Lanthanide-Catalyzed Tandem Insertion of Secondary Amines with 2-Alkynylbenzonitriles: Synthesis of Aminoisoindoles

Article abstract of DOI:10.1002/asia.201801252

A lanthanide-catalyzed intermolecular hydroamination of 2-alkynylbenzonitriles with secondary amines has been disclosed, providing a streamlined access to a range of aminoisoindoles in moderate to excellent yields. The salient features of this reaction in

Full text of DOI:10.1002/asia.201801252

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Lanthanide-Catalyzed Tandem Insertion of Secondary Amines
with 2-Alkynylbenzonitriles: Synthesis of Aminoisoindoles
Authors: Pengqing Ye, Yinlin Shao, Leping Xie, Keting Shen, Tianxing
Cheng, and Jiuxi Chen
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Lanthanide-Catalyzed Tandem Insertion of Secondary Amines
with 2-Alkynylbenzonitriles: Synthesis of Aminoisoindoles
Pengqing Ye, Yinlin Shao,* Leping Xie, Keting Shen, Tianxing Cheng, and Jiuxi Chen*
Abstract: A lanthanide-catalyzed intermolecular hydroamination of 2-
alkynylbenzonitriles with secondary amines has been disclosed,
providing a streamlined access to a range of aminoisoindoles in
moderate to excellent yields. The salient features of this reaction
include high bond-formation efficiency, mild reaction conditions, 100%
atomic efficiency and good functional group tolerance. This
methodology has also been successfully applied to the construction
of other nitrogen-containing compounds such as 5H-imidazo[2,1-
a]isoindoles and isoquinolines. A plausible mechanism for the
formation of aminoisoindoles involving initial N-H activation by
lanthanide complex followed by C≡N insertion into a Ln-N bond to
form an amidinate lanthanide intermediate which undergoes the
cyclization is proposed.
of them require prefunctionalization of less environmentally
benign halogenated reagents, multistep procedures, harsh
conditions as well as narrow scope, stimulate the development of
more efficient methodologies for the synthesis of aminoisoindoles.
Transition-metal-catalyzed addition of an N-H bond across
carbon-carbon or carbon-heteroatom unsaturation, offers a
helpful strategy to nitrogen-containing compounds and tandem
insertion/annulation of different functionalities into an N-H bond
doubtless represent an efficient, atom-economical route to
numerous N-heterocycles.[8] Recently, Ohno,[9a-c] Wan,[9d]
Yoshimatsu[9e] and Skrydstrup9f developed Au-, Ag-, Ni/Pd-
catalyzed intramolecular diinsertion of N-H bond to different C≡C
triple bonds for the construction of diverse nitrogen-containing
compounds. Meanwhile, multicomponent domino insertion
reactions from amine and different kinds of unsaturated
substrates have also been nicely applied for the synthesis of
polysubstituted pyrroles and other heterocycles.[10] Demir showed
an ideal strategy affording pyrroles by AuI/ZnII catalyzed tandem
hydroamination/annulation reaction of 4-yne-nitriles with amines
(Scheme 1a).[11] In contrast to the late-transition-metal catalysis,
lanthanide played an important role in this type of transformation
owing to the high activity that are observed in the absence of
complex additives and showed unprecedented types of
reactivity.[12] The elegant work of Marks and Molander involving
lanthanide-catalyzed intramolecular multiple insertion of C≡C or
C=C bonds into an N-H bond allows facile access to bi- and
tricyclic fused azacycles (Scheme 1b).[13a,b] Furthermore, rare-
earth metal catalyzed intermolecular hydroamination/cyclization
and intramolecular hydroamination/bicyclization of olefins and
alkynes has also been studied.[13c] Recently, Zhou found that
lanthanide bis(trimethylsilyl)amides can efficiently catalyze the
cycloaddition of nitriles with aminoalkenes or aminoalkynes to
form corresponding imidazolines or imidazoles (Scheme 1c).[13d-e]
Inspired by these works, we envisioned that a rare-earth
catalyzed sequential addition/annulation reaction of amine
towards 2-alkynylbenzonitrile derivatives would result in a tandem
procedure for the preparation of aminoisoindoles. As is illustrated
in Scheme 1d, we anticipate the reaction is initiated by
deprotonation of amine with lanthanide catalyst, coordination and
sequential insertion of C≡N triple bond to Ln-N species A gives
lanthanide-amidinate intermediate B. Further cis-addition of Ln-N
bond to C≡C bond leads to cyclization, providing intermediate C.
Finally, protonation of C with another amine would furnish the
desire product aminoisoindoles. As part of our efforts on the
development of novel transformations of nitriles,[14] herein we
report lanthanide-catalyzed tandem insertion of secondary
amines with 2-alkynylbenzonitriles for the synthesis of
aminoisoindoles.
Introduction
The construction of aminoisoindole scaffolds is a fundamentally
important task in organic chemistry due to their widespread use
in ligand design.[1] Furthermore, compounds containing
aminoisoindole motifs show excellent optical properties which are
customarily used as synthetic dyes,[2] potential photosensitizers[3]
as well as functional materials.[4] Hence, their facile, general, and
economical synthesis holds extreme significance. Traditionally,
aminoisoindole structures are constructed by the condensation of
phthalonitrile with ammonia, and followed by nucleophilic
substitution with alkyl or arylamines, which is limited in scope and
inconvenient operation.[5] Late-transition-metal-catalyzed cross-
coupling or direct C-H bond activation from benzamidine
derivatives have been well established as another reliable tool for
accessing these compounds.[6] Xie[7a] and Anand[7b]
independently reported titanium- and zinc-catalyzed tandem
insertion/cyclization reaction of 2-(phenylethynyl)benzonitriles
with aliphatic amines for the synthesis of aminoisoindoles.
Although impressive achievements have been made, the
drawbacks accompanying these strategies particularly that most
P. Ye, Dr. Y. Shao, L. Xie, K. Shen, T. Cheng, Prof. Dr. J. Chen
College of Chemistry and Materials Engineering, Wenzhou
University
Chashan Town, Wenzhou 325035 (China)
E-mail: shaoyl@wzu.edu.cn; jiuxichen@wzu.edu.cn
Supporting information for this article is given via a link at the end of
the document. https://doi.org/10.1002/asia.2018xxxxxxx
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structure of Z-3aa and E-3aa were confirmed by X-ray diffraction
analysis (Figure 1).[15]
Table 1. Optimization of the reaction conditions.[a]
[a] Reaction conditions: 1a (0.30 mmol), catalyst (x), mole ratio of 2a/1a (y),
solvent (3 mL), N2. [b] Yield of the crude reaction mixture determined by 1H
NMR (internal standard: ferrocene). [c] Isolated yield.
Scheme 1. Design for the construction of aminoisoindoles.
Results and Discussion
With the above-described idea in mind, we initiated our
investigation by synthesis of aminoisoindole 3aa from 2-
(phenylethynyl)benzonitrile (1a) and pyrrolidine (2a) as model
substrates for optimization experiments. First, five lanthanide
catalysts were tested by performing the reaction at room
temperature for 12 h in toluene. La[N(SiMe3)2]3 was found to be
superior in furnishing the aiming cyclized product 3aa in 92%
NMR yield (Table 1, entries 1-5). The cyclization process could
not be prompted further to 24 h (Table 1, entry 6). To our delight,
the NMR yield of 3aa increased to 99% immediately while 1.2
equivalent of 2a was used (Table1, entry 7). The NMR yield of
3aa diminished to 90% when catalyst loading was 2 mol% (Table
1, entry 8). A survey of solvent revealed that THF was optimal to
give a comparable 96% yield, and the use of hexane and 1,2-
dichloroethane (DCE) decreased the yield to 88% and 85%,
respectively (Table 1, entries 9-11). Encouraged by the promising
result, we further examined the reaction time and found 6 h was
enough for such tandem addition/cyclization progress and Z-3aa
was observed as the single isomer (Table 1, entries 12-13). The
reaction did not work in the absence of rare earth metal catalyst
(Table 1, entry 14). Replacement of La[N(SiMe3)2]3 with other rare
earth metal sources, such as Yb(OTf)3 or YCl3, was ineffective
(Table 1, entries 15-16). In addition, the configuration of C=C
bonds was assigned according to NOESY experiments (Figure 1).
Indeed, NOE effect was clearly observed in the structure Z-3aa
between the H atom at C7 (s, 1H, 6.26 ppm) with H1/H5 and H10
respectively (See supporting information). Furthermore, the
Figure 1. X-ray diffraction analysis of Z-3aa and E-3aa, and NOESY
correlations of Z-3aa, outlined with curly arrows.
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Figure 2. 1H NMR monitoring spectra for the progress of the model reaction.
1H NMR spectra for the progress of the model reaction was
investigated (Figure 2). The H NMR monitoring results clearly
proceed smoothly with aliphatic amines, arylamines are
incompatible even with a higher reaction temperature. This
advantage probably due to the bifunctional catalytic properties
bearing the strong Lewis acid of the lanthanide ion and the Brönst
base of the bis(trimethylsilyl)amido anion ligand, which facilitate
deprotonation of the arylamines. In general, the presence of
strong coordinating atoms on the substrate has a negative
influence on the lanthanide catalytic reaction because of their
competing coordination to the highly Lewis-acidic Ln3+ ions. For
examples, reaction of 1a with anilines (eg. 2d, 2f) gave inferior
1
revealed that addition of 2a to 1a under standard conditions
afforded E-3aa at first, which was further converted to Z-3aa. It
was suggested that the Z/E ratio of 3aa was dominated by both
thermodynamic stability and kinetic effect, and the configuration
of Z-3aa seems more thermodynamic stable. Furthermore,
tautomerism reaction of 3aa was conducted and the result was
consistent with our hypotheses (Scheme 2).
Table 2. Substrate scope of secondary amines.[a]
Scheme 2. Tautomerism reaction of 3aa.
Having the optimized conditions in hand, we examined the
scope of the reaction with respect to amines first, and the results
are illustrated in Table 2. To our delight, the catalytic system is
effective for the transformation of both secondary aliphatic amines
and arylamines. In contrast, the Zn[7b] catalytic system can only
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), La[N(TMS)2]3 (5 mol%),
toluene (3 mL), sealed Schlenk tube equipped with a Teflon cap under N2,
25 oC, 6 h, isolated yield.
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results for the preparation of 3ad and 3af (Table 2, entries 3, 5).
Notably, the electronic effect on the aniline ring has an effect.
Table 3. Substrate scope of 2-alkynylbenzonitriles.[a]
Specifically, the aniline bearing
a
moderately electron-
withdrawing chloro group (2g) gave expected product 3ag in a
lower yield (Table 2, entry 6). Diisopropylamine (2h) could not go
through such transformation probably owing to a steric effect
(Table 2, entry 7). However, when primary amine such as
benzylamine (2i) was used as the substrate, this cyclization
reaction did not proceed well under same conditions (Table 2,
entry 8).
For the scope of reaction to be expanded further,
transformation
with
respect
to
various
2-
(phenylethynyl)benzonitrile substrates were conducted (Table 3).
First, both electron-rich and electron-poor aryl substituents
attached to the alkyne part underwent insertion/cyclization
reaction smoothly with secondary amines and the desired
products 3ba-3dc were obtained in good to excellent yields (Table
3, entries 1-11). 2-Alkynylbenzonitrile with a terminal C≡C bond is
incompatible with this reaction, probably caused by competing
deprotonation between terminal alkyne and amine with lanthanide
complex (Table 3, entry 12). The electronic effect of the
substituent on the aryl ring was further examined with
representative substrates (1g, 1h, 1i, and 1j). It is obvious that
either did electron-donating groups (eg. 4-CH3, 4-OCH3) or
electron-withdrawing groups (eg. 4-CF3, 5-Cl) decreased the
cyclization yield to some extent, probably due to the influence of
both electron density for C≡N and C≡C bond caused by
substituent groups (Table 3, entries 13-20).[13e] 2-
Alkynylbenzonitrile bearing a 2-pyridyl group (1k) was ineffective
(Table 3, entry 21). In the case of aliphatic substituent such as
cyclopropyl attached to the alkyne part, the corresponding
products 3lb and 3lc could be obtained, albeit in moderate yields
(Table 3, entries 22-23).
[a] Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), La[N(TMS)2]3 (5 mol%),
toluene (3 mL), sealed Schlenk tube equipped with a Teflon cap under N2,
25 oC, 6 h, isolated yield.
Fused N-heterocyclic building blocks are ubiquitous in natural
products and play a significant role in the pharmaceutical industry
and materials science.[16] Therefore, we applied the current
lanthanide-catalyzed cross-diinsertion of N-H bond to C≡C/C≡N
reaction in an intramolecular way to build a tricyclic fused N-
heterocycle which was usually synthesized in harsh conditions.[17]
To our delight, the desired tricyclic 2-methyl-5H-imidazo[2,1-
a]isoindoles (5ab) was obtained in 82% isolated yield by
lanthanide-catalyzed intramolecular cyclization reaction of 2-
((prop-2-yn-1-ylamino)methyl) benzonitrile (5a) (Scheme 4).
The present synthetic route to aminoisoindole could be readily
scaled up to gram quantity without difficulty. For instance, the
reaction at the 5 mmol scale afforded the corresponding product
Z-3aa in 85% isolated yield. In addition, N-methylation of Z-3aa
gave aminoisoindolium iodide Z-4aa in 50% yield (Scheme 3).
Furthermore, this methodology has also been successfully
applied to the synthesis of isoquinolines. The tandem reaction of
2-(2-(phenylethynyl) phenyl)acetonitrile (6a) with 2a as
a
Scheme 3. Gram-scale synthesis of Z-3aa and subsequent methylation.
representative example is shown in Scheme 5 with modified
conditions, affording the desired 1-benzyl-3-(pyrrolidin-1-
yl)isoquinoline (6aa) in 40% yield.
Scheme 4. Synthesis of 5H-imidazo[2,1-a]isoindoles
Scheme 5. Synthesis of isoquinolines.
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CHCl3 at 77.16 ppm for 13C unless otherwise noted. High-resolution mass
spectra were recorded on an ESI-Q-TOF mass spectrometer. Melting
points are uncorrected. Column chromatography was performed using EM
silica gel 60 (300−400 mesh).
General Procedure for the Synthesis of 2-Alkynylbenzonitriles
Derivatives (1a-1l)
To a 100 mL Schlenk bottle containing 2-Iodobenzonitrile (10 mmol) and
ethynylbenzene (11 mmol) in Et3N (25 mL) was added Pd(PPh3)2Cl2 (0.1
o
mmol) and CuI (0.2 mmol). The mixture was stirred at 80 C under N2
atmosphere for 30 h, then quenched with saturated NH4Cl (30 mL) and
extracted with ethyl acetate (30 mL × 3). The combined organic layers
were dried over MgSO4, filtered and the solvent was evaporated in rotary
evaporator under reduced pressure to obtain the residue. The residue was
purified by flash column chromatography on silica gel to isolate the pure
product (hexane/ethyl acetate as eluent).
Scheme 6. Possible mechanism for lanthanide-catalyzed tandem
addition/cyclization of secondary amines with 2-alkynylbenzonitriles.
A plausible mechanism for the lanthanide-catalyzed cyclization
is shown in Scheme 6. Activation of the secondary amine leads to
the formation of a lanthanide-amido complex A with the liberation
of HN(SiMe3)2. Coordination and sequential insertion of C≡N into
General Procedure for the Synthesis of 5a
the Ln-N bond of A gives a lanthanide-amidinate intermediate B.
Intermolecular cis-addition of C≡C bond to the Ln-N bond of B
To a flask containing 2-Propynylamine (45 mmol) and K2CO3 (45 mmol) in
CH2Cl2 (50 mL) were slowly added 2-Bromobenzyl cyanide (30 mmol) at
0 oC. The mixture was stirred at room temperature for 48 h, quenched with
saturated NH4Cl (30 mL) and extracted with ethyl acetate (50 mL × 3). The
combined organic layers were dried over MgSO4, filtered and the solvent
was evaporated in rotary evaporator under reduced pressure to obtain the
residue. The residue was purified by flash column chromatography on
silica gel (hexane/ethyl acetate as eluent) to isolate the pure product
(3.06g, 60%).
leads to cyclization, affording vinyl complex C. Then, protonation
of C with another amine affords kinetic product E-3aa which could
be further transformed into more thermodynamic stable
configuration Z-3aa and regenerates active intermediate A.
Conclusions
In summary, we have developed a newapproach for the synthesis
of aminoisoindoles by the lanthanide-catalyzed tandem
intermolecular cross-diinsertion reaction of 2-alkynylbenzonitriles
and secondary amines. In addition, the protocol was successfully
applied to the synthesis of 5H-imidazo[2,1-a]isoindoles and
isoquinolines. Moreover, the current rare-earth catalytic progress
provides an important supplement towards late-transition-metal-
catalyzed approaches to aminoisoindoles with mild reaction
conditions and broader amine compatibility. Further studies on
lanthanide-catalyzed tandem insertion/cyclization reactions for
the construction of other useful N-heterocycles are underway in
our laboratory.
General Procedure for the Synthesis of 6a
To a 100-mL Schlenk bottle containing 2-Bromobenzyl cyanide (10 mmol)
and ethynylbenzene (11 mmol) in Et3N (25 mL) was added Pd(PPh3)2Cl2
(0.1 mmol) and CuI (0.2 mmol). The mixture was stirred at 80 oC under N2
atmosphere for 30 h, quenched with saturated NH4Cl (30 mL) and
extracted with ethyl acetate (30 mL × 3). The combined organic layers
were dried over MgSO4, filtered and the solvent was evaporated in rotary
evaporator under reduced pressure to obtain the residue. The residue was
purified by flash column chromatography on silica gel (hexane/ethyl
acetate as eluent) to isolate the pure product (1.78g, 82%).
Experimental Section
o
2-(Phenylethynyl)benzonitrile (1a)[19] Brown solid, mp 48-50 C. 1H NMR
(CDCl3, 500 MHz, ppm): δ 7.66 (d, J = 7.6 Hz, 1H), 7.63-7.61 (m, 3H), 7.56
(t, J = 7.6 Hz, 1H), 7.42-7.35 (m, 4H). 13C NMR (CDCl3, 125 MHz, ppm): δ
132.7, 132.4, 132.2, 132.1, 129.3, 128.5, 128.3, 127.3, 122.1, 117.6, 115.4,
96.1, 85.7. Spectroscopic data for the title compound were consistent with
those reported in the literature.
General Information
All reactions related to lanthanide catalyst were carried out under a
moisture- and oxygen-free nitrogen atmosphere. Toluene, hexane and
tetrahydrofuran (THF) were taken from a solvent purification system (PS-
[18]
400-5, Unilab Mbraun, Inc.). Ln[N(TMS)2]3
and 2-alkynylbenzonitriles
2-(p-Tolylethynyl)benzonitrile (1b)[19] Brown solid, mp 59-60 oC. 1H NMR
(CDCl3, 500 MHz, ppm): δ 7.65 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz,
1H), 7.56-7.50 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H),
2.38 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 139.6, 132.7, 132.4,
132.0, 131.9, 129.3, 128.1, 127.5, 119.0, 117.7, 115.1, 96.4, 85.2, 21.7.
derivatives[19] were synthesized according to the corresponding literatures.
Deuterated solvents were obtained from Cambridge Isotope. Benzene-d6
was dried over sodium chips. 1H NMR and 13C NMR spectra were recorded
1
on a 500 MHz spectrometer (500 MHz for H; 125 MHz for 13C) at room
temperature. All chemical shift values are quoted in ppm referenced to an
internal tetramethylsilane at 0.00 ppm for 1H NMR and relative to residual
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Spectroscopic data for the title compound were consistent with those
2-(Pyridin-2-ylethynyl)benzonitrile (1k)[22] Brown solid, mp 60-61 oC. 1H
NMR (CDCl3, 500 MHz, ppm): δ 8.63 (d, J = 5.0 Hz, 1H), 7.71-7.64 (m,
4H), 7.59-7.56 (m, 1H), 7.46-7.43 (m, 1H), 7.29-7.27 (m, 1H). 13C NMR
(CDCl3, 125 MHz, ppm): δ 150.3, 142.5, 136.4, 132.8, 132.6, 129.1, 128.2,
126.3, 123.7, 117.4, 115.8, 94.6, 85.0. Spectroscopic data for the title
compound were consistent with those reported in the literature.
reported in the literature.
2-((4-Bromophenyl)ethynyl)benzonitrile (1c)[20] Brown solid, mp 87-88 oC.
1H NMR (CDCl3, 500 MHz, ppm): δ 7.66 (d, J = 7.5 Hz, 1H), 7.60 (d, J =
7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.50-7.44 (m, 4H), 7.41 (t, J = 7.5 Hz,
1H). 13C NMR (CDCl3, 125 MHz, ppm): δ 133.4, 132.7, 132.5, 132.1, 131.8,
128.6, 126.9, 123.8, 121.1, 117.5, 115.4, 94.9, 86.8. Spectroscopic data
for the title compound were consistent with those reported in the literature.
2-(Cyclopropylethynyl)benzonitrile (1l) Brown oil. 1H NMR (CDCl3, 500
MHz, ppm): δ 7.55 (d, J = 7.5 Hz, 1H), 7.47-7.41 (m, 2H), 7.29 (t, J = 7.5
Hz, 1H), 1.51-1.46 (m, 1H), 0.94-0.86 (m, 4H). 13C NMR (CDCl3, 125 MHz,
ppm): δ 132.4, 132.2, 132.1, 128.0, 127.5, 117.7, 115.3, 101.3, 72.4, 9.2,
0.38. HRMS (ESI, m/z): Calcd for C12H9NNa [M+Na]+ 190.0633; Found:
190.0633.
2-((4-(Trifluoromethyl)phenyl)ethynyl)benzonitrile (1d)[21] Brown solid, mp
46-48 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.69 (t, J = 8.0 Hz, 3H), 7.64-
7.56 (m, 4H), 7.44 (t, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 125 MHz, ppm): δ
132.8, 132.6, 132.3, 132.2, 130.8 (q, J = 33.0 Hz), 129.0, 126.5, 125.9,
125.4 (q, J = 3.0 Hz), 123.9 (q, J = 271.0 Hz), 117.5, 115.6, 94.2, 87.7.
Spectroscopic data for the title compound were consistent with those
reported in the literature.
2-((Prop-2-yn-1-ylamino)methyl)benzonitrile (5a) Brown oil. 1H NMR
(CDCl3, 500 MHz, ppm): δ 7.58 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H),
7.39-7.37 (m, 2H), 5.58 (s, 1H), 4.48 (s, 2H), 4.38 (d, J = 2.0 Hz, 2H), 2.25
(s, 1H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.3, 139.9, 132.8, 130.6,
127.7, 122.9, 121.8, 78.7, 72.3, 51.8, 33.0. HRMS (ESI, m/z): Calcd for
C11H11N2 [M+H]+ 171.0917; Found: 171.0917.
2-Ethynylbenzonitrile (1e)[19] Brown solid, mp 69-70 C. H NMR (CDCl3,
500 MHz, ppm): δ 7.63 (d, J = 8.0 Hz, 1H), 7.59-7.52 (m, 2H), 7.43 (t, J =
7.6 Hz, 1H), 3.47 (s, 1H). 13C NMR (CDCl3, 125 MHz, ppm): δ 133.0, 132.7,
132.5, 129.1, 125.8, 117.3, 115.7, 83.9, 79.6. Spectroscopic data for the
title compound were consistent with those reported in the literature.
o
1
o
2-(2-(Phenylethynyl)phenyl)acetonitrile (6a)[7a] Brown solid, mp 47-48 C.
1H NMR (CDCl3, 500 MHz, ppm): δ 7.59-7.56 (m, 3H), 7.52-7.50 (m, 1H),
7.41-7.35 (m, 5H), 3.98 (s, 2H). 13C NMR (CDCl3, 125 MHz, ppm): δ 132.5,
131.8, 131.7, 129.1, 129.0, 128.6, 128.3, 122.9, 122.6, 117.6, 95.8, 86.1,
22.9. Spectroscopic data for the title compound were consistent with those
reported in the literature.
2-((4-Methoxyphenyl)ethynyl)benzonitrile (1f)[19] Brown solid, mp 78-79 oC.
1H NMR (CDCl3, 500 MHz, ppm): δ 7.65 (d, J = 7.5 Hz, 1H), 7.59-7.52 (m,
4H), 7.37 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H). 13C
NMR (CDCl3, 125 MHz, ppm): δ 160.6, 133.7, 132.7, 132.4, 131.9, 127.9,
127.8, 117.8, 115.2, 114.3, 114.2, 96.5, 84.8, 55.5. Spectroscopic data for
the title compound were consistent with those reported in the literature.
General Procedure for the Synthesis of Aminoisoindoles.
4-Methyl-2-(phenylethynyl)benzonitrile (1g) Brown solid, mp 80-81 oC. 1H
NMR (CDCl3, 500 MHz, ppm): δ 7.62-7.59 (m, 2H), 7.53 (d, J = 7.6 Hz,
1H), 7.43 (s, 1H), 7.39-7.35 (m, 3H), 7.19 (d, J = 7.2 Hz, 1H), 2.40 (s, 3H).
13C NMR (CDCl3, 125 MHz, ppm): δ 143.5, 132.8, 132.6, 132.1, 129.3,
129.2, 128.5, 127.1, 122.3, 117.9, 112.4, 95.6, 85.9, 21.7. HRMS (ESI,
m/z): Calcd for C16H12N [M+H]+ 218.0964; Found: 218.0971.
In a glovebox, La[N(SiMe3)2]3 (9.3 mg, 0.015 mmol, 5 mol%) was added to
a Schlenk tube equipped with a magnetic stirring bar and a Teflon cap.
Then, a mixture of 2-alkynylbenzonitrile derivatives (0.30 mmol) and amine
(0.36 mmol) in 3 mL toluene was added. The sealed tube was taken out
from the glovebox, and stirred at 25 oC for 6 h. After completion of the
reaction, the crude product was purified by flash column chromatography
on silica gel with ethyl acetate/hexane as eluent.
4-Methoxy-2-(phenylethynyl)benzonitrile (1h) Brown solid, mp 66-68 oC.
1H NMR (CDCl3, 500 MHz, ppm): δ 7.62-7.56 (m, 3H), 7.38-7.37 (m, 3H),
(Z)-1-Benzylidene-3-(pyrrolidin-1-yl)-1H-isoindole (Z-3aa)[7a] Yellow solid,
mp 213-214 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.29 (d, J = 8.0 Hz,
2H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.43-7.38 (m, 3H),
7.31 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.62 (s, 1H), 3.99 (s, 4H),
2.07 (s, 4H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.0, 148.5, 145.0,
137.8, 132.1, 130.4, 128.4, 126.9, 126.5, 122.2, 119.9, 112.3, 49.7. 48.1,
26.7, 24.4. Spectroscopic data for the title compound were consistent with
those reported in the literature.
7.10 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 2.0, 9.0 Hz, 1H), 3.87 (s, 3H). 13
C
NMR (CDCl3, 125 MHz, ppm): δ 162.5, 134.3, 132.2, 129.4, 129.1, 128.6,
122.1, 118.0, 117.1, 115.2, 107.4, 95.8, 85.8, 55.8. HRMS (ESI, m/z):
Calcd for C16H12NO [M+H]+ 234.0914; Found: 234.0911.
2-(Phenylethynyl)-4-(trifluoromethyl)benzonitrile (1i) Brown solid, mp 73-
74 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.89 (s, 1H), 7.80 (d, J = 8.4 Hz,
1H), 7.66-7.62 (m, 3H), 7.45-7.38 (m, 3H). 13C NMR (CDCl3, 125 MHz,
ppm): δ 134.6 (q, J = 33.8 Hz), 133.3, 132.3, 129.9, 129.0 (q, J = 3.8 Hz),
128.7, 128.5, 124.8 (q, J = 3.8 Hz), 122.9 (q, J = 272.5 Hz), 121.5, 118.7,
116.5, 98.2, 84.6. HRMS (ESI, m/z): Calcd for C16H9F3N [M+H]+ 272.0682;
Found: 272.0684.
(E)-1-Benzylidene-3-(pyrrolidin-1-yl)-1H-isoindole (E-3aa) Yellow solid.
mp 202-205 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.66 (d, J = 7.5 Hz,
1H), 7.58 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 8.0 Hz,
2H), 7.29-7.23 (m, 2H), 7.16-7.13 (m, 2H), 3.90 (s, 4H), 2.01 (s, 4H). 13
C
NMR (CDCl3, 125 MHz, ppm): δ 162.6, 149.5, 140.8, 137.4, 134.9, 129.6,
128.3, 128.2, 127.5, 127.0, 123.5, 121.9, 120.7, 48.8, 25.5. HRMS (ESI,
m/z): Calcd for C19H19N2 [M+H]+ 275.1543; Found: 275.1549.
5-Chloro-2-(phenylethynyl)benzonitrile (1j) Brown oil. 1H NMR (CDCl3, 500
MHz, ppm): δ 7.60-7.58 (m, 3H), 7.53-7.47 (m, 2H), 7.41-7.34 (m, 3H). 13
C
NMR (CDCl3, 125 MHz, ppm): δ 134.2, 133.1, 132.8, 132.2, 132.0, 129.5,
128.5, 125.7, 121.7, 116.6, 116.3, 97.1, 84.8. HRMS (ESI, m/z): Calcd for
C15H8ClNNa [M+Na]+ 260.0243; Found: 260.0253.
(Z)-N-Benzyl-1-benzylidene-N-methyl-1H-isoindol-3-amine
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.28 (d, J = 8.0 Hz, 2H),
(Z-3ab)
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7.84 (d, J = 7.5 Hz, 1H), 7.61 (s, 1H), 7.42-7.36 (m, 7H), 7.31 (t, J = 7.0
Hz, 1H), 7.26-7.21 (m, 2H), 6.69 (s, 1H), 5.11 (s, 2H), 3.48 (s, 3H). 13C
NMR (CDCl3, 125 MHz, ppm): δ 166.6, 147.7, 145.5, 137.7, 137.6, 131.5,
130.6, 128.9, 128.5, 128.4, 127.6, 127.5, 127.1, 126.9, 122.8, 120.0, 113.5,
55.6, 38.2. HRMS (ESI, m/z): Calcd for C23H21N2 [M+H]+ 325.1699; Found:
325.1703.
122.8, 119.6, 115.7, 41.9. HRMS (ESI, m/z): Calcd for C22H18ClN2 [M+H]+
345.1153; Found: 345.1155.
(E)-1-Benzylidene-N-(4-chlorophenyl)-N-methyl-1H-isoindol-3-amine (E-
1
3ag) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 7.57 (d, J = 8.0 Hz,
1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41 (t, J = 7.5 Hz, 4H), 7.35-7.33 (m, 2H),
7.25 (s, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.23 (d, J =
8.0 Hz, 1H), 3.67 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 163.7, 148.9,
144.2, 140.4, 136.8, 134.3, 132.7, 129.8, 129.7, 128.5, 128.4, 128.2, 127.6,
127.3, 124.3, 123.3, 122.7, 41.8. HRMS (ESI, m/z): Calcd for C22H18ClN2
[M+H]+ 345.1153; Found: 345.1155.
(E)-N-Benzyl-1-benzylidene-N-methyl-1H-isoindol-3-amine
(E-3ab)
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.64 (d, J = 7.6 Hz, 1H),
7.55 (t, J = 7.6 Hz, 3H), 7.43-7.32 (m, 8H), 7.24-7.15 (m, 3H), 5.03 (s, 2H),
3.39 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.3, 148.9, 141.2,
137.6, 137.3, 134.3, 129.7, 128.9, 128.4, 128.3, 127.8, 127.6, 127.3, 127.2,
123.6, 122.4, 122.2, 55.5, 38.2. HRMS (ESI, m/z): Calcd for C23H21N2
[M+H]+ 325.1699; Found: 325.1703.
(Z)-1-(4-Methylbenzylidene)-3-(pyrrolidin-1-yl)-1H-isoindole
(Z-3ba)
Yellow solid, mp 171-172 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.17 (d,
J = 8.0 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.40 (t,
J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.61 (s,
1H), 3.99 (s, 4H), 2.38 (s, 3H), 2.07 (s, 4H). 13C NMR (CDCl3, 125 MHz,
ppm): δ 163.7, 147.7, 145.1, 136.4, 135.0, 132.0, 130.5, 129.2, 128.3,
126.7, 122.2, 119.8, 112.7, 49.3, 48.6, 26.4, 24.7, 21.5. HRMS (ESI, m/z):
Calcd for C20H21N2 [M+H]+ 289.1699; Found:289.1698.
(Z)-1-Benzylidene-N-methyl-N-phenyl-1H-isoindol-3-amine
(Z-3ac)
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.22 (d, J = 7.5 Hz, 2H),
7.66 (d, J = 7.5 Hz, 1H), 7.37-7.31 (m, 5H), 7.25 (s, 1H), 7.20-7.14 (m, 3H),
6.86 (t, J = 7.5 Hz, 1H), 6.66 (s, 1H), 6.01 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H).
13C NMR (CDCl3, 125 MHz, ppm):δ 165.3, 147.8, 145.2, 144.7, 137.4,
131.7, 130.8, 129.7, 128.5, 128.1, 127.7, 127.5, 127.2, 126.6, 123.0, 119.5,
114.9, 41.9. HRMS (ESI, m/z): Calcd for C22H19N2 [M+H]+ 311.1543;
Found: 311.1543.
(Z)-1-(4-Bromobenzylidene)-3-(pyrrolidin-1-yl)-1H-isoindole
(Z-3ca)
Yellow solid, mp 204-205 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.14 (d,
J = 8.5 Hz, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.48 (d,
J = 8.0 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 6.50 (s,
1H), 3.98 (s, 4H), 2.10 (s, 4H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.2,
149.3, 144.9, 136.9, 132.2, 131.9, 131.5, 128.6, 127.2, 122.3, 120.2, 120.0,
110.8, 49.8, 48.3, 26.8, 24.4. HRMS (ESI, m/z): Calcd for C19H18BrN2
[M+H]+ 353.0648; Found: 353.0653.
(E)-4-(1-Benzylidene-1H-isoindol-3-yl)morpholine (E-3ad)[7a] Yellow oil. 1H
NMR (CDCl3, 500 MHz, ppm): δ 7.63 (dd, J =4.0, 8.0 Hz, 2H), 7.52 (d, J =
8.0 Hz, 2H), 7.41(t, J = 7.6 Hz, 2H), 7.35-7.27 (m, 2H), 7.22 (s, 1H), 7.21-
7.17 (m, 1H), 3.90 (s, 7.41(t, J = 7.6 Hz, 2H), 7.35-7.27 (m, 2H), 7.22 (s,
1H), 7.21-7.17 (m, 1H), 3.90 (s, 8H). 13C NMR (CDCl3, 125 MHz, ppm): δ
165.0, 148.4, 140.8, 136.7, 134.1, 129.6, 128.4, 127.8, 127.6, 123.8, 123.6,
121.9, 66.8, 47.7. Spectroscopic data for the title compound were
consistent with those reported in the literature.
(E)-3-(Pyrrolidin-1-yl)-1-(4-(trifluoromethyl)benzylidene)-1H-isoindole (E-
1
3da) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 7.72 (d, J = 8.0 Hz,
1H), 7.63-7.59 (m, 4H), 7.56 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H),
7.21 (t, J = 7.5 Hz, 1H), 7.06 (s, 1H), 3.95 (s, 4H), 2.07 (s, 4H). 13C NMR
(CDCl3, 125 MHz, ppm): δ 163.1, 150.7, 141.3, 140.6, 135.2, 130.0, 128.9
(q, J = 32.5 Hz), 128.7, 128.1, 125.3 (q, J = 3.8 Hz), 124.5 (q, J = 270.0
Hz), 123.5, 122.3, 118.5, 49.2, 25.6. HRMS (ESI, m/z): Calcd for
C20H18F3N2 [M+H]+ 343.1417; Found: 343.1430.
(Z)-1-(1-Benzylidene-1H-isoindol-3-yl)indoline (Z-3ae)[7a] Yellow solid, mp
152-153 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.74 (d, J = 7.5 Hz, 1H),
8.28 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),
7.46-7.42 (m, 3H), 7.34 (t, J = 7.0 Hz, 2H), 7.30-7.23 (m, 3H), 7.04 (t, J =
7.5 Hz, 1H), 6.81 (s, 1H), 4.66 (t, J = 8.5 Hz, 2H), 3.34 (t, J = 8.5 Hz, 2H).
13C NMR (CDCl3, 125 MHz, ppm): δ 161.4, 147.9, 144.5, 143.8, 137.2,
132.7, 131.7, 130.6, 128.5, 127.6, 127.3, 127.2, 124.5, 122.9, 122.5, 120.0,
117.0, 115.5, 50.2, 28.6. Spectroscopic data for the title compound were
consistent with those reported in the literature.
(Z)-N-Benzyl-N-methyl-1-(4-methylbenzylidene)-1H-isoindol-3-amine (Z-
1
3bb) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 8.09 (d, J = 8.0 Hz,
2H), 7.73 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.36-7.28 (m, 5H),
7.21 (t, J = 7.0 Hz, 1H), 7.16-7.13 (m, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.60
(s, 1H), 5.00 (s, 2H), 3.37 (s, 3H), 2.28 (s, 3H). 13C NMR (CDCl3, 125 MHz,
ppm): δ 166.2, 147.0, 145.5, 137.8, 136.8, 134.8, 131.4, 130.6, 129.2,
128.9, 128.2, 127.6, 127.5, 126.9, 122.7, 119.9, 113.7, 55.6, 38.1, 21.5.
HRMS (ESI, m/z): Calcd for C24H23N2 [M+H]+ 339.1856; Found: 339.1856.
(E)-1-Benzylidene-N-(4-methoxyphenyl)-N-methyl-1H-isoindol-3-amine
(E-3af) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.56-7.53 (m, 3H),
7.40 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.27-7.26 (m, 2H), 7.24 (s,
1H), 7.05 (t, J = 8.0 Hz, 1H), 6.97-6.92 (m, 3H), 6.13 (d, J = 8.0 Hz, 1H),
3.86 (s, 3H), 3.66 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.1, 158.9,
149.1, 140.5, 138.4, 137.1, 134.6, 129.7, 128.7, 128.4, 128.0, 127.4, 127.2,
123.1, 122.9, 122.8, 114.9, 55.6, 42.0. HRMS (ESI, m/z): Calcd for
C23H21N2O [M+H]+ 341.1649; Found: 341.1650.
(E)-N-Benzyl-N-methyl-1-(4-methylbenzylidene)-1H-isoindol-3-amine (E-
1
3bb) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 7.72 (d, J = 7.5 Hz,
1H), 7.56 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 6.5 Hz,
4H), 7.32-7.30 (m, 1H), 7.23 (s, 1H), 7.22-7.18(m, 4H), 5.02 (s, 2H), 3.38
(s, 3H), 2.42 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.1, 148.4,
141.2, 137.6, 137.2, 134.2, 129.7, 129.2, 129.0, 128.3, 127.7, 127.6, 127.2,
123.7, 122.5, 122.3, 55.5, 38.3, 21.5. HRMS (ESI, m/z): Calcd for C24H23N2
[M+H]+ 339.1856; Found: 339.1856.
(Z)-1-Benzylidene-N-(4-chlorophenyl)-N-methyl-1H-isoindol-3-amine (Z-
1
3ag) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 8.28 (d, J = 7.2 Hz,
2H), 7.75 (d, J = 7.6 Hz, 1H), 7.42-7.38 (m, 4H), 7.31-7.27 (m, 2H), 7.24-
7.23 (m, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.22 (d, J = 7.6 Hz, 1H),
3.75 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.0, 147.5, 144.6,
143.8, 137.2, 133.0, 131.5, 130.9, 129.9, 128.7, 128.6, 128.3, 127.4, 126.7,
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(Z)-N-Methyl-1-(4-methylbenzylidene)-N-phenyl-1H-isoindol-3-amine (Z-
3bc) Yellow solid, mp 144-146 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.23
(d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.41
(t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.0 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.25
(d, J = 7.5 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.77 (s, 1H), 6.13 (d, J = 8.0
Hz, 1H), 3.81 (s, 3H), 2.41 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ
165.0, 147.0, 145.3, 144.7, 137.1, 134.6, 131.6, 130.8, 129.7, 129.3, 128.0,
127.6, 127.4, 126.4, 123.0, 119.4, 115.2, 41.9, 21.6. HRMS (ESI, m/z):
Calcd for C23H21N2 [M+H]+ 325.1699; Found: 325.1700.
(d, J = 8.8 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49-
7.43 (m, 3H), 7.37-7.35 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2
Hz, 1H), 6.65 (s, 1H), 6.09 (d, J = 8.0 Hz, 1H), 3.79 (s, 3H). 13C NMR
(CDCl3, 125 MHz, ppm): δ 165.4, 148.4, 144.9, 144.4, 136.4, 132.1, 131.8,
131.6, 129.8, 128.3, 127.8, 127.7, 126.8, 123.1, 120.9, 119.5, 113.1, 41.9.
HRMS (ESI, m/z): Calcd for C22H18BrN2 [M+H]+ 389.0648; Found:
389.0654.
(E)-1-(4-Bromobenzylidene)-N-methyl-N-phenyl-1H-isoindol-3-amine (E-
3cc) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.55-7.52 (m, 3H),
7.47-7.44 (m, 2H), 7.41 (d, J = 8.4 Hz, 3H), 7.33 (d, J = 7.6 Hz, 2H), 7.19
(s, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.10 (d, J = 8.0
Hz, 1H), 3.71 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.0, 149.3,
145.2, 140.2, 135.9, 134.5, 131.6, 131.4, 129.8, 128.2, 127.5, 127.4, 123.1,
123.0, 121.6, 121.4, 41.9. HRMS (ESI, m/z): Calcd for C22H18BrN2 [M+H]+
389.0648; Found: 389.0654.
(E)-N-Methyl-1-(4-methylbenzylidene)-N-phenyl-1H-isoindol-3-amine (E-
1
3bc) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 7.65 (d, J = 8.0 Hz,
1H), 7.44 (t, J = 8.0 Hz, 4H), 7.38 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 8.0 Hz,
2H), 7.30 (s, 1H), 7.22 (d, J = 7.5 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 6.93 (t,
J = 7.5 Hz, 1H), 6.13 (d, J = 7.5 Hz, 1H), 3.71 (s, 3H), 2.41 (s, 3H). 13C
NMR (CDCl3, 125 MHz, ppm): δ 163.8, 148.6, 145.6, 140.5, 137.4, 134.5,
134.0, 129.7, 129.2, 128.0, 127.4, 127.2, 127.1, 123.8, 123.2, 122.8, 41.8,
21.5. HRMS (ESI, m/z): Calcd for C23H21N2 [M+H]+ 325.1699; Found:
325.1700.
(E)-N-Benzyl-N-methyl-1-(4-(trifluoromethyl) benzylidene)-1H-isoindol-3-
amine (E-3db) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.66 (s, 4H),
7.62 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.40-7.31 (m, 5H), 7.26-
7.18 (m, 2H), 7.14 (s, 1H), 5.04 (s, 2H), 3.40 (s, 3H). 13C NMR (CDCl3, 125
MHz, ppm): δ 165.7, 150.1, 141.1, 141.0, 137.3, 134.5, 130.0, 129.4 (q, J
= 32.5 Hz), 129.0, 128.6, 128.2, 127.7, 127.2, 125.4 (q, J = 3.8 Hz), 124.4
(q, J = 270.0 Hz), 123.5, 122.7, 119.7, 55.5, 38.3. HRMS (ESI, m/z): Calcd
for C24H20F3N2 [M+H]+ 393.1573; Found: 393.1573.
(E)-N-Benzyl-1-(4-methoxybenzylidene)-N-methyl-1H-isoindol-3-amine
(E-3fb) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.74 (d, J = 6.8 Hz,
1H), 7.55 (d, J = 6.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.40-7.35 (m, 4H),
7.32-7.30 (m, 1H), 7.23-7.17 (m, 3H), 6.96 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H),
3.86 (s, 3H), 3.37 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.9, 159.0,
148.0, 141.0, 137.5, 134.0, 131.0, 129.4, 128.9, 128.2, 127.6, 127.5, 127.1,
123.4, 122.3, 122.2, 113.8, 55.4, 55.3, 38.3. HRMS (ESI, m/z): Calcd for
C24H23N2O [M+H]+ 355.1805; Found: 355.1805.
(E)-N-Methyl-N-phenyl-1-(4-(trifluoromethyl) benzylidene)-1H-isoindol-3-
amine (E-3dc) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.66 (s, 4H),
7.51 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.40 (t, J = 7.5 Hz, 1H),
7.34 (d, J = 7.5 Hz, 2H), 7.23 (s, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.95 (t, J =
7.5 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H). 13C NMR (CDCl3, 125
MHz, ppm): δ 164.4, 150.2, 145.2, 140.9, 140.2, 134.8, 130.0, 129.8, 129.3
(q, J = 32.5 Hz), 128.3, 127.7, 127.6, 127.5, 125.4 (q, J = 3.8 Hz), 124.4
(q, J = 270.0 Hz), 123.1, 123.0, 121.0, 41.9. HRMS (ESI, m/z): Calcd for
C23H18F3N2 [M+H]+ 379.1417; Found: 379.1427.
(E)-1-(4-Methoxybenzylidene)-N-methyl-N-phenyl-1H-isoindol-3-amine
(E-3fc) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.66 (d, J = 7.6 Hz,
1H), 7.49 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 7.2 Hz, 2H), 7.37 (d, J = 7.2 Hz,
1H), 7.32 (d, J = 7.2 Hz, 2H), 7.26 (s, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.96-
6.91 (m, 3H), 6.14 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.69 (s, 3H). 13C NMR
(CDCl3, 125 MHz, ppm): δ 163.6, 159.1, 148.2, 145.5, 140.3, 134.4, 131.0,
129.6, 129.2, 127.9, 127.3, 127.1, 127.0, 123.5, 123.0, 122.8, 113.9, 55.4,
41.7. HRMS (ESI, m/z): Calcd for C23H21N2O [M+H]+ 341.1649; Found:
341.1649.
(E)-N-Benzyl-1-benzylidene-N,6-dimethyl-1H-isoindol-3-amine
(E-3gb)
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.55 (d, J = 7.5 Hz, 2H),
7.49 (s, 1H), 7.42 (t, J = 7.5 Hz, 3H), 7.39-7.34 (m, 5H), 7.32-7.29 (m, 1H),
7.19 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H), 3.37 (s, 3H), 2.24 (s,
3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.3, 148.8, 141.6, 138.5, 137.6,
137.3, 131.9, 129.8, 128.9, 128.8, 128.3, 127.5, 127.3, 127.2, 124.2, 122.1,
121.7, 55.4, 38.2, 21.6. HRMS (ESI, m/z): Calcd for C24H23N2 [M+H]+
339.1856; Found: 339.1857.
(Z)-N-Benzyl-1-(4-bromobenzylidene)-N-methyl-1H-isoindol-3-amine (Z-
3cb) Yellow solid, mp 178-179 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.14
(d, J = 8.8 Hz, 2H), 7.81 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.48 (d, J = 8.4
Hz, 2H), 7.43-7.35 (m, 5H), 7.33-7.27 (m, 2H), 6.59 (s,1H), 5.10 (s, 2H),
3.47 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 166.7, 148.4, 145.4,
137.6, 136.6, 132.1, 131.7, 131.5, 129.0, 128.6, 127.7, 127.5, 127.4, 122.9,
120.6, 120.1, 111.9, 55.8, 38.3. HRMS (ESI, m/z): Calcd for C23H20BrN2
[M+H]+ 403.0805; Found: 403.0798.
(Z)-N-Benzyl-1-benzylidene-N,6-dimethyl-1H-isoindol-3-amine
(Z-3gb)
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.26 (d, J = 7.6 Hz, 2H),
7.64 (s, 1H), 7.52-7.43 (m, 1H), 7.40-7.34 (m, 6H), 7.32-7.29 (m, 1H), 7.21
(t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 5.09 (s, 2H), 3.46
(s, 3H), 2.47 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 166.6, 147.8,
146.0, 138.7, 137.8, 137.7, 130.6, 129.3, 128.9, 128.4, 128.2, 127.6, 127.5,
126.8, 122.5, 120.6, 112.9, 55.6, 38.1, 21.7. HRMS (ESI, m/z): Calcd for
C24H23N2 [M+H]+ 339.1856; Found: 339.1857.
(E)-N-Benzyl-1-(4-bromobenzylidene)-N-methyl-1H-isoindol-3-amine (E-
1
3cb) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 7.64 (d, J = 8.0 Hz,
1H), 7.57-7.52 (m, 3H), 7.41-7.30 (m, 7H), 7.25-7.19 (m, 2H), 7.07 (s, 1H),
5.02 (s, 2H), 3.78 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.5, 149.3,
141.0, 137.4, 136.2, 134.4, 131.6, 131.4, 129.0, 128.4, 128.0, 127.6, 127.2,
123.5, 122.5, 121.2, 120.4, 55.5, 38.3. HRMS (ESI, m/z): Calcd for
C23H20BrN2 [M+H]+ 403.0805; Found: 403.0798.
(Z)-1-Benzylidene-N,6-dimethyl-N-phenyl-1H-isoindol-3-amine
(Z-3gc)
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.30 (d, J = 7.6 Hz, 2H),
7.57 (s, 1H), 7.48-7.40 (m, 5H), 7.36 (d, J = 7.2 Hz, 2H), 7.26 (s, 1H), 6.78
(d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 5.97 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 2.39
(Z)-1-(4-Bromobenzylidene)-N-methyl-N-phenyl-1H-isoindol-3-amine (Z-
3cc) Yellow solid, mp 155-156 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.19
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(s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.4, 147.9, 145.3, 145.2,
138.5, 137.5, 130.7, 129.7, 129.5, 128.5, 127.7, 127.6, 127.5, 127.1, 122.7,
120.1, 114.4, 41.8, 21.7. HRMS (ESI, m/z): Calcd for C23H21N2 [M+H]+
325.1699; Found: 325.1698.
(E)-1-Benzylidene-5-chloro-N-methyl-N-phenyl-1H-isoindol-3-amine (E-
3jc) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.51 (d, J = 7.6 Hz, 2H),
7.49-7.39 (m, 6H), 7.36-7.33 (m, 2H), 7.31 (s, 2H), 7.02 (dd, J = 1.6, 8.4
Hz, 1H), 6.00 (d, J = 1.6 Hz, 1H), 3.69 (s, 3H). 13C NMR (CDCl3, 125 MHz,
ppm): δ 162.8, 148.1, 145.0, 138.8, 136.7, 136.0, 132.0, 129.9, 129.7,
128.6, 128.1, 127.8, 127.7, 127.4, 124.2, 123.9, 123.0, 41.8. HRMS (ESI,
m/z): Calcd for C22H18ClN2 [M+H]+ 345.1153; Found: 345.1155.
(E)-1-Benzylidene-N,6-dimethyl-N-phenyl-1H-isoindol-3-amine
(E-3gc)
Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.57 (d, J = 7.6 Hz, 2H),
7.45-7.36 (m, 6H), 7.36-7.32 (m, 3H), 7.28 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H),
6.00 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 2.17 (s, 3H). 13C NMR (CDCl3, 125
MHz, ppm): δ 164.0, 149.0, 145.6, 140.9, 138.2, 137.1, 132.3, 129.8, 129.6,
128.3, 128.2, 127.4, 127.3, 127.2, 123.6, 123.0, 122.5, 41.6, 21.6. HRMS
(ESI, m/z): Calcd for C23H21N2 [M+H]+ 325.1699; Found: 325.1698.
(Z)-1-Benzylidene-5-chloro-N-methyl-N-phenyl-1H-isoindol-3-amine (Z-
3jc) Yellow solid, mp 197-199 oC. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.28
(d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.50-7.40 (m, 5H), 7.34 (d, J
= 7.2 Hz, 2H), 7.29-7.25 (m, 2H), 6.72 (s, 1H), 5.99 (s, 1H), 3.79 (s, 3H).
13C NMR (CDCl3, 125 MHz, ppm): δ 164.0, 144.7, 142.9, 137.0, 132.9,
132.3, 130.9, 130.0, 128.6, 128.3, 128.0, 127.6, 127.5, 123.2, 120.3, 115.8,
42.0. HRMS (ESI, m/z): Calcd for C22H18ClN2 [M+H]+ 345.1153; Found:
345.1155.
(E)-N-Benzyl-1-benzylidene-6-methoxy-N-methyl-1H-isoindol-3-amine (E-
1
3hb) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 7.54 (d, J = 7.5 Hz,
2H), 7.41 (t, J = 8.0 Hz, 3H), 7.38-7.30 (m, 7H), 7.20 (s, 1H), 7.11 (d, J =
2.5 Hz, 1H), 6.74 (dd, J = 2.5, 8.5 Hz, 1H), 4.99 (s, 2H), 3.58 (s, 3H), 3.36
(s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 165.1, 160.1, 148.6, 143.5,
137.5, 137.3, 130.5, 129.6, 129.0, 128.4, 127.6, 127.4, 127.1, 123.3, 121.5,
114.6, 108.3, 55.5, 55.3, 38.3. HRMS (ESI, m/z): Calcd for C24H23N2O
[M+H]+ 355.1805; Found: 355.1805.
(Z)-N-Benzyl-1-(cyclopropylmethylene)-N-methyl-1H-isoindol-3-amine (Z-
3lb) Tawny oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.11 (d, J = 7.5 Hz, 1H),
7.59 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.37-7.32 (m, 4H), 7.30-
7.24 (m, 2H), 5.74 (d, J = 10.0 Hz, 1H), 4.95 (s, 2H), 3.29 (s, 3H), 2.28-
2.23 (m, 1H), 1.08-1.04 (m, 2H), 0.69-0.66 (m, 2H). 13C NMR (CDCl3, 125
MHz, ppm): δ 163.6, 147.3, 141.5, 137.9, 133.8, 129.8, 128.9, 128.3, 127.5,
127.2, 126.9, 123.4, 122.5, 55.5, 38.2, 11.4, 9.2. HRMS (ESI, m/z): Calcd
for C20H21N2 [M+H]+ 289.1699; Found: 289.1699.
(Z)-1-Benzylidene-6-methoxy-N-methyl-N-phenyl-1H-isoindol-3-amine (Z-
1
3hc) Yellow oil. H NMR (CDCl3, 500 MHz, ppm): δ 8.30 (d, J = 7.6 Hz,
2H), 7.47-7.39 (m, 5H), 7.36-7.34 (m, 2H), 7.24-7.22 (m, 2H), 6.68 (s, 1H),
6.50 (d, J = 8.8 Hz, 1H), 5.96 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H).
13C NMR (CDCl3, 125 MHz, ppm): δ 165.2, 160.4, 147.7, 147.0, 145.1,
137.3, 130.6, 129.7, 128.5, 127.7, 127.6, 127.1, 125.0, 123.9, 114.1, 113.7,
103.9, 55.6, 41.7. HRMS (ESI, m/z): Calcd for C23H21N2O [M+H]+
341.1649; Found: 341.1649.
(Z)-1-(Cyclopropylmethylene)-N-methyl-N-phenyl-1H-isoindol-3-amine (Z-
3lc) Tawny oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.02 (d, J = 8.0 Hz, 1H),
7.40 (t, J = 7.6 Hz, 2H), 7.34-7.27 (m, 4H), 6.98 (t, J = 7.6 Hz, 1H), 6.22
(d, J = 8.0 Hz, 1H), 5.81 (d, J = 10.0 Hz, 1H), 3.61 (s, 3H), 2.30-2.26 (m,
1H), 1.09-1.04 (m, 2H), 0.71-0.67 (m, 2H). 13C NMR (CDCl3, 125 MHz,
ppm): δ 162.2, 147.5, 146.1, 140.8, 134.1, 131.2, 129.6, 128.0, 127.1,
126.7, 126.4, 122.9, 122.8, 41.7, 11.5, 9.3. HRMS (ESI, m/z): Calcd for
C19H19N2 [M+H]+ 275.1543; Found: 275.1543.
(E)-N-Benzyl-1-benzylidene-N-methyl-6-(trifluoromethyl) -1H-isoindol-3-
amine (E-3ib) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.89 (s, 1H),
7.65 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.48-7.42 (m, 3H), 7.40-
7.37 (m, 3H), 7.35-7.32 (m, 4H), 5.03 (s, 2H), 3.41 (s, 3H). 13C NMR (CDCl3,
125 MHz, ppm): δ 164.0, 147.6, 141.4, 137.1, 136.5, 136.4, 130.2 (q, J =
32.5 Hz), 129.6, 129.1, 128.6, 128.1, 127.8, 127.1, 124.8 (q, J = 3.8 Hz),
124.3, 124.1 (q, J = 271.3 Hz), 122.6, 120.5 (q, J = 3.8 Hz), 55.6, 38.5.
HRMS (ESI, m/z): Calcd for C24H20F3N2 [M+H]+ 393.1573; Found:
393.1573.
(Z)-1-Benzylidene-2-methyl-3-(pyrrolidin-1-yl)-1H-isoindol-2-ium
iodide
(Z-4aa) Yellow solid, mp 225-226 oC. 1H NMR (d6-DMSO, 500 MHz, ppm):
δ 8.28 (t, J = 8.4 Hz, 2H), 7.89 (t, J = 7.6 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H),
7.62 (d, J = 7.6 Hz, 2H), 7.53-7.49 (m, 3H), 7.42 (t, J = 7.2 Hz, 1H), 4.31-
4.26 (m, 4H), 3.37 (s, 3H), 2.19-2.12 (m, 2H), 2.06-1.99 (m, 2H). 13C NMR
(d6-DMSO, 125 MHz, ppm): δ 162.4, 138.7, 137.8, 133.7, 133.2, 130.4,
129.9, 128.6, 128.5, 126.5, 125.9, 120.9, 113.6, 55.2, 52.9, 52.7, 25.3,
25.0. Calcd for C20H21N2 [M-I]+ 289.1699; Found: 289.1700.
(E)-1-Benzylidene-N-methyl-N-phenyl-6-(trifluoromethyl) -1H-isoindol-3-
amine (E-3ic) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.81 (s, 1H),
7.54 (d, J = 7.2 Hz, 2H), 7.48-7.38 (m, 7H), 7.34-7.31 (m, 2H), 7.19 (d, J =
8.4 Hz, 1H), 6.18 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H). 13C NMR (CDCl3, 125
MHz, ppm): δ 162.8, 148.0, 145.1, 140.7, 137.0, 136.2, 129.9 (q, J = 32.5
Hz), 129.8, 129.7, 128.6, 128.2, 127.7, 127.4, 125.4, 124.2 (q, J = 3.8 Hz),
124.1 (q, J = 271.3 Hz), 123.1, 120.0 (q, J = 3.8 Hz), 41.9. HRMS (ESI,
m/z): Calcd for C23H18F3N2 [M+H]+ 379.1417; Found: 379.1427.
2-Methyl-5H-imidazo[2,1-a]isoindole (5ab) Colourless oil. 1H NMR (CDCl3,
500 MHz, ppm): δ 7.78 (d, J = 8.0 Hz, 1H), 7.40-7.37 (m, 2H), 7.28 (d, J =
8.5 Hz, 1H), 6.89 (s, 1H), 4.77 (s, 2H), 2.33 (s, 3H). 13C NMR (CDCl3, 125
MHz, ppm): δ 153.1, 142.9, 141.9, 130.3, 128.5, 127.2, 123.4, 119.8, 112.5,
48.7, 14.5. HRMS (ESI, m/z): Calcd for C11H11N2 [M+H]+ 171.0917; Found:
171.0918.
(E)-N-Benzyl-1-benzylidene-5-chloro-N-methyl-1H-isoindol-3-amine (E-
3jb) Yellow oil. 1H NMR (CDCl3, 500 MHz, ppm): δ 7.56-7.55 (m, 2H), 7.51
(d, J = 7.6 Hz, 2H), 7.43-7.31 (m, 8H), 7.23 (s, 1H), 7.14 (d, J = 7.6 Hz,
1H), 4.99 (s, 2H), 3.36 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm): δ 164.0,
147.9, 139.6, 137.2, 136.9, 135.7, 133.5, 129.7, 129.0, 128.5, 128.2, 127.7,
127.6, 127.3, 124.3, 123.0, 122.5, 55.5, 38.2. HRMS (ESI, m/z): Calcd for
C23H20ClN2 [M+H]+ 359.1310; Found: 359.1327.
1
1-Benzyl-3-(pyrrolidin-1-yl)isoquinoline (6aa) Colourless oil. H NMR (d6-
DMSO, 500 MHz, ppm): δ 8.04 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H),
7.43-7.39 (m, 1H), 7.34 (d, J = 6.8 Hz, 2H), 7.24 (t, J = 8.0 Hz, 2H), 7.16-
7.07 (m, 2H), 6.44 (s, 1H), 4.47 (s, 2H), 3.47-3.44 (m, 4H), 1.99-1.95 (m,
4H). 13C NMR (d6-DMSO, 125 MHz, ppm): δ 158.8, 153.1, 139.7, 139.4,
129.6, 128.5, 128.2, 125.9, 125.8, 125.3, 121.5, 119.7, 95.1, 46.6, 40.7,
25.0. HRMS (ESI, m/z): Calcd for C20H21N2 [M+H]+ 289.1699; Found:
289.1699.
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Acknowledgements
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(Nos. LQ18B020006 and LY16B020012), Zhejiang Educational
Committee of China (Y201737383), Xinmiao Foundation of
Zhejiang Province (No. 2018R429056) and Wenzhou University
for financial support.
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10.1002/asia.201801252
Chemistry - An Asian Journal
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Pengqing Ye, Yinlin Shao*,
Leping Xie, Keting Shen,
Tianxing Cheng, and Jiuxi
Chen*
A
lanthanide-catalyzed
tandem
hydroamination/cyclization
reaction was developed for the
construction
aminoisoindoles as well as
other nitrogen-containing
of
Page No. – Page No.
Lanthanide-Catalyzed
compounds such as 5H-
imidazo[2,1-a]isoindoles and
isoquinolines in moderate to
excellent yields. The salient
features of this reaction include
high bond-formation efficiency,
mild reaction conditions, 100%
atomic efficiency and good
functional group tolerance.
Tandem
Secondary Amines with 2-
Alkynylbenzonitriles:
Synthesis
Aminoisoindoles
Insertion
of
of
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