
treatment of ready available 2-ethylbenzonitriles with NBS and
catalytic amount of AIBN in acetonitrile/water as solvent. The
obtained 2-acetylbenzonitriles have been successfully used as
electrophiles under very mild conditions in efficient tandem
processes for the synthesis of new 3,3-disubstituted
isoindolinones in yields from 80% to 99%. Among the tested
nucleophiles, the addition of water was favorably achieved,
leading to the useful 3-hydroxy-3-methyl isoindolinones in
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
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excellent yields. Other studies are in course to enlarge the
applications of the developed methodologies and the
transformations of the obtained isoindolinones.
Scheme 8. Proposed mechanism of the tandem reaction
MHz, 300 MHz, 250 MHz, 1H; 150 MHz, 100 MHz, 75 MHz, 62.5
MHz 13C). Spectra were referenced to residual CHCl3 (7.26 ppm,
1H; 77.00 ppm, 13C), CH3OH (3.33 ppm, 1H; 49.0 ppm, 13C) or
1
(CH3)2SO (2.50 ppm, H; 39.52 ppm, 13C) when indicated. The
following abbreviations are used to indicate the multiplicity in
NMR spectra: s – singlet; d – doublet; t – triplet; q – quartet; dd –
double doublet; ddd – doublet of doublet of doublet; m –
multiplet; bs – broad signal. Coupling constants (J) are quoted in
hertz. Yields are given for isolated products showing one spot on
a TLC plate and no impurities detectable in the NMR spectrum.
FTIR spectra were recorded as thin films on KBr plates using
Bruker VERTEX 70 spectrometer and absorption maxima are
reported in wavenumber (cm-1). High resolution mass spectra
(HRMS) were acquired using a Bruker solariX XR Fourier
transform ion cyclotron resonance mass spectrometer (Bruker
Daltonik GmbH, Bremen, Germany) equipped with a 7 T
refrigerated actively-shielded superconducting magnet. The
samples were ionized in positive ion mode using an electrospray
(ESI) ionization source or the MALDI ion source. Compounds 2a,
2c and 8a were identified comparing their spectral data with the
17e, 18a]
those reported in literature.[9a,
Spectroscopic data are
given only for compounds never previously described.
Scheme 7. Scope of the tandem reaction
2-ethyl-5-nitrobenzonitrile (3). A mixture of fuming HNO3 (1.2
mL) and concentrated H2SO4 (2.4 mL) was stirred at room
temperature for 1 h. Then, 2-ethylbenzonitrile (1.2 g, 1.23 mL,
9.16 mmol) was added slowly at 0°C and the solution stirred at
room temperature 1h. The crude mixture was poured into
ice/water and extracted twice with CH2Cl2. The combined
organic phases were washed with saturated NaHCO3 solution,
dried over Na2SO4 and concentrated in vacuo. The product was
obtained quantitatively (1.59 g, 95/5 mixture of para/ortho
regioisomers) as a yellow solid without further purification. Mp:
77-78°C (lit. 73.5°C). [19] 1H NMR (250 MHz, CDCl3) δ 8.41 (d, J
Experimental Section
Experimental Details. Reactions were performed using
commercially available compounds without further purification
and analytical grade solvents. All the reactions were monitored
by thin layer chromatography (TLC) on precoated silica gel
plates (0.25 mm) and visualized by fluorescence quenching at
254 nm. Flash chromatography was carried out using silica gel
60 (70–230 mesh, Merck). The NMR spectra were recorded on
Bruker Avance 600, 400, 300, 250 spectrometers (600 MHz, 400
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
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= 2.4 Hz, 1H), 8.32 (dd, J = 8.6, 2.4 Hz, 1H), 7.55 (d, J = 8.6 Hz,
1H), 2.95 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H). 13C NMR
(65 MHz, CDCl3) δ 155.2, 137.3, 130.3, 128.0, 127.7, 116.0,
113.6, 28.1, 14.7. HRMS (ESI) m/z: calcd for C9H9N2O2 ([M+
H]+) 177.0658; found 177.0651.
in H2SO4 33% (5 mL) and the mixture was stirred for 40 min.
Then, the reaction mixture was added into a refluxed solution of
Na2SO4 (1.53 g, 10.8 mmol) in H2O (1 mL) and concentrated
H2SO4 (2 mL). The resulting mixture was refluxed for 1 h and
stirred at room temperature overnight. Extraction with ethyl
acetate for three times gave a yellow oil, which was dissolved in
anhydrous THF (3 mL). To this solution, NaH 60% (2 eq., 1.79
mmol, 70 mg) and iodomethane (5 eq., 4.45 mmol, 277 µL)
were added and the reaction mixture was stirred at 50 °C for
48h. After quenching with water, the solvent was removed under
reduced pressure and the residue taken up with
dichloromethane was washed with water. The crude product
was purified by flash chromatography (silica gel, petroleum
ether-ethyl acetate, 98:2) to afford a colorless liquid (200 mg,
57%, 95/5 mixture of para/ortho regioisomers). 1H NMR (250
MHz, CDCl3) δ 7.26–7.16 (m, 1H), 7.06-7.02 (m, 2H), 3.79 (s,
3H), 2.79 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 157.3, 137.0, 129.8, 127.4, 124.2, 114.4,
112.9, 55.6, 22.4, 14.0. HRMS (ESI) m/z: calcd for C10H12NO
([M+ H]+) 162.0913; found 162.0928.
5-amino-2-ethylbenzonitrile (4). To a solution of 2-ethyl-5-
nitrobenzonitrile (1.2 g, 6.82 mmol) in methanol (40 mL), zinc
powder (4 eq., 1.762 g, 27.2 mmol) and concentrated HCl (6
mL) were added. The mixture was stirred at room temperature
for 2 h. Subsequently, NaOH 1 M was added to basify and the
mixture was extracted with ethyl acetate (three times). The
combined organic phases were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, hexane−ethyl acetate 70/30) to give
the desidered product (1.0 g, 95/5 mixture of para/ortho
1
regioisomers) quantitatively as a yellow oil. H NMR (300 MHz,
MeOD) δ 7.07 (d, J = 7.8 Hz, 1H), 6.95 – 6.82 (m, 2H), 2.67 (q, J
= 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz,
MeOD) δ 146.0, 136.4, 129.3, 119.9, 118.1, 117.4, 111.1, 26.3,
14.6. HRMS (ESI) m/z: calcd for C9H11N2 ([M+ H]+) 147.0917;
found 147.0928.
N-(3-cyano-4-ethylphenyl)acetamide (6). Acetic anhydride
(260 µL, 2.74 mmol) was added at room temperature to a
solution of 5-amino-2-ethylbenzonitrile (200 mg, 1.37 mmol) in
dichloromethane (2.0 mL) and the mixture was stirred for 0.5 h.
The solvent was removed under reduced pressure and the
crude product was purified by flash chromatography (silica gel,
petroleum ether-ethyl acetate 1:1) to afford the desidered
product as a white solid (237 mg, 92%). Mp: 115-116°C. 1H
NMR (400 MHz, CDCl3) δ 8.58 (bs, 1H), 7.90 (s, 1H), 7.64 (d, J
= 8.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 2.80 (q, J = 7.6 Hz, 2H),
2.19 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 169.3, 143.6, 136.6, 129.3, 124.6, 123.6, 117.9, 111.9, 27.1,
24.2, 15.0. HRMS (ESI) calcd for C11H13N2O m/z: ([M+ H]+)
189.1022; found 189.1034.
General Procedure for the Synthesis of 5-halogeno 2-
ethylbenzonitriles 5
A solution of NaNO2 (1.5 eq., 2.03 mmol, 138 mg) in H2O (500
µL) was added at 0°C to
a
solution of 5-amino-2-
ethylbenzonitrile (200 mg, 1.37 mmol) in acetic acid (2.6 mL).
Then, concentrated H2SO4 (500 µL) was added and the mixture
was stirred for 0.5 h. The mixture was warmed to room
temperature and a solution of CuX (2.2 eq., 1.5 mmol) in HX
(HCl 37% or HBr 48%) (2.5 mL) was added under inert
atmosphere. After 45 minutes, the mixture was extracted with
ethyl acetate twice. The combined organic phases were washed
with saturated NaHCO3 solution, dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether-ethyl acetate, 99:1)
to afford a colorless liquid.
N-(3-cyano-4-ethylphenyl)-N-methylacetamide (7). Under
nitrogen atmosphere, CH3I (644 µL, 10.4 mmol) was added to a
solution of N-(3-cyano-4-ethylphenyl)acetamide (196 mg, 1.04
mmol) in THF dry (4.0 mL) and sodium hydride 60% (128 mg,
3.16 mmol). The mixture was stirred overnight at room
temperature. Then, water was added, the solvent removed
under reduced pressure and the mixture was extracted with
dichloromethane twice. The combined organic phases were
combined, dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography (silica gel,
petroleum ether-ethyl acetate, 60:40) to afford the product as a
white solid (180 mg, 85%). Mp: 95-96°C. 1H NMR (300 MHz,
CDCl3) δ 7.46 (s, 1H), 7.43 – 7.32 (m, 2H), 3.24 (s, 3H), 2.90 (q,
5-chloro-2-ethylbenzonitrile (5a). Colorless liquid (149 mg,
66%, 95/5 mixture of para/ortho regioisomers). 1H NMR (250
MHz, CDCl3) δ 7.54 (bs, 1H), 7.47 (dd, J = 8.2, 1.4 Hz, 1H), 7.27
(d, J = 8.2 Hz, 1H), 2.83 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz,
3H). 13C NMR (65 MHz, CDCl3) δ 146.7, 133.4, 132.3, 130.4,
117.0, 113.7, 27.4, 15.2. HRMS (ESI) m/z: calcd for C9H9ClN2
([M+ H]+) 166.0418; found 166.0402.
5-bromo-2-ethylbenzonitrile (5b). Colorless liquid (224 mg,
78%, 95/5 mixture of para/ortho regioisomers). 1H NMR (300
MHz, CDCl3) δ 7.72 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 8.3, 2.2 Hz, J = 7.6 Hz, 2H), 1.87 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H). 13C NMR
1H), 7.23 (d, J = 8.3 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.29 (t, J
= 7.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 146.9, 136.0, 134.9,
130.3, 119.4, 116.5, 113.8, 27.2, 14.8. HRMS (ESI) m/z: calcd
for C9H9BrN2 ([M+ H]+) 209.9913; found 209.9928.
(75 MHz, CDCl3) δ 170.0, 147.5, 142.7, 131.7, 130.9, 130.3,
116.8, 113.3, 37.0, 27.3, 22.4, 14.8. HRMS (ESI) m/z: calcd for
C11H15N2O ([M+ H]+) 203.1179; found 203.1166.
General Procedure for the Synthesis of 2-
2-ethyl-5-methoxybenzonitrile (5c). A solution of NaNO2 (1.2
eq., 2.62 mmol, 180 mg) in H2O (1.2 mL) was added at 0°C to a
suspension of 5-amino-2-ethylbenzonitrile (320 mg, 2.19 mmol)
acetylbenzonitriles 2a-2h
A mixture of benzonitrile (0.76 mmol), N-Bromosuccinimide (3.5
eq., 2.7 mmol, 478 mg) and AIBN (0.1 eq., 0.076 mmol, 12 mg)
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
FULL PAPER
in CH3CN/H2O 4/1 (3.5 mL) was heated at 80°C under stirring
for the indicated time. After cooling to room temperature, the
solvent was removed under reduced pressure and the residue
taken up with dichloromethane was washed with water. The
organic phase was dried over Na2SO4 and concentrated in
vacuo. The crude product was purified by flash chromatography.
2-acetyl-5-methoxybenzonitrile (2g). Purified by flash
chromatography (silica gel, hexane-ethyl acetate, 80/20). White
solid (23 mg, 18%). Mp: 126-127°C (lit. 126-128°C). [9a] HRMS
(ESI) m/z: calcd for C10H9NNaO2 [(M+Na)+] 198.0525; found:
198.0509. IR and NMR data are in agreement with the
literature.[9a]
2-acetylbenzonitrile (2a). Purified by flash chromatography
(silica gel, hexane-ethyl acetate, 80/20). White solid (92 mg,
82%). Mp: 47-48°C (lit. 47-49°C). [9a]HRMS (ESI) m/z: calcd for
C9H7NNaO [(M+Na)+] 168.0425; found: 168.0419. IR and NMR
data are in agreement with the literature. [9a]
6-acetyl-2-bromo-3-methoxybenzonitrile (2h). Prepared using
5 eq. of N-Bromosuccinimide. Purified by flash chromatography
(silica gel, hexane-chloroform, 60/40). White solid (134 mg,
70%). Mp: 120-122°C. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J =
9.0 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 3.90 (s, 3H), 2.59 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 198.5, 155.6, 135.9, 135.0, 116.8,
116.7, 115.1, 113.5, 56.3, 31.1. FT-IR (KBr): 3024, 2226, 1695,
1579, 1360, 1263, 960, 863 cm-1. HRMS (ESI) m/z: calcd for
C10H8BrNNaO2 [(M+Na)+] 275.9631; found: 275.9645.
2-acetyl-5-nitrobenzonitrile (2b). Prepared using 7 eq. of N-
Bromosuccinimide. Purified by flash chromatography (silica gel,
dichlorometane-petroleum ether, 60/30). White solid (85 mg,
1
59%). Mp: 78-80°C. H NMR (250 MHz, CDCl3) δ 8.65 (d, J =
2.3 Hz, 1H), 8.53 (dd, J = 8.6, 2.3 Hz, 1H), 8.12 (d, J = 8.6 Hz,
1H), 2.78 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 194.6, 149.2,
144.2, 130.8, 129.8, 127.4, 115.8, 112.6, 28.2. FT-IR (KBr):
3365, 2231, 1703, 1665, 1521 cm-1. HRMS (ESI) m/z: calcd for
C9H6NNaO3 [(M+Na)+] 213.0271; found: 213.0265.
General
procedure
for
tandem
reaction
of
2-
acetylbenzonitriles with the hydroxide anion.
To a solution of 2-acetylbenzonitrile 2a-2h (0.2 mmol) in
acetonitrile (2 mL), KOH (0.3 eq) in water (200 µL) was added
and the mixture was stirred at room temperature until
disappearance of the starting material (TLC hexane-acetyl
acetate 3:7). After 1-3h, the solution was diluted with
dichloromethane, dried over Na2SO4, filtered and concentrated
in vacuo. The crude product was purified by flash
chromatography .
2-acetyl-5-chlorobenzonitrile
(2c).
Purified
by
flash
chromatography (silica gel, hexane-ethyl acetate 80/20). White
solid (95 mg, 70%). Mp: 86-87°C (lit. 85-87°C). [9a[ HRMS (ESI)
m/z: calcd for C9H6ClNNaO [(M+Na)+] 202.0030; found:
202.0038. IR and NMR data are in agreement with the
literature.[9a[
3-hydroxy-3-methylisoindolin-1-one (8a). Purified by flash
chromatography (silica gel, hexane−ethyl acetate, 40/60). White
solid (31 mg, 93%). Mp: 113-115°C. HRMS (ESI) m/z: calcd for
C9H10NO2 [(M+ H)+] 164.0706; found: 164.0713. NMR data are
in accordance with the literature. [18e]
2-acetyl-5-bromobenzonitrile
(2d).
Purified
by
flash
chromatography (silica gel, hexane-ethyl acetate 85/15). White
solid (122 mg, 72%). Mp: 117-118°C. 1H NMR (300 MHz, CDCl3)
δ 7.99 – 7.92 (m, 1H), 7.89 – 7.80 (m, 2H), 2.69 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 194.9, 138.3, 137.7, 135.8, 131.0,
127.0, 116.6, 112.6, 27.7. FT-IR (KBr): 2924, 2224, 1685 cm-1.
HRMS (ESI) m/z: calcd for C9H6BrNNaO [(M+Na)+] 245.9525;
found: 245.9534.
3-hydroxy-3-methyl-6-nitroisoindolin-1-one (8b).
Purified by flash chromatography (silica gel, hexane−ethyl
acetate, 40/60). White solid (38 mg, 91%). Mp: 197 °C (dec.). 1H
NMR (250 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.47 (dd, J = 8.3, 2.1
Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 6.45
(s, 1H), 1.66 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 165.6,
156.5, 149.1, 133.1, 127.9, 124.2, 117.9, 85.4, 26.5. FT-IR
(KBr): 3369, 3200, 1717, 1547 cm-1. HRMS (ESI) m/z: calcd for
C9H9N2O4 [(M+ H)+] 209.0557; found: 209.0563.
N-(4-acetyl-2-bromo-3-cyanophenyl)acetamide (2e). Purified
by flash chromatography (silica gel, ethyl acetate-hexane 50/50).
1
White solid (30 mg, 14%). Mp: 203-204°C. H NMR (250 MHz,
CDCl3) δ 8.78 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 2.67
(s, 3H), 2.32 (s, 3H). 13C NMR (250 MHz, CDCl3) δ 194.3, 168.8,
140.3, 136.7, 130.2, 123.5, 119.2, 116.2, 114.9, 27.9, 25.4. FT-
IR (KBr): 3291, 2232, 1704, 1690, 1526 cm-1. HRMS (ESI) m/z:
calcd for C11H9BrN2NaO2 [(M+ Na)+] 302.9739; found 302.9740.
6-chloro-3-hydroxy-3-methylisoindolin-1-one (8c). Purified by
flash chromatography (silica gel, hexane−ethyl acetate, 50/50).
White solid (38 mg, 94%). Mp: 134-135°C. H NMR (400 MHz,
1
CDCl3) δ 7.56 (dd, J = 8.0, 1.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H),
7.40 (d, J = 1.9 Hz, 1H), 7.29 (bs, 1H), 1.78 (s, 3H). 13C NMR
N-(4-acetyl-3-cyanophenyl)-N-methylacetamide (2f). Purified
by flash chromatography (silica gel, hexane-ethyl acetate, 70/30). (100 MHz, CDCl3) δ 167.6, 147.4, 135.8, 133.2, 131.5, 123.5,
1
Pale yellow solid (113 mg, 70%). Mp: 105-106°C. H NMR (250
MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H),
7.61 (d, J = 8.4 Hz, 1H), 3.37 (s, 3H), 2.72 (s, 3H), 2.09 (s, 3H).
13C NMR ( 65 MHz, CDCl3) δ 195.2, 170.2, 148.0, 137.8, 132.9,
131.4, 130.6, 117.4, 112.6, 37.7, 28.0, 22.9. FT-IR (KBr): 2230,
1690, 1662 cm-1. HRMS (ESI) m/z: calcd for C12H12N2NaO2 [(M+
Na)+] 239.0791; found 239.0782.
123.1, 85.9, 25.8. FT-IR (KBr): 3363, 3206, 1717, 1665 cm-1.
HRMS (ESI) m/z: calcd for C9H9ClNO2 [(M+H)+] 198.0132;
found: 198.0137.
6-bromo-3-hydroxy-3-methylisoindolin-1-one (8d). Purified by
flash chromatography (silica gel, hexane−ethyl acetate, 40/60).
1
White solid (46 mg, 95%). Mp: 180°C (dec.). H NMR (300 MHz,
DMSO-d6) δ 8.99 (s, 1H), 7.78 (dd, J = 8.0, 1.9 Hz, 1H), 7.69 (d,
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
FULL PAPER
J = 1.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 1.60 (s,
3H). 13C NMR (75 MHz, DMSO-d6) δ 166.2, 149.8, 135.2, 133.8,
125.4, 124.6, 122.2, 85.2, 26.6. FT-IR (KBr): 3346, 3207, 1718,
1664 cm-1. HRMS (ESI) m/z: calcd for C9H9BrNO2 [(M+H)+]
241.9811; found: 241.9816.
dimethyl 2-(1-methyl-3-oxoisoindolin-1-yl)malonate (9a).
White solid (58 mg, 87%). Mp: 123-125°C. H NMR (400 MHz,
1
CDCl3) δ 7.83 (d, J = 7.7 Hz, 1H), 7.63 – 7.54 (m, 1H), 7.51 –
7.46 (m, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.11 (bs, 1H), 3.85 (s, 1H),
3.82 (s, 3H), 3.45 (s, 3H), 1.70 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 168.9, 167.9, 166.1, 148.6, 132.0, 130.9, 128.9, 124.0,
121.7, 60.7, 58.8, 52.9, 52.7, 24.8. FT-IR (KBr): 3208, 1767,
1740, 1682 cm-1. HRMS (ESI) m/z: calcd for C14H16NO5 [(M+
H)+] 278.1023; found: 278.1028.
N-(4-bromo-1-hydroxy-1-methyl-3-oxoisoindolin-5-
yl)acetamide (8e). Purified by flash chromatography (silica gel,
ethyl acetate). White solid (53 mg, 90% yield). Mp: 241-242°C.
1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.00 (s, 1H), 7.73
(d, J = 7.9 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 6.14 (s, 1H), 2.10 (s, 2-(1-methyl-3-oxoisoindolin-1-yl)malononitrile (9b). Reaction
3H), 1.59 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 169.1, 165.7,
150.0, 137.9, 131.3, 129.2, 121.4, 113.9, 83.1, 26.7, 23.6. FT-IR
(KBr): 3340, 3200, 1714, 1668 cm-1. HRMS (ESI) m/z: calcd for
C11H12BrN2O3 [(M+ H)+] 299.0026; found: 299.0034.
carried out at room temperature. After 3h acetic acid (15 μL)
diluted in dichloromethane (1 mL) was added and the solution
was filtered. Purified by flash chromatography (silica gel,
hexane-ethyl acetate 60/40). White solid (45 mg, 89%). Mp: 134-
136°C. 1H NMR (250 MHz, CDCl3) δ 7.99 – 7.85 (m, 1H), 7.80 –
7.57 (m, 3H), 4.21 (s, 1H), 1.93 (s, 3H). 13C NMR (65 MHz,
CDCl3) δ 169.7, 145.5, 133.8, 131.1, 130.9, 125.0, 122.0, 111.0,
110.7, 61.9, 35.0, 23.2. FT-IR (KBr): 32381 2224, 2206, 1728,
N-(1-hydroxy-1-methyl-3-oxoisoindolin-5-yl)-N-
methylacetamide (8f). Purified by flash chromatography (silica
gel, dichloromethane-methanol, 95/5). White solid (41 mg, 87%).
Mp: 110-112°C. 1H NMR (250 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 1704, 1693 cm-1. HRMS (ESI) m/z: calcd for C12H10N3O [(M+H)+]
1H), 7.58 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.0, 1.9 Hz, 1H), 7.18
(s, 1H), 3.28 (s, 3H), 1.88 (s, 3H), 1.83 (s, 3H). 13C NMR (65
MHz, CDCl3) δ 170.5, 167.7, 148.5, 146.1, 132.2, 131.9, 123.5,
122.3, 86.0, 37.5, 26.2, 22.7. FT-IR (KBr): 3260, 1712, 1608 cm-
1. HRMS (ESI) m/z: calcd for C12H15N2O3 [(M+ H)+] 235.1077;
found: 235.1069.
212.0818; found 212.0823.
3-(benzylamino)-3-methylisoindolin-1-one (9c). White solid
(60 mg, 99%). Mp: 136-138°C. 1H NMR (300 MHz, CDCl3) δ
7.85 (dd, J = 7.5, 0.8 Hz, 1H), 7.71 – 7.58 (m, 2H), 7.54 (dt, J =
8.4, 4.3 Hz, 1H), 7.32 – 7.13 (m, 5H), 7.02 (bs, 1H), 3.67 (d, J =
12.6 Hz, 1H), 3.22 (d, J = 12.6 Hz, 1H), 1.80 (s, 3H). 13C NMR
(65 MHz, CDCl3) δ 169.6, 148.9, 139.4, 132.8, 131.9, 129.4,
128.6, 128.5, 127.4, 123.9, 122.3, 76.1, 46.7, 27.9. FT-IR (KBr):
3272, 1692, 1691 cm-1. HRMS (ESI) m/z: calcd for C16H17N2O
[(M+H)+] 253.1335; found: 253.1322.
3-hydroxy-6-methoxy-3-methylisoindolin-1-one (8g). Purified
by flash chromatography (silica gel, hexane−ethyl acetate,
40/60). White solid (36 mg, 92%). Mp: 180°C (dec.). 1H NMR
(300 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H),
7.13 (dd, J = 8.2, 2.4 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.03 (s,
1H), 3.81 (s, 3H), 1.57 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ
167.5, 160.4, 143.1, 133.0, 123.3, 119.2, 106.4, 84.9, 55.9, 27.1.
FT-IR (KBr): 3346, 3207, 1718 cm-1. HRMS (ESI) m/z: calcd for
C10H12NO3 [(M+H)+] 194.0812; found: 194.0816.
3-methyl-3-(nitromethyl)isoindolin-1-one (9d). Acetic acid (15
μL) diluted in dichloromethane (1 mL) was added and the
solution was filtered. Purified by flash chromatography (silica gel,
hexane-ethyl acetate 60/40). White solid (47 mg, 94%). Mp: 135-
1
136°C. H NMR (250 MHz, CDCl3) δ 7.89 (d, J = 7.4 Hz, 1H),
7-bromo-6-methoxy-3-hydroxy-3-methylisoindolin-1-one
(8h). Purified by flash chromatography (silica gel, hexane−ethyl
acetate, 40/60). White solid (52 mg, 96%). Mp: 189°C (dec.). H
NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.57 (d, J = 9.0 Hz,
1H), 7.14 (d, J = 9.0 Hz, 1H), 5.96 (s, 1H), 3.85 (s, 3H), 1.65 (s,
3H). 13C NMR (75 MHz, DMSO-d6) δ 165.3, 154.6, 139.2, 135.1,
129.6, 117.3, 107.0, 83.4, 56.3, 25.0. FT-IR (KBr): 3359, 3210,
1712 cm-1. HRMS (ESI) m/z: calcd for C10H11BrNO3 [(M+H)+]
271.9917; found: 271.9923.
7.73 – 7.50 (m, 2H), 7.43 (d, J = 7.4 Hz, 1H), 7.24 (bs, 1H), 4.86
(d, J = 12.8 Hz, 1H), 4.41 (d, J = 12.8 Hz, 1H), 1.68 (s, 3H). 13C
NMR (65 MHz, CDCl3) δ 168.7, 146.6, 132.8, 130.9, 129.8,
124.8, 121.3, 82.7, 59.4, 23.2. FT-IR (KBr): 3412, 1714, 1542
cm-1. HRMS (ESI) m/z: calcd for C10H11N2O3 [(M+H)+] 207.0764;
found: 207.0769.
1
3-(butylamino)-3-methylisoindolin-1-one (9e). White solid (52
1
mg, 99%). Mp: 112-114 °C. H NMR (250 MHz, CDCl3) δ 7.83 –
7.75 (m, 1H), 7.65 – 7.53 (m, 1H), 7.51 – 7.41 (m, 2H), 6.28 (bs,
1H), 2.47 (dt, J = 11.2, 6.9 Hz, 1H), 1.99 (dt, J = 11.2, 6.9 Hz,
1H), 1.68 (s, 3H), 1.39 – 1.16 (m, 4H), 0.80 (d, J = 7.1 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 169.4, 149.6, 132.5, 131.8, 129.0,
123.7, 121.0, 76.0, 41.9, 32.6, 28.0, 20.4, 14.0. FT-IR (KBr):
3285, 1686 cm-1. HRMS (ESI) calcd for C13H19N2O [(M+ H)+]
219.1492; found: 219.1487.
General Procedure for Tandem Reaction of 2-
acetylbenzonitriles with carbon- and hetero-nucleophiles 9
2-Acetylbenzonitrile 2a-2f (0.24 mmol) were added to a solution
of the nucleophile (2 eq., 0.48 mmol) and K2CO3 (1eq., 0.24
mmol) in acetonitrile (80 µL) and the mixture was stirred at 50°C
until disappearance of the starting material (TLC hexane-acetyl
acetate 3:7). After 18 h, dichloromethane was added and the
mixture was filtered and the solvent evaporated in vacuo. The
crude product was purified by flash chromatography (silica gel,
hexane-ethyl acetate 60/40-ethyl acetate).
dimethyl 2-(1-methyl-5-nitro-3-oxoisoindolin-1-yl)malonate
(9f). White solid (62 mg, 80%). Mp: 151-153°C. 1H NMR (250
MHz, CDCl3) δ 8.65 (d, J = 2.1 Hz, 1H), 8.45 (dd, J = 8.7, 2.1 Hz,
1H), 7.60 (d, J = 8.7 Hz, 1H), 7.28 (bs, 1H), 3.90 (s, 1H), 3.84 (s,
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
FULL PAPER
3H), 3.50 (s, 3H), 1.72 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
167.8, 166.2, 165.9, 154.6, 149.1, 133.2, 127.3, 123.3, 119.9,
61.2, 58.6, 53.4, 53.2, 25.2. FT-IR (KBr): 3218, 1765, 1742,
1689, 1549 cm-1. HRMS (ESI) m/z: calcd for C14H15N2O7 [(M+
H)+] 323.0874; found: 323.0871.
3-(benzylamino)-6-chloro-3-methylisoindolin-1-one
White solid (63 mg, 92%). Mp: 140-142°C. H NMR (250 MHz,
(9l).
1
CDCl3) δ 7.78 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.1, 1.9 Hz, 1H),
7.43 (d, J = 8.1 Hz, 1H), 7.35 – 7.11 (m, 5H), 6.43 (bs, 1H), 3.62
(d, J = 12.7 Hz, 1H), 3.19 (d, J = 12.7 Hz, 1H), 1.73 (s, 3H). 13C
NMR (65 MHz, CDCl3) δ 168.1, 147.5, 139.8, 135.4, 133.7,
132.8, 128.6, 128.2, 127.4, 124.0, 123.6, 76.0, 46.8, 28.1. FT-IR
(KBr): 3316, 1698, 1656 cm-1. HRMS (ESI) m/z: calcd for
dimethyl 2-(5-bromo-1-methyl-3-oxoisoindolin-1-yl)malonate
1
(9g). White solid (80 mg, 93%). Mp: 138-140 °C. H NMR (300
MHz, CDCl3) δ 7.96 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.2, 2.0 Hz, C16H16ClN2O [(M+ H)+] 287.0946; found: 287.0931.
1H), 7.30 (d, J = 8.2 Hz, 1H), 7.20 (bs, 1H), 3.84 (s, 1H), 3.82 (s,
3H), 3.51 (s, 3H), 1.70 (s, 3H). 13C NMR (65 MHz, CDCl3) δ
168.0, 167.6, 166.3, 147.6, 135.3, 133.4, 127.4, 123.8, 123.3,
60.9, 58.8, 53.2, 53.0, 25.0. FT-IR (KBr): 3224, 1763, 1741,
1685 cm-1. HRMS (ESI) m/z: calcd for C14H15BrNO5 [(M+ H)+]
356.0128; found: 356.0134.
3-(butylamino)-6-chloro-3-methylisoindolin-1-one
(9m).
1
White solid (54 mg, 89%). Mp: 130-132°C. H NMR (300 MHz,
CDCl3) δ 7.76 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.1, 2.0 Hz, 1H),
7.40 (d, J = 8.1 Hz, 1H), 6.77 (bs, 1H), 2.48 (dt, J = 11.2, 6.7 Hz,
1H), 1.99 (dt, J = 11.2, 6.7 Hz, 1H), 1.69 (s, 3H), 1.40 – 1.14 (m,
4H), 0.82 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 168.0,
147.8, 135.2, 133.6, 132.6, 123.9, 123.4, 75.9, 41.9, 32.6, 28.0,
20.4, 14.0. FT-IR (KBr): 3285, 1691 cm-1. HRMS (ESI) m/z: calcd
dimethyl 2-(5-chloro-1-methyl-3-oxoisoindolin-1-yl)malonate
(9h). White solid (67 mg, 89%). Mp: 138-140°C. 1H NMR (300
MHz, CDCl3) δ 7.80 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.2, 2.0 Hz, for C13H18ClN2O [(M+ H)+] 253.1102; found: 253.1097.
1H), 7.35 (d, J = 8.2 Hz, 1H), 7.16 (bs, 1H), 3.89 – 3.77 (m, 4H),
3.51 (s, 3H), 1.69 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.8,
167.5, 166.1, 146.8, 135.3, 132.9, 132.3, 124.3, 123.2, 60.6,
58.7, 53.0, 52.9, 24.9. FT-IR (KBr): 3216, 1764, 1742, 1685 cm-
1. HRMS (ESI) m/z: calcd for C14H15ClNO5 [(M+ H)+] 312.0633;
found: 312.0637.
Acknowledgements
This work was supported by MIUR and University of Salerno.
Keywords: Cascade, domino, tandem reactions; ketones as
dimethyl 2-(5-acetamido-4-bromo-1-methyl-3-oxoisoindolin-
1-yl)malonate (9i). Waxy solid (83 mg, 84%). 1H NMR (300
MHz, CDCl3) δ 8.64 (d, J = 8.3 Hz, 1H), 7.97 (bs, 1H), 7.34 (d, J
= 8.4 Hz, 1H), 7.22 (bs, 1H), 3.84 (s, 3H), 3.82 (s, 1H), 3.53 (s,
3H), 2.30 (s, 3H), 1.68 (s, 3H). 13C NMR (65 MHz, CDCl3) δ
168.7, 168.1, 166.9, 166.3, 145.9, 137.0, 128.8, 125.0, 121.6,
109.4, 59.0, 58.9, 53.2, 53.1, 25.2, 25.2. FT-IR (KBr): 3216,
1764, 1742, 1724, 1685 cm-1. HRMS (ESI) m/z: calcd for
C16H18BrN2O6 [(M+H)+] 413.0343; found: 413.0338.
electrophiles; heterocycles; oxidation.
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HRMS (ESI) m/z: calcd for C10H10ClN2O3 [(M+ H)+] 241.0374;
found: 241.0368.
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10.1002/ejoc.201800240
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10.1002/ejoc.201800240
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
Layout 2:
FULL PAPER
Heterocycles
Antonia Di Mola, Miriam Di Martino, Vito
Capaccio, Giovanni Pierri, Laura
Palombi, Consiglia Tedesco and Antonio
Massa*
Page No. – Page No.
Synthesis and reactivity of 2-
acetylbenzonitriles
in
tandem
reactions with carbon- and hetero-
nucleophiles: easy access to 3,3-
disubstituted isoindolinones.
In only two steps: from readily available 2-ethylbenzonitriles to 3-hydroxy-3-methyl isoindolinones and other novel 3,3-disubstituted
derivatives.
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