Ugi Reaction Followed by Intramolecular Diels–Alder Reaction and Elimination of HCl: One-Pot Approach to Arene-Fused Isoindolinones

Article abstract of DOI:10.1002/ejoc.201700747

A one-pot procedure involving a four-component Ugi reaction followed by an intramolecular Diels–Alder reaction/HCl elimination cascade has been developed to provide rapid access to the isoindolinone framework in a diversity-oriented fashion. The scope of

Full text of DOI:10.1002/ejoc.201700747

A Journal of
Accepted Article
Title: Ugi Reaction Followed by the Intramolecular Diels-Alder and
HCl-Elimination: a One-Pot Approach towards Arene-Fused
Isoindolinones
Authors: Jianjun Huang, Xiaochen Du, Kristof Van Hecke, Erik V. Van
der Eycken, Olga P. Pereshivko, and Vsevolod A. Peshkov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700747
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700747
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10.1002/ejoc.201700747
European Journal of Organic Chemistry
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Ugi Reaction Followed by the Intramolecular Diels-Alder and HCl-
Elimination: a One-Pot Approach towards Arene-Fused
Isoindolinones
Jianjun Huang,#[a] Xiaochen Du,#[a] Kristof Van Hecke,[b] Erik V. Van der Eycken,[c,d] Olga P.
Pereshivko,*[a] Vsevolod A. Peshkov*[a]
Abstract: A one-pot procedure involving a four-component Ugi
reaction followed by an intramolecular Diels-Alder/HCl-elimination
cascade has been developed to provide rapid access to the
isoindolinone framework in a diversity-oriented fashion. The scope of
the process has been investigated with respect to all four
components and a comparison between the one-pot and sequential
strategies for converting Ugi adducts into heterocycles. Others
and we have demonstrated that propiolic acid-derived Ugi
adducts could be readily converted into various types of
pyrrolones[6] and β-lactams[7] taking advantage of the
nucleophilicity of the peptidyl position through enolization-
triggered
5-endo-dig
and
4-exo-dig
carbocyclizations,
approaches is given. The possibility of
a
late-stage one-pot
respectively. Using propiolic acid-derived Ugi adducts bearing
an additional nucleophilic reactive center, a wide range of
medium-ring-containing heterocycles[8] and structurally unique
polycyclic frameworks[9] could be assembled through the
activation of the triple bond towards nucleophilic attack, with the
aid of coinage metal catalysts or strong Brønsted acids. The
functionalization through Suzuki coupling has been explored.
Introduction
post-Ugi processes involving triple-bond carbopalladation have
Multicomponent reactions (MCRs),[1] cascade processes[2] and
one-pot approaches[3] are considered to be efficient tools for the
rapid assembly of complex molecules. Furthermore, these
intensification processes can help chemists to shorten reaction
times and lower the costs of synthetic preparations, at the same
time minimizing the amount of generated waste. The four-
component Ugi reaction accompanied by a suitable post-
transformation has become a landmark for the diversity-oriented
[10]
been extensively utilized to prepare indol-2-ones,
emissive isoquinolines[11] and 3-benzazepines. [12]
blue
[4,5]
synthesis of libraries of complex heterocyclic scaffolds.
Especially attractive are sequences where the Ugi reaction and
the associated post-transformation could be accomplished in a
one-pot or cascade manner. In this regard, the use of propiolic
acids in combination with post-MCR triple bond functionalization
has emerged as one of the most productive and convenient
[a]
J. Huang, X. Du, O. P. Pereshivko, V. A. Peshkov
College of Chemistry, Chemical Engineering and Materials Science
Soochow University
Scheme 1. Post-Ugi intramolecular Diels-Alder reaction for the synthesis of
isoindolinones 5, 7 and 10.
Dushu Lake Campus, Suzhou, 215123, China
E-mails: olga@suda.edu.cn; vsevolod@suda.edu.cn
http://www.seb-group.org/
[b]
[c]
K. Van Hecke
In 2002, Wright and co-workers described a sequence towards
isoindolinones 5 that involved Ugi reaction followed by Yb(OTf)3-
catalyzed intramolecular Diels–Alder reaction of furan (IMDAF)
and subsequent oxo-bridge opening isomerization (Scheme 1a).
In that process, propiolic acid 2 and furfural 1 were used as
dienophile and diene source, respectively. In 2005, Fathi, Chen,
XStruct, Department of Inorganic and Physical Chemistry
Ghent University
Krijgslaan 281-S3, B-9000, Ghent, Belgium
E. V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry
University of Leuven (KU Leuven)
Celestijnenlaan 200F, 3001 Leuven, Belgium
E. V. Van der Eycken
Peoples Friendship University of Russia (RUDN University)
6 Miklukho-Maklaya street, Moscow, 117198, Russia
These authors contributed equally to this work.
[13]
Yang and coworkers developed
encompassing Ugi reaction, intramolecular Diels-Alder reaction
and oxidative aromatization to access arene-fused
a
one-pot approach
[d]
[#]
isoindolinones 7 (Scheme 1b). [14] In this case, the diene moiety
was introduced with (E)-3-arylacrylaldehydes 6, and the best
results in the sequence were obtained for the substrates bearing
an electron-rich 3-aryl group. In the above transformations, the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700747
European Journal of Organic Chemistry
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propiolic acid-originated fragments were exploited as
dienophiles, while in the process elaborated by Vachhani, Van
der Eycken and co-workers, phenyl propiolic acid was used as a
the whole Ugi/Diels-Alder/HCl-elimination sequence under one-
pot settings (Table 1, entry 8).
source of enyne whereas the dienophile was brought by the
[15]
propargylamine 8 (Scheme 1c).
access to benzo[f]isoindolones 10.
This strategy provided
Table 1. Optimization of the intramolecular Diels-Alder/HCl-elimination
cascade.[a]
Entry
Time, min
Solvent
Conversion
Yield
7a, %[b]
30
60
92
85
88
67
73
of
of 12a, %[b]
1
2
3
4
5
6
7
8
9
60
60
60
40
60
60
180
180
120
Toluene
DMF
DMF/H2O (4:1)
DMF/H2O (4:1)
DMF/H2O (1:1)
i-PrOH
i-PrOH
i-PrOH/H2O (4:1)
i-PrOH/H2O (4:1)
70
93
100
92
100
79
97
100
95
Results and Discussion
Inspired by these results, we designed an additional route for the
assembly of isoindoles of type 7 via a post-Ugi Diels-Alder/HCl
elimination
cascade
that
employs
(Z)-3-chloro-3-
arylacrylaldehydes 11 (diene source) and propiolic acids 2
(dienophile source, Scheme 2).
88
86
[a] The reaction were run at 115 °C on 0.25 mmol scale in 2 mL of solvent.
[b] The conversion of 12a and the yield of 7a were determined by NMR
using 3,4,5-trimethoxybenzaldehyde as internal standard.
Keeping these results in mind, we proceeded with exploring the
scope of our methodology (Table 2). We selected (Z)-3-chloro-3-
phenylacrylaldehyde (11a) to study the reaction with various
propiolic acids 2, amines 3, and isocyanides 4 (Table 2, entries
1-12). Propiolic and pentinoic acids 2a,b worked equally well
(Table 1, entries 1,5,9 and entries 2,6,10) while phenyl propiolic
acid 2c initially displayed some selectivity issues that were
successfully resolved after minor adjustments to the reaction
conditions (Table 1, entry 3). Supposedly the electron-rich
nature of 2c allows spontaneous oxidation to compete with the
HCl-elimination producing minor amounts of isoindolinone 7cʹ.
For the amine component, a range of aliphatic amines 3b-d and
aniline 3e was tested (Table 2, entries 4-8). The use of the bulky
tert-butyl amine (3c) led to only moderate efficiency despite that
the Ugi adducts 12e,f started to convert into final isoindolinones
7e,f already at room temperature (Table 2, entries 5 and 6).
Application of n-butyl isocyanide (4b) furnished isoindolinones
7i,j in up to 91% yield for the one-pot procedure (Table 2, entries
9 and 10). Aromatic isocyanides 4c,d yielded isoindolinones 7k,l
in up to 52% yield with the Ugi step being a limiting factor for the
overall efficiency (Table 2, entries 11 and 12). Next, we
evaluated the aldehyde substrate scope (Table 2, entries 13-22).
(Z)-3-Chloro-3-(4-fluorophenyl)acrylaldehyde (11b) and (Z)-3-
chloro-3-(4-(trifluoromethyl)phenyl)acrylaldehyde (11c) worked
well delivering a series of products 7m-q with the yields ranging
from 48% to 69% (Table 2, entries 13-17, one-pot settings)
highlighting the suitability of our method for the synthesis of
electron-deficient isoindolinones. Additionally, in one case we
could detect and isolate minor amounts of non-aromatized
isoindolinone 7pʹʹ (Table 2, entry 16, stepwise settings). The
Scheme 2. Post-Ugi Diels-Alder/HCl elimination cascade for the synthesis of
isoindolinones 7.
We have selected (Z)-3-chloro-3-phenylacrylaldehyde (11a), 2-
butynoic acid (2a), benzyl amine (3a), and tert-butyl isocyanide
(4a) to conduct the model synthesis. Attempting Ugi reaction
under the classical settings with the methanol as solvent led to
the formation of the unwanted acetal 13, while the desired Ugi
adduct 12a was obtained in only low yield of 15%. However,
when switching to isopropanol the Ugi adduct 12a could be
isolated in 69% yield (Scheme 1). Next, we have moved onto
optimizing
the
intramolecular
Diels-Alder/HCl-elimination
cascade (Table 1). Heating 12a at 115 °C in toluene for 60 min
resulted in 70% conversion and only 30% yield of 7a as was
determined by the NMR analysis (Table 1, entry 1). Therefore,
we decided to attempt the reaction in DMF hoping that a more
basic solvent may facilitate the HCl-elimination step. As
expected, the conversion of 12a and yield of 7a significantly
improved reaching 93% and 60%, respectively (Table 1, entry 2).
It is well known that the use of water as a (co-)solvent may
increase the rate and improve the outcome of the Diels-Alder
reactions.[16,17,18] Therefore, attempted several reactions in
DMF/H2O mixtures (Table 1, entries 3-5). The best result was
obtained for DMF/H2O (4:1) that in 1 h allowed achieving full
conversion of 12a yielding 7a in 92% (Table 1, entry 3). Finally,
we have investigated the reactions in isopropanol and an
isopropanol/H2O (4:1) mixture (Table 1, entries 6-9). The
reaction in isopropanol/H2O (4:1) could be accomplished in three
hours furnishing 7a in 88% yield, opening the way for conducting
electron-rich
(Z)-3-chloro-3-(4-methoxyphenyl)acrylaldehyde
(11d) initially gave poor results under the one-pot settings but
then showed some improvements when the reaction was
conducted in isopropanol/DMF/H2O (1.5:1.5:1) mixture (Table 2,
entries 18 and 19). The application of another electron-rich
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Table 2. The scope of the process.
Entry
11
2, R1
3, R2
4, R3
Product code
Yields[a]
12
7+7ʹʹ
7+7ʹ
stepwise from 12
one-pot[b]
1
2a, Me
3a, Bn
4a, t-Bu
a
69
83
89
71
2
3
11a
11a
2b, Et
2c, Ph
3a, Bn
3a, Bn
4a, t-Bu
4a, t-Bu
b
c
84
-
73
(32)[d]+(7)[d]
[c]
-
(43)[d]+(3)[d] (C)
52 (D)
59
40
4
5
11a
11a
2a, Me
2a, Me
3b, PMB
3c, t-Bu
4a, t-Bu
4a, t-Bu
d
e
63
81
-
[c]
-
[c]
6
7
8
9
10
11
12
11a
11a
11a
11a
11a
11a
11a
2b, Et
3c, t-Bu
3d, n-Bu
3e, Ph
3a, Bn
3a, Bn
3a, Bn
3a, Bn
4a, t-Bu
4a, t-Bu
4a, t-Bu
4b, n-Bu
4b, n-Bu
4c, p-Tol
4d, 2-naphtyl
f
-
-
44
59
61 (B)
91
78 (B)
52
2a, Me
2a, Me
2a, Me
2b, Et
2a, Me
2a, Me
g
h
i
j
k
l
77
62
82
75
95
94
-
81
68
[e]
-
52
43
39 (B)
[e]
13
2b, Me
3a, Bn
4a, t-Bu
m
-
-
62
14
15
11b
11b
2b, Et
2b, Et
3a, Bn
3a, Bn
4a, t-Bu
4b, n-Bu
n
o
64
-
80
-
68
69
[e]
16
17
18
2a, Me
2b, Et
2a, Me
3a, Bn
3a, Bn
3a, Bn
4a, t-Bu
4a, t-Bu
4a, t-Bu
p
q
r
68
58 (66)[d] +6 (10)[d]
48
[e]
11c
11d
11e
-
-
53 (B)
14[f] (B)
44 (D)
66
71
58
19[f] (B)
51 (D)
19
2a, Me
3a, Bn
4b, n-Bu
s
54
[c]
20
21
22
2a, Me
2b, Et
2a, Me
3a, Bn
3a, Bn
3a, Bn
4a, t-Bu
4a, t-Bu
4b, n-Bu
t
-
-
-
-
17 (21)[d]+9 (11)[d]
23 (26)[d]+(10)[d] (B)
92
[c]
u
v
-
[e]
-
[a] Isolated yields. [b] Conditions A were used unless otherwise stated. [c] The Ugi adduct could not be isolated as the spontaneous cyclization takes places. [d]
NMR yields are given in parenthesis. [e] Not attempted. [f] The formation of unidentified byproducts was observed.
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Figure 1. X-ray crystallographic molecular structures of compounds 7pʹʹ, 7t and 7tʹ, showing thermal displacement ellipsoids at the 50% probability level.
substrate
(Z)-3-chloro-3-(thiophen-3-yl)acrylaldehyde
(11e)
always led to the formation of two kinds of isoindolinone
products 7 and 7ʹ that resulted from following the standard Diels-
Alder/HCl-elimination and competing Diels-Alder/oxidation
pathways, respectively (Table 2, entries 20 and 21). In one case,
we were able to obtain both 7t and 7tʹ in pure form and to
perform their complete characterization (Table 2, entry 20).
Engaging (Z)-3-(4-bromophenyl)-3-chloroacrylaldehyde (11f) in
our process delivered isoindolinone 7v in high 92% yield (Table
2, entry 22) providing a handle for the late-stage one-pot
derivatizations of the isoindolinone core via Suzuki couplings
(Scheme 3).
Scheme 4. An attempt to employ propargylamine 8 as a dienophile source.
Adding Pd catalyst, base and an appropriate boronic acid 14 to
the reaction mixture containing isoindolinone 7v allowed to attain
a series of additionally decorated isoindolinones 15 with rather
good overall yields for this three-step one-pot process (Scheme
3).
The prepared isoindolinones
7a-w, 7tʹ and 15a-d were
characterized by H- and 13C-NMR spectroscopy, infra-red (IR)
spectroscopy and HRMS. In addition, the structures of 7pʹʹ, 7t
and 7tʹ were assured by single-crystal X-ray diffraction analysis
(Figure 1).[19]
1
Conclusions
In summary, we have elaborated an efficient Ugi/Diels-
Alder/HCl-elimination process for the rapid one-pot synthesis of
complex arene-fused isoindolinones from readily available (Z)-3-
chloro-3-arylacrylaldehydes, propiolic acids, amines and
isocyanides. Importantly, the developed protocol was found to
be suitable for the assembly of electron-deficient isoindolinones
rather than electron-rich making it complementary to the known
Ugi/Diels-Alder/oxidation process. In addition, it was found to be
compatible with a late-stage one-pot functionalization of title
compounds through Suzuki coupling
Scheme 3. Late-stage functionalization of isoindolinone core using Suzuki
coupling.
We have also evaluated propargylamine 8 as a dienophile
source. Unfortunately, the corresponding reaction failed as no
isoindolinone 17a was obtained (Scheme 4a). When both
propiolic acid- and propargylamine-derived triple bonds were
present, not unexpectedly only the propiolic acid-derived triple
bond reacted to give product 7w albeit in a low yield of 18%
(Scheme 4b).
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Procedure C: (Z)-3-Chloro-3-phenylacrylaldehyde 11a (100 mg, 0.6
mmol) was dissolved in isopropanol (2.25 mL) followed by the addition of
H2O (0.75 mL), benzylamine 3a (64 mg, 0.6 mmol), 3-phenylpropiolic
acid 2c (88 mg, 0.6 mmol) and tert-butyl isocyanide 4a (50 mg, 0.6
mmol). The reaction mixture was flashed with argon, sealed and stirred
at room temperature for 36 h. Upon completion of this time the reaction
mixture was heated at 115°C for 6 h. The resulting mixture was diluted
with EtOAc and concentrated with silica. Column chromatography with
petroleum ether/EtOAc (9:1) as eluent delivered the mixture of
isoindolinones 7c and 7c′.
Experimental Section
General Procedure for Ugi Reaction
(Z)-3-Chloro-3-arylacrylaldehyde 11 (1.2 mmol) was dissolved in
isopropanol (6.0 mL) followed by the addition of amine 3 (1.2 mmol),
propiolic acid 2 (1.2 mmol) and isocyanide 4 (1.2 mmol). The reaction
mixture was sealed and stirred at room temperature for 36 h. The
resulting mixture was diluted with EtOAc and concentrated with silica.
Column chromatography with petroleum ether/EtOAc (the ratio was
adjusted according to TLC) as eluent delivered Ugi adduct 12. Reacting
substrates 11a, 2a, 3a and 4a in methanol instead of isopropanol led to
the formation of acetal 13 as a major product, while the desired Ugi
adduct 12a was obtained in only low yield of 15%.
Procedure D: (Z)-3-Chloro-3-arylacrylaldehyde 11 (0.6 mmol) was
dissolved in isopropanol/DMF 1: 1 mixture (2.2 mL) followed by the
addition of H2O (0.75 mL), amine 3 (0.6 mmol), propiolic acid 2 (0.6
mmol) and isocyanide 4 (0.6 mmol). The reaction mixture was flashed
with argon, sealed and stirred at room temperature for 36 h. Upon
completion of this time the reaction mixture was heated at 115°C for 3 h
(6 h for the synthesis of 7c). The resulting mixture was diluted by EtOAc
and washed with H2O. The organic layer was dried with sodium sulfate
and concentrated with silica. Column chromatography with petroleum
ether/EtOAc (the ratio was adjusted according to TLC) as eluent
delivered isoindolinone 7.
General procedure for the post-Ugi Diels-Alder/HCl elimination
cascade
The Ugi adduct 12 (0.5 mmol) was dissolved in DMF (3.2 mL) followed
by addition of H2O (0.8 mL). The reaction mixture was flashed with argon,
sealed and stirred at 115°C for 1 h. The resulting mixture was diluted by
EtOAc and washed with H2O. The organic layer was dried with sodium
sulfate and concentrated with silica. Column chromatography with
petroleum ether/EtOAc (the ratio was adjusted according to TLC) as
eluent delivered desired isoindolinone 7. The product 7l was purified by
column chromatography with petroleum ether/DCM as eluent followed by
washing with Et2O. The product 7p was isolated using petroleum
ether/DCM/EtOAc (7:2:1) mixture as eluent. The mixed fractions
containing 7p and 7pʹʹ were subjected to big board preparative TLC with
petroleum ether/DCM/EtOAc (7:2:1) mixture as eluent to give pure 7pʹʹ.
2-Benzyl-N-(tert-butyl)-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7a). Yield: 89% (stepwise from 12a),
71% (one-pot, procedure A); pale yellow solid; mp 194-195°C ; 1H NMR
(400 MHz, CDCl3): δ 8.22-8.15 (m, 1H), 7.92-7.84 (m, 2H), 7.62-7.55 (m,
Hz, 2H), 7.41-7.26 (m, 5H), 5.54 (bs, 1H), 5.13 (d, J = 14.7 Hz, 1H), 4.82
(d, J = 0.8 Hz, 1H), 4.49 (d, J = 14.7 Hz, 1H), 3.15 (s, 3H), 1.17 (s, 9H);
13C NMR (100 MHz, CDCl3): δ 171.0, 167.5, 136.9, 136.8, 136.4, 135.1,
133.4, 129.2, 129.1, 128.8, 128.2, 127.8, 126.6, 125.3, 124.3, 119.8,
64.4, 51.6, 46.7, 28.5, 12.2; IR (ATR): 3266, 3066, 3033, 2965, 2922,
1688, 1653, 1551, 1393, 1254, 1221, 1196, 767, 707, 692 cm–1; HRMS
(ESI, [M+H]+) for C25H27N2O2+ calcd 387.2067; found 387.2068.
General procedures for the one-pot synthesis of isoindolinones 7
Procedure A: (Z)-3-Chloro-3-arylacrylaldehyde 11 (0.8 mmol) was
dissolved in isopropanol (4.0 mL) followed by the addition of amine 3 (0.8
mmol), propiolic acid 2 (0.8 mmol) and isocyanide 4 (0.8 mmol). The
reaction mixture was sealed and stirred at room temperature for 36 h.
Upon completion of this time H2O (1 mL) was added. The reaction
mixture was flashed with argon, sealed and stirred at 115°C for 3 h. The
resulting mixture was diluted with EtOAc and concentrated with silica.
Column chromatography with petroleum ether/EtOAc (the ratio was
adjusted according to TLC) as eluent delivered isoindolinone 7. Using
substrates 11a, 2c, 3a and 4a led to the formation of isoindolinones 7c
and 7c′ that were obtained as a mixture after the column chromatography.
Using substrates 11e, 2a, 3a and 4a, led to the formation of
isoindolinones 7t and 7t′ that were successfully separated by the column
chromatography.
2-Benzyl-N-(tert-butyl)-4-ethyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7b). Yield: 84% (stepwise from 12b),
73% (one-pot, procedure A); pale yellow solid; mp 181-182°C ; 1H NMR
(400 MHz, CDCl3): δ 8.30-8.21 (m, 1H), 7.93-7.84 (m, 2H), 7.63-7.54 (m,
2H), 7.42-7.26 (m, 5H), 5.47 (bs, 1H), 5.11 (d, J = 14.7 Hz, 1H), 4.81 (d,
J = 0.8 Hz, 1H), 4.50 (d, J = 14.7 Hz, 1H), 3.86 (dq, J = 12.9, 7.5 Hz, 1H),
3.71 (dq, J = 12.9, 7.5 Hz, 1H), 1.41 (t, J = 7.5 Hz, 3H), 1.16 (s, 9H); 13C
NMR (100 MHz, CDCl3): δ 170.6, 167.5, 143.2, 136.8, 136.5, 135.6,
132.3, 129.3, 129.2, 128.9, 128.2, 127.8, 126.6, 125.2, 123.6, 112.0,
64.5, 51.6, 46.8, 28.5, 19.4, 16.0; IR (ATR): 3275, 3071, 2965, 2932,
2905, 1676, 1658, 1551, 1397, 1251, 1220, 761, 701 cm–1; HRMS (ESI,
[M+H]+) for C26H29N2O2+ calcd 401.2224, found 401.2216.
2-Benzyl-N-(tert-butyl)-3-oxo-4-phenyl-2,3-dihydro-1H-
Procedure B: (Z)-3-Chloro-3-arylacrylaldehyde 11 (0.6 mmol) was
dissolved in isopropanol (2.25 mL) followed by the addition of amine 3
(0.6 mmol), propiolic acid 2 (0.6 mmol) and isocyanide 4 (0.6 mmol). The
reaction mixture was sealed and stirred at room temperature for 36 h.
Upon completion of this time H2O (0.75 mL) was added. The reaction
mixture was flashed with argon, sealed and stirred at 115°C for 3 h. The
resulting mixture was diluted with EtOAc and concentrated with silica.
Column chromatography with petroleum ether/EtOAc (the ratio was
adjusted according to TLC) as eluent delivered isoindolinone 7. The
product 7l was purified by column chromatography with petroleum
ether/DCM as eluent followed by washing with Et2O. Using substrates
11e, 2b, 3a and 4a, led to the formation of isoindolinones 7u and 7u′.
The major product 7u was isolated by the column chromatography.
benzo[f]isoindole-1-carboxamide (7c). Yield: 52% (one-pot, procedure
D); pale yellow solid; mp 193-196°C ; 1H NMR (400 MHz, CDCl3): δ 8.09
(s, 1H), 7.99-7.91 (m, 1H), 7.81-7.73 (m, 1H), 7.62-7.52 (m, 4H), 7.49-
7.41 (m, 3H), 7.37-7.26 (m, 5H), 5.49 (bs, 1H), 5.06 (d, J = 14.7 Hz, 1H),
4.86 (d, J = 0.8 Hz, 1H), 4.41 (d, J = 14.7 Hz, 1H), 1.19 (s, 9H); 13C NMR
(100 MHz, CDCl3): δ 169.2, 167.3, 139.9, 136.5, 136.4, 135.4, 135.3,
133.1, 130.5, 130.1, 129.1, 128.9, 128.5, 128.14, 128.07, 127.99, 127.93,
127.91, 127.8, 126.7, 124.1, 121.4, 64.2, 51.6, 46.7, 28.5; IR (ATR):
3334, 2974, 2915, 1686, 1671, 1509, 1454, 1394, 1361, 1248, 1212, 766,
+
752, 699 cm–1; HRMS (ESI, [M+H]+) for: C30H29N2O2 calcd 449.2224,
found 449.2222.
N-(tert-Butyl)-2-(4-methoxybenzyl)-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7d). Yield: 81% (stepwise from 12d),
59% (one-pot, procedure A); pale yellow solid; mp 183- 186°C ; 1H NMR
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10.1002/ejoc.201700747
European Journal of Organic Chemistry
FULL PAPER
(400 MHz, CDCl3): δ 8.24-8.15 (m, 1H), 7.93-7.84 (m, 2H), 7.63-7.55 (m,
2H), 7.30 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.52 (bs, 1H), 5.10
(d, J = 14.6 Hz, 1H), 4.80 (d, J = 0.8 Hz, 1H), 4.39 (d, J = 14.6 Hz, 1H),
3.78 (s, 3H), 3.16 (s, 3H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
170.9, 167.6, 159.6, 136.8, 136.4, 135.1, 133.4, 130.3, 129.1, 128.8,
127.8, 126.6, 125.3, 124.4, 119.8, 114.5, 64.2, 55.5, 51.6, 46.0, 28.5,
12.2; IR (ATR): 3273, 3070, 2969, 2926, 1682, 1655, 1550, 1514, 1453,
1396, 1362, 1293, 1241, 1218, 1178, 1047, 1026, 764 cm–1; HRMS (ESI,
[M+H]+) for C26H29N2O3+ calcd 417.2173, found 417.2161.
3.04 (s, 3H), 1.39-1.28 (m, 2H), 1.28-1.15 (m, 2H), 0.84 (t, J = 7.3 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 170.7, 168.4, 136.8, 136.3, 136.1,
135.0, 133.4, 129.1, 129.0, 128.7, 128.2, 127.9, 126.6, 125.2, 124.3,
120.1, 63.2, 46.1, 39.5, 31.4, 20.1, 13.8, 12.0; IR (ATR): 3291, 2956,
2924, 2871, 1689, 1654, 1547, 1449, 1391, 1238, 1198, 1015, 968, 886,
+
766, 750, 711, 696 cm–1; HRMS (ESI, [M+H]+) for C25H27N2O2 calcd
387.2067, found 387.2074.
2-Benzyl-N-butyl-4-ethyl-3-oxo-2,3-dihydro-1H-benzo[f]isoindole-1-
carboxamide (7j). Yield: 78% (one-pot, procedure B); pale yellow solid;
mp 206-208°C; 1H NMR (400 MHz, CDCl3): δ 8.24-8.16 (m, 1H), 7.92-
7.83 (m, 2H), 7.62-7.53 (m, 2H), 7.37-7.25 (m, 5H), 5.94 (t, J = 5.5 Hz,
1H), 5.32 (d, J = 14.7 Hz, 1H), 4.93 (d, J = 0.9 Hz, 1H), 4.34 (d, J = 14.7
Hz, 1H), 3.75 (dq, J = 12.9, 7.5 Hz, 1H), 3.63 (dq, J = 12.9, 7.5 Hz, 1H),
3.29-3.16 (m, 1H), 3.13-3.01 (m, 1H), 1.40-1.28 (m, 5H), 1.27-1.15 (m,
2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.2, 168.4,
143.1, 136.3, 136.2, 135.5, 132.2, 129.2, 129.1, 128.7, 128.1, 127.8,
126.6, 125.1, 123.6, 120.2, 63.1, 46.1, 39.5, 31.4, 20.1, 19.1, 15.9, 13.8;
IR (ATR): 3275, 2956, 2927, 2871, 1686, 1657, 1543, 1453, 1396, 1241,
N,2-di-tert-Butyl-4-methyl-3-oxo-2,3-dihydro-1H-benzo[f]isoindole-1-
carboxamide (7e). Yield: 40% (one-pot, procedure A); pale yellow solid;
mp 242-245°C ; 1H NMR (400 MHz, CDCl3): δ 8.25-8.17 (m, 1H), 7.94-
7.86 (m, 2H), 7.63-7.54 (m, 2H), 5.62 (bs, 1H), 5.10 (d, J = 0.7 Hz, 1H),
3.15 (s, 3H), 1.63 (s, 9H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
172.0, 169.8, 136.5, 136.1, 135.0, 133.4, 129.0, 127.6, 126.4, 125.6,
125.2, 119.1, 64.4, 56.4, 51.5, 28.5, 28.3, 11.9; IR (ATR): 3311, 2976,
2923, 2854, 1692, 1650, 1538, 1454, 1373, 1362, 1248, 1211, 1201, 883,
+
761, 739, 712, 672 cm–1; HRMS (ESI, [M+H]+) for C22H29N2O2 calcd
+
353.2224, found 353.2237.
1201, 766, 711, 695 cm–1; HRMS (ESI, [M+H]+) for C26H29N2O2 calcd
401.2224, found 401.2225.
N,2-di-tert-Butyl-4-ethyl-3-oxo-2,3-dihydro-1H-benzo[f]isoindole-1-
carboxamide (7f). Yield: 44% (one-pot, procedure A); white solid; mp
243-244°C; 1H NMR (400 MHz, CDCl3): δ 8.28-8.20(m, 1H), 7.95-7.86 (m,
2H), 7.61-7.53 (m, 2H), 5.62 (bs, 1H), 5.09 (d, J = 0.8 Hz, 1H), 3.85 (dq,
J = 12.9, 7.5 Hz, 1H), 3.64 (dq, J = 12.9, 7.5 Hz, 1H), 1.63 (s, 9H), 1.38 (t,
J = 7.5 Hz, 3H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.5, 169.9,
142.6, 136.7, 135.5, 132.3, 129.3, 127.5, 126.4, 125.1, 124.9, 119.3,
64.4, 56.4, 51.5, 28.5, 28.3, 19.1, 15.9; IR (ATR): 3309, 2976, 2923,
2-Benzyl-4-methyl-3-oxo-N-(p-tolyl)-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide. (7k). Yield: 81% (stepwise from 12k),
52% (one-pot, procedure A); pale yellow solid; mp 211-213°C ; 1H NMR
(400 MHz, CDCl3): δ 8.16 (bs, 1H), 8.01-7.91 (m, 2H), 7.90-7.81 (m, 1H),
7.62-7.48 (m, 2H), 7.43-7.25 (m, 7H), 7.07 (d, J = 8.3 Hz, 2H), 5.40 (d, J
= 14.8 Hz, 1H), 5.08 (s, 1H), 4.50 (d, J = 14.8 Hz, 1H), 2.78 (s, 3H), 2.28
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.8, 166.7, 137.1, 136.2, 135.6,
135.0, 134.9, 134.6, 133.4, 129.5, 129.3, 129.0, 128.8, 128.3, 128.0,
126.7, 125.2, 124.2, 120.3, 120.2, 64.0, 46.4, 21.0, 11.8; IR (ATR): 3060,
3034, 2922, 2855, 1688, 1655, 1607, 1541, 1514, 1410, 1249, 1203, 820,
760, 746, 701 cm–1; HRMS (ESI, [M+Na]+) for C28H24N2O2Na+ calcd
443.1730, found 443.1726.
2851, 1683, 1657, 1542, 1452, 1361, 1248, 1220, 766, 746, 671 cm–1
;
HRMS (ESI, [M+H]+) for C23H31N2O2+ calcd 367.2380, found 367.2393.
N-(tert-Butyl)-2-butyl-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7g). Yield: 75% (stepwise from 12g),
59% (one-pot, procedure A); pale yellow solid; mp 207-208°C ; 1H NMR
(400 MHz, CDCl3): δ 8.24-8.16 (m, 1H), 7.98-7.87 (m, 2H), 7.63-7.56 (m,
2H), 5.54 (bs, 1H), 4.98 (d, J = 0.8 Hz, 1H), 4.10-3.97 (m, 1H), 3.25-3.15
(m, 1H), 3.13 (s, 3H), 1.74-1.61 (m, 2H), 1.44-1.32 (m, 2H), 1.26 (s, 9H),
0.96 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.7, 168.0,
136.5, 136.3, 135.0, 133.4, 129.1, 127.7, 126.6, 125.3, 124.7, 119.7,
64.3, 51.8, 42.1, 30.1, 28.7, 20.4, 13.9, 12.1; IR (ATR): 3273, 2962, 2925,
2-Benzyl-4-methyl-N-(naphthalen-2-yl)-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7l). Yield: 68% (stepwise from 12l),
39% (one-pot, procedure B); brown solid; mp 251-253°C ; 1H NMR (400
MHz, CDCl3): δ 8.68 (bs, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.02 (s, 1H), 7.87
(t, J = 8.7 Hz, 2H), 7.79-7.70 (m, 3H), 7.61-7.55 (m, 1H), 7.55-7.26 (m,
9H), 5.47 (d, J = 14.8 Hz, 1H), 5.18 (s, 1H), 4.61 (d, J = 14.8 Hz, 1H),
2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 167.2, 137.1, 136.1,
135.6, 135.2, 135.0, 133.8, 133.3, 130.9, 129.3, 129.0, 128.9, 128.7,
128.4, 128.1, 127.9, 127.6, 126.7, 126.6, 125.3, 125.2, 124.2, 120.3,
120.1, 117.3, 64.3, 46.5, 11.6; IR (ATR): 3248, 3087, 3058, 2923, 2853,
1693, 1662, 1587, 1561, 1397, 1236, 863, 828, 762, 703 cm–1; HRMS
(ESI, [M+H]+) for C31H25N2O2+ calcd 457.1911, found 457.1900.
2873, 1680, 1653, 1552, 1457, 1393, 1365, 1255, 1221, 1200, 890, 767,
+
744, 711, 692 cm–1
;
HRMS (ESI, [M+H]+) for C22H29N2O2 calcd
353.2224, found 353.2235.
N-(tert-Butyl)-4-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7h). Yield: 95% (stepwise from 12h),
61% (one-pot, procedure B); pale yellow solid; mp 227-229°C ; 1H NMR
(400 MHz, CDCl3): δ 8.30-8.22 (m, 1H), 8.08 (s, 1H), 8.00-7.92 (m, 1H),
7.87-7.78 (m, 2H), 7.68-7.58 (m, 2H), 7.51-7.43 (m, 2H), 7.29-7.21 (m,
2-Benzyl-N-(tert-butyl)-7-fluoro-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamid (7m). Yield: 62% (one-pot, procedure
A); yellow solid; 1H NMR (400 MHz, CDCl3): δ 7.92-7.83 (m, 2H), 7.74
(dd, J = 11.0, 2.4 Hz, 1H), 7.41-7.26 (m, 6H), 5.58 (bs, 1H), 5.12 (d, J =
14.7 Hz, 1H), 4.81 (s, 1H), 4.49 (d, J = 14.7 Hz, 1H), 3.05 (s, 3H), 1.17 (s,
9H); 13C NMR (100 MHz, CDCl3): δ 170.6, 167.4, 161.1 (d, J = 247.5 Hz),
136.6, 135.9 (d, J = 6.0 Hz), 135.8 (d, J = 2.7 Hz), 134.5 (d, J = 8.5 Hz),
132.0, 131.3 (d, J = 9.0 Hz), 129.2, 128.8, 128.2, 125.2, 119.7, 118.2 (d,
J = 25.4 Hz), 108.9 (d, J = 21.6 Hz), 64.2, 51.7, 46.6, 28.5, 12.2; IR
(ATR): 3363, 3331, 2969, 2923, 1684, 1666, 1618, 1527, 1387, 1363,
1292, 1224, 1200, 1171, 967, 857, 817, 750, 696, 679, 668 cm–1; HRMS
(ESI, [M+H]+) for C25H26FN2O2+ calcd 405.1973, found 405.1974.
1H), 5.60 (d, J = 0.9 Hz, 1H), 5.46 (bs, 1H), 3.21 (s, 3H), 1.09 (s, 9H); 13
C
NMR (100 MHz, CDCl3): δ 169.1, 167.5, 138.2, 137.6, 135.4, 135.1,
133.5, 129.5, 129.1, 128.0, 126.7, 125.5, 125.3, 124.6, 120.7, 119.8,
64.7, 51.7, 28.4, 12.2; IR (ATR): 3356, 2967, 2922, 2852, 1690, 1669,
1600, 1528, 1497, 1456, 1355, 1295, 1220, 1199, 762, 753, 739, 687
+
cm–1; HRMS (ESI, [M+H]+) for C24H25N2O2 calcd 373.1911, found
373.1914.
2-Benzyl-N-butyl-4-methyl-3-oxo-2,3-dihydro-1H-benzo[f]isoindole-
1-carboxamide (7i). Yield: 94% (stepwise from 12i), 91% (one-pot,
procedure A); yellow solid; mp 217-219°C ; 1H NMR (400 MHz, CDCl3): δ
8.17-8.07 (m, 1H), 7.93-7.82 (m, 2H), 7.63-7.53 (m, 2H), 7.37-7.25 (m,
5H), 6.02 (bt, J = 5.4 Hz, 1H), 5.33 (d, J = 14.7 Hz, 1H), 4.94 (d, J = 0.8
Hz, 1H), 4.33 (d, J = 14.7 Hz, 1H), 3.29-3.16 (m, 1H), 3.15-3.05 (m, 1H),
2-Benzyl-N-(tert-butyl)-4-ethyl-7-fluoro-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7n). Yield: 80% (stepwise from 12n),
68% (one-pot, procedure A); yellow solid; mp 142-144°C ; 1H NMR (400
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10.1002/ejoc.201700747
European Journal of Organic Chemistry
FULL PAPER
MHz, CDCl3) δ 7.93-7.78 (m, 3H), 7.41-7.26 (m, 6H), 5.48 (bs, 1H), 5.10
(d, J = 14.7 Hz, 1H), 4.80 (s, 1H), 4.50 (d, J = 14.7 Hz, 1H), 3.79 (dq, J =
13.1, 7.5 Hz, 1H), 3.61 (dq, J = 13.1, 7.5 Hz, 1H), 1.39 (t, J = 7.5 Hz, 3H),
1.17 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 170.3, 167.4, 161.2 (d, J =
247.0 Hz), 142.4 (d, J = 6.0 Hz), 136.7, 136.0 (d, J = 2.6 Hz), 133.4 (d, J
= 8.5 Hz), 132.5, 131.6 (d, J = 9.0 Hz), 129.2, 128.9, 128.2, 124.5, 119.9,
118.2 (d, J = 25.5 Hz), 108.8 (d, J = 21.7 Hz), 64.4, 51.7, 46.8, 28.5, 19.5,
15.7; IR (ATR): 3277, 2968, 2925, 1669, 1656, 1619, 1543, 1516, 1456,
1396, 1363, 1222, 1173, 1080, 886, 816, 750, 700 cm–1; HRMS (ESI,
[M+Na]+) for C26H27FN2O2Na+ calcd 441.1949, found 441.1962.
28.5, 19.3, 16.1; IR (ATR): 3309, 3272, 3070, 2970, 2932, 2877, 1681,
1656, 1552, 1454, 1330, 1301, 1219, 1164, 1123, 1072, 886, 701 cm–1
;
HRMS (ESI, [M+H]+) for C27H28F3N2O2+ calcd 469.2097, found 469.2082.
2-Benzyl-N-(tert-butyl)-7-methoxy-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7r). Yield: 58% (stepwise from 12r),
14% (one-pot, procedure B), 44% (one-pot, procedure D); pale yellow
solid; mp 176-178°C ; 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.78 (d,
J = 9.0 Hz, 1H), 7.41-7.23 (m, 7H), 5.52 (bs, 1H), 5.12 (d, J = 14.7 Hz,
1H), 4.79 (d, J = 0.8 Hz, 1H), 4.48 (d, J = 14.7 Hz, 1H), 3.96 (s, 3H), 3.09
(s, 3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.0, 167.7, 158.2,
136.8, 134.9, 134.6, 134.4, 130.5, 130.4, 129.2, 128.8, 128.1, 124.8,
120.5, 119.5, 103.4, 64.3, 55.4, 51.6, 46.5, 28.5, 12.2; IR (ATR): 3318,
2-Benzyl-N-butyl-4-ethyl-7-fluoro-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7o). Yield: 69% (one-pot, procedure
A); pale yellow solid; mp 200-203°C ; 1H NMR (400 MHz, CDCl3): δ 7.89
(s, 1H), 7.86 (dd, J = 9.1, 5.9 Hz, 1H), 7.77 (dd, J = 11.2, 2.2 Hz, 1H),
7.40-7.26 (m, 6H), 5.96 (bt, J = 5.4 Hz, 1H), 5.31 (d, J = 14.7 Hz, 1H),
4.92 (s, 1H), 4.34 (d, J = 14.7 Hz, 1H), 3.68 (dq, J = 13.1, 7.5 Hz, 1H),
3.52 (dq, J = 13.1, 7.5 Hz, 1H), 3.30-3.17 (m, 1H), 3.14-3.01 (m, 1H),
1.38-1.16 (m, 7H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
169.9, 168.3, 161.2 (d, J = 247.1 Hz), 142.1 (d, J = 6.0 Hz), 136.2, 135.7
(d, J = 2.5 Hz), 133.2 (d, J = 8.6 Hz), 132.4, 131.5 (d, J = 9.0 Hz), 129.1,
128.6, 128.2, 124.5, 120.2, 118.2 (d, J = 25.5 Hz), 108.6 (d, J = 21.7 Hz),
63.0, 46.1, 39.6, 31.4, 20.1, 19.1, 15.5, 13.7; IR (ATR): 3285, 2954, 2925,
2871, 1687, 1652, 1618, 1553, 1514, 1457, 1387, 1225, 1172, 1080, 985,
2969, 2921, 1671, 1616, 1531, 1425, 1391, 1297, 1233, 1193, 1174,
+
1021, 698, 678 cm–1
;
HRMS (ESI, [M+H]+) for C26H29N2O3 calcd
417.2173, found 417.2161.
2-Benzyl-N-butyl-7-methoxy-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7s). Yield: 54% (stepwise from 12s),
19% (one-pot, procedure B), 51% (one-pot, procedure D); pale yellow
solid; mp 203-206°C ; 1H NMR (400 MHz, CDCl3): δ 7.82 (s, 1H), 7.77 (d,
J = 9.0 Hz, 1H), 7.37-7.21 (m, 7H), 6.07 (t, J = 5.3 Hz, 1H), 5.33 (d, J =
14.7 Hz, 1H), 4.91 (s, 1H), 4.33 (d, J = 14.7 Hz, 1H), 3.92 (s, 3H), 3.30-
3.18 (m, 1H), 3.16-3.02 (m, 1H), 2.92 (s, 3H), 1.39-1.17 (m, 4H), 0.84 (t,
J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.7, 168.6, 158.2,
136.4, 134.9, 134.6, 134.2, 130.43, 130.42, 129.1, 128.7, 128.2, 124.7,
120.6, 119.8, 103.3, 63.1, 55.4, 46.1, 39.5, 31.5, 20.2, 13.8, 11.9; IR
(ATR): 3288, 2962, 2926, 2872, 1688, 1652, 1617, 1542, 1427, 1396,
+
884, 860, 812, 720, 698 cm–1; HRMS (ESI, [M+H]+) for C26H28FN2O2
calcd 419.2129, found 419.2135.
2-Benzyl-N-(tert-butyl)-4-methyl-3-oxo-7-(trifluoromethyl)-2,3-
dihydro-1H-benzo[f]isoindole-1-carboxamide
(7p).
Yield: 58%
1230, 1175, 1015, 838, 710, 694 cm–1
;
HRMS (ESI, [M+H]+) for
(stepwise from 12p), 48% (one-pot, procedure A); pale yellow solid; mp
154-157°C ; 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 7.99 (d, J = 8.6
Hz, 1H), 7.96 (s, 1H), 7.75 (dd, J = 8.6, 1.4 Hz, 1H), 7.41-7.28 (m, 5H),
5.51 (bs, 1H), 5.11 (d, J = 14.7 Hz, 1H), 4.84 (s, 1H), 4.51 (d, J = 14.7 Hz,
1H), 3.21 (s, 3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3): 170.4, 167.0,
138.6, 137.9, 136.5, 136.3, 132.5, 130.2, 129.3, 128.9, 128.5 (q, J = 32.2
Hz), 128.3, 125.6, 124.4 (q, J = 272.3 Hz), 123.4 (q, J = 3.0 Hz), 123.0 (q,
J = 4.6 Hz), 119.8, 64.4, 51.8, 46.8, 28.5, 12.2; IR (ATR): 3350, 3287,
2967, 2925, 2856, 1685, 1658, 1539, 1455, 1327, 1302, 1220, 1170,
1116, 1066, 893, 699 cm–1; HRMS (ESI, [M+H]+) for C26H26F3N2O2+ calcd
455.1941, found 455.1929.
C26H29N2O3+ calcd 417.2173, found 417.2182.
6-Benzyl-N-(tert-butyl)-4-methyl-5-oxo-6,7-dihydro-5H-thieno[2,3-
f]isoindole-7-carboxamide (7t). Yield: 17% (one-pot, procedure A);
yellow solid; mp 194-197°C ; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H),
7.53 (d, J = 5.7 Hz, 1H), 7.52 (d, J = 5.7 Hz, 1H), 7.39-7.26 (m, 5H), 5.53
(bs, 1H), 5.08 (d, J = 14.8 Hz, 1H), 4.76 (d, J = 0.7 Hz, 1H), 4.47 (d, J =
14.8 Hz, 1H), 3.03 (s, 3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
170.9, 167.3, 143.6, 140.6, 137.4, 136.8, 133.6, 129.2, 128.7, 128.1,
127.4, 123.5, 122.3, 114.2, 64.4, 51.6, 46.5, 28.5, 13.9; IR (ATR): 3299,
2960, 2917, 2852, 1682, 1657, 1605, 1529, 1439, 1402, 1247, 1211,
1169, 1024, 757, 724, 694, 672 cm–1
;
HRMS (ESI, [M+H]+) for
(±)-(1S,9S,9aS)-2-Benzyl-N-(tert-butyl)-9-chloro-4-methyl-3-oxo-6-
(trifluoromethyl)-2,3,9,9a-tetrahydro-1H-benzo[f]isoindole-1-
carboxamide (7pʹʹ). Yield: 6% (stepwise from 12p); white solid; 1H NMR
(400 MHz, CDCl3): δ 7.85 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J =
8.1 Hz, 1H), 7.42-7.24 (m, 5H), 5.49 (s, 1H), 5.38 (d, J = 15.0 Hz, 1H),
4.96 (d, J = 14.7 Hz, 1H), 3.85 (d, J = 15.1 Hz, 1H), 3.52 (d, J = 6.0 Hz,
1H), 3.47-3.34 (m, 1H), 2.67 (d, J = 2.6 Hz, 3H), 1.37 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 167.6, 166.9, 138.2, 137.7, 136.7, 135.9, 131.3 (q, J
= 32.7 Hz), 129.0, 128.8, 128.1, 127.3, 126.9, 126.1 (q, J = 3.7 Hz),
123.9 (q, J = 272.5 Hz), 122.3 (q, J = 3.6 Hz), 64.2, 62.2, 52.2, 45.3, 44.9,
28.6, 12.7; HRMS (ESI, [M+H]+) for C27H26ClF3NO2 cacld 491.1706,
found 491.1716.
C23H25N2O2S+ calcd 393.1631, found 393.1644.
6-Benzyl-N-(tert-butyl)-8-methyl-5-oxo-6,7-dihydro-5H-thieno[2,3-
f]isoindole-7-carboxamide (7t′). Yield: 9% (one-pot, procedure A);
yellow solid, mp 194-197°C; 1H NMR (400 MHz, CDCl3): δ 7.59 (d, J =
5.6 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.38-7.26 (m, 5H), 5.42 (d, J = 15.0
Hz, 1H), 5.38 (bs, 1H), 4.67 (s, 1H), 4.09 (d, J = 15.0 Hz, 1H), 3.05 (s,
3H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 168.7, 165.1, 142.46,
142.39, 136.6, 133.5, 132.6, 129.0, 128.8, 128.2, 128.0, 127.3, 123.6,
120.2, 63.2, 52.3, 45.0, 28.6, 13.8; IR (ATR): 3324, 3076, 2967, 2920,
1698, 1680, 1659, 1555, 1541, 1439, 1398, 1360, 1331, 1247, 1224,
1000, 755, 730, 694 cm–1; HRMS (ESI, [M+H]+) for C23H23ClN2O2SNa+
calcd 449.1061, found 449.1050.
2-Benzyl-N-(tert-butyl)-4-ethyl-3-oxo-7-(trifluoromethyl)-2,3-dihydro-
1H-benzo[f]isoindole-1-carboxamide (7q). Yield: 53% (one-pot,
procedure B); white solid; mp 158-160°C ; 1H NMR (400 MHz, CDCl3): δ
8.53 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.74 (dd, J = 8.6, 1.2
Hz, 1H), 7.42-7.28 (m, 5H), 5.45 (bs, 1H), 5.10 (d, J = 14.7 Hz, 1H), 4.84
(s, 1H), 4.53 (d, J = 14.7 Hz, 1H), 3.90 (dq, J = 13.1, 7.5 Hz, 1H), 3.74
(dq, J = 13.1, 7.4 Hz, 1H), 1.42 (t, J = 7.5 Hz, 3H), 1.16 (s, 9H); 13C NMR
(100 MHz, CDCl3): 169.9, 167.0, 144.2, 138.8, 136.8, 136.6, 131.3, 130.4,
129.3, 128.9, 128.5 (q, J = 32.3 Hz), 128.3, 124.9, 124.4 (q, J = 272.3
Hz), 123.3 (q, J = 2.9 Hz), 122.8 (q, J = 4.5 Hz), 119.9, 64.5, 51.7, 46.8,
6-Benzyl-N-(tert-butyl)-4-ethyl-5-oxo-6,7-dihydro-5H-thieno[2,3-
f]isoindole-7-carboxamide (7u). Yield: 23% (one-pot, procedure B);
yellow solid; mp 162-165°C ; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H),
7.57 (d, J = 5.6 Hz, 1H), 7.53 (d, J = 5.6 Hz, 1H), 7.39-7.26 (m, 5H), 5.47
(bs, 1H), 5.07 (d, J = 14.8 Hz, 1H), 4.75 (s, 1H), 4.47 (d, J = 14.7 Hz, 1H),
3.66 (dq, J = 12.7, 7.5 Hz, 1H), 3.51 (dq, J = 12.7, 7.5 Hz, 1H), 1.39 (t, J
= 7.5 Hz, 3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 170.5, 167.3,
144.0, 140.2, 139.8, 137.5, 136.8, 129.1, 128.7, 128.1, 127.4, 122.7,
122.1, 114.3, 64.4, 51.6, 46.6, 28.5, 21.5, 15.8; IR (ATR): 3262, 3069,
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10.1002/ejoc.201700747
European Journal of Organic Chemistry
FULL PAPER
2961, 2926, 2872, 1680, 1656, 1552, 1455, 1436, 1399, 1362, 1246,
1221, 1176, 752, 698 cm–1; HRMS (ESI, [M+H]+) for C24H27N2O2S+ calcd
407.1788, found 407.1786.
mp 272-275°C; 1H NMR (400 MHz, CDCl3): δ 8.31 (s, 1H), 8.05 (d, J =
8.2 Hz, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.85 (dd, J = 8.5, 1.2
Hz, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.40-7.26 (m, 5H), 6.11 (bt, J = 5.6 Hz,
1H), 5.34 (d, J = 14.7 Hz, 1H), 4.96 (s, 1H), 4.36 (d, J = 14.7 Hz, 1H),
3.31-3.18 (m, 1H), 3.18-3.03 (m, 4H), 2.66 (s, 3H), 1.41-1.17 (m, 4H),
0.85 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 197.8, 170.5,
168.3, 145.3, 137.9, 137.1, 136.7, 136.23, 136.20, 134.6, 133.5, 129.9,
129.18, 129.15, 128.7, 128.3, 127.6, 127.2, 125.0, 123.6, 119.9, 63.2,
46.2, 39.6, 31.5, 26.8, 20.1, 13.8, 12.1; IR (ATR): 3306, 2962, 2923,
2867, 1690, 1676, 1653, 1603, 1545, 1390, 1357, 1270, 1224, 1183, 967,
885, 838, 807, 714, 697 cm–1; HRMS (ESI, [M+Na]+) for C33H32N2O3Na+
calcd 527.2305, found 527.2298.
2-Benzyl-7-bromo-N-butyl-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7v). Yield: 92% (one-pot, procedure
A); yellow solid; mp 215-218°C ; 1H NMR (400 MHz, CDCl3): δ 8.22 (s,
1H), 7.86 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.64 (dd, J = 8.7, 1.3 Hz, 1H),
7.38-7.26 (m, 5H), 6.19 (t, J = 5.1 Hz, 1H), 5.32 (d, J = 14.7 Hz, 1H), 4.91
(s, 1H), 4.33 (d, J = 14.7 Hz, 1H), 3.29-3.18 (m, 1H), 3.17-3.04 (m, 1H),
2.93 (s, 3H), 1.40-1.16 (m, 4H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 170.3, 168.1, 136.6, 136.1, 135.9, 134.6, 133.4, 131.3,
130.5, 129.2, 128.7, 128.3, 127.6, 125.2, 121.1, 120.1, 63.1, 46.2, 39.6,
31.4, 20.1, 13.8, 12.0; IR (ATR): 3278, 2961, 2922, 2859, 1687, 1656,
2-Benzyl-N-butyl-7-(3,5-dimethylisoxazol-4-yl)-4-methyl-3-oxo-2,3-
dihydro-1H-benzo[f]isoindole-1-carboxamide (15c). Yield: 61%;
yellow solid; mp 199-202°C; 1H NMR (400 MHz, CDCl3): δ 8.02-7.98 (m,
1H), 7.97-7.90 (m, 2H), 7.51-7.45 (m, 1H), 7.35 - 7.26 (m, 5H), 6.29 (bt, J
= 5.7 Hz, 1H), 5.34 (d, J = 14.7 Hz, 1H), 4.95 (s, 1H), 4.33 (d, J = 14.8 Hz,
1H), 3.31-3.19 (m, 1H), 3.18-3.02 (m, 4H), 2.44 (s, 3H), 2.29 (s, 3H),
1.41-1.31 (m, 2H), 1.29-1.18 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 170.4, 168.2, 165.7, 158.7, 136.6, 136.4, 136.2,
134.0, 133.4, 129.6, 129.1, 128.7 (two merged signals), 128.6, 128.2,
125.3, 125.1, 120.0, 116.7, 63.0, 46.1, 39.5, 31.4, 20.1, 13.7, 12.1, 11.7,
11.0; IR (ATR): 3277, 2960, 2926, 2872, 1689, 1655, 1544, 1421, 1396,
1238, 1030, 885, 699 cm–1; HRMS (ESI, [M+Na]+) for C30H31N3O3Na+
calcd 504.2258, found 504.2241.
1557, 1395, 1237, 884, 739, 696 cm–1 HRMS (ESI, [M+H]+) for
;
C25H25BrN2O2Na+ calcd 487.0992, found 487.0980.
N-Butyl-4-methyl-3-oxo-2-(prop-2-yn-1-yl)-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (7w). Yield: 18% (one-pot, procedure
B); yellow solid; mp 178-180°C; 1H NMR (400 MHz, CDCl3): δ 8.17-8.09
(m, 1H), 7.98 (s, 1H), 7.94-7.85 (m, 1H), 7.66-7.54 (m, 2H), 6.20 (bt, J =
5.2 Hz, 1H), 5.26 (s, 1H), 4.74 (dd, J = 17.6, 2.0 Hz, 1H), 4.17 (dd, J =
17.6, 2.0 Hz, 1H), 3.40-3.24 (m, 1H), 3.21-3.07 (m, 1H), 3.00 (s, 3H),
2.33 (t, J = 2.1 Hz, 1H), 1.48-1.36 (m, 2H), 1.31-1.20 (m, 2H), 0.85 (t, J =
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.4, 168.3, 137.0, 136.0,
135.1, 133.3, 129.1, 128.0, 126.7, 125.3, 123.8, 120.2, 77.5, 73.6, 63.2,
39.6, 32.0, 31.4, 20.1, 13.8, 12.0; HRMS (ESI, [M+Na]+) for
C21H22N2O2Na+ calcd 357.1573, found 357.1572.
2-Benzyl-N-butyl-4-methyl-3-oxo-7-(pyrimidin-5-yl)-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (15d). Yield: 66%; pale yellow solid;
mp 278-279°C; 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 9.06 (s, 2H),
8.32 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.97 (s, 1H), 7.80 (dd, J = 8.5, 1.5
Hz, 1H), 7.40-7.27 (m, 5H), 5.92 (bt, J = 5.8 Hz, 1H), 5.32 (d, J = 14.7 Hz,
1H), 4.97 (s, 1H), 4.37 (d, J = 14.7 Hz, 1H), 3.28-3.05 (m, 5H), 1.38-1.15
(m, 4H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.3,
168.1, 157.9, 155.2, 137.3, 137.1, 136.2, 134.8, 134.1, 133.6, 132.4,
130.6, 129.2, 128.8, 128.3, 126.3, 125.4, 123.6, 120.1, 63.2, 46.3, 39.6,
31.4, 20.1, 13.8, 12.1; IR (ATR): 3270, 3062, 3032, 2960, 2928, 2870,
1683, 1652, 1547, 1412, 1352, 1231, 807, 720, 700, 638 cm–1; HRMS
(ESI, [M+Na]+) for C29H28N4O2Na+ calcd 487.2104, found 487.2093.
General Procedure for the three-step one-pot synthesis of
isoindolinones 15
(Z)-3-(4-Bromophenyl)-3-chloroacrylaldehyde 11f (123 mg, 0.5 mmol)
was dissolved in isopropanol (2.5 mL) followed by the addition of
benzylamine 3a (54 mg, 0.6 mmol), but-2-ynoic acid 2a (42 mg, 0.6
mmol) and n-butyl isocyanide 4b (42 mg, 0.6 mmol). The reaction
mixture was sealed and stirred at room temperature for 36 h. Upon
completion of this time H2O (0.6 mL) was added. The reaction mixture
was flashed with argon, sealed and stirred at 115°C for 3 h. Upon
completion of this time the reaction mixture was cooled down followed by
addition of boronic acid 14 (0.75 mmol), Pd(PPh3)2Cl2 (11 mg, 0.015
mmol) and K2CO3 (207 mg, 1.5 mmol). The reaction mixture was flashed
with argon, sealed and stirred at 115°C for another 1.5 h. The resulting
mixture was diluted with DCM and washed with H2O. The organic layer
was dried with sodium sulfate and concentrated with silica. Column
chromatography with DCM/EtOAc (the ratio was adjusted according to
TLC) as eluent delivered isoindolinone 15.
Acknowledgements
This work was supported by the start-up fund from Soochow
University (grant Q410900714), National Natural Science
Foundation of China (grant 21650110445), Natural Science
Foundation of Jiangsu Province of China (grant BK20160310)
and the Priority Academic Program Development of Jiangsu
Higher Education Institutions (PAPD). K.V.H. thanks the
Hercules Foundation (project AUGE/11/029 ‘3D-SPACE: 3D
Structural Platform Aiming for Chemical Excellence’) and the
Research Foundation - Flanders (FWO) for funding. E.V.V.d.E.
acknowledges the financial support from The Ministry of
Education and Science of the Russian Federation (the
Agreement number 02.a03.0008).
2-Benzyl-N-butyl-4-methyl-3-oxo-7-phenyl-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (15a). Yield: 61%; pale yellow solid;
mp 257-259°C; 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.99-7.89 (m,
2H), 7.88-7.80 (m, 1H), 7.74-7.65 (m, 2H), 7.54-7.45 (m, 2H), 7.44-7.26
(m, 6H), 5.98 (bt, J = 5.4 Hz, 1H), 5.33 (d, J = 14.7 Hz, 1H), 4.96 (s, 1H),
4.35 (d, J = 14.7 Hz, 1H), 3.29-3.03 (m, 5H), 1.39-1.15 (m, 4H), 0.84 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 170.6, 168.4, 140.8, 139.4,
136.9, 136.3, 136.2, 134.1, 133.6, 129.5, 129.1, 129.0, 128.7, 128.2,
127.8, 127.61, 127.57, 124.8, 123.0, 119.9, 63.2, 46.1, 39.6, 31.5, 20.1,
13.8, 12.1; IR (ATR): 3300, 2961, 2924, 2874, 1690, 1655, 1546, 1450,
1390, 1234, 1184, 887, 754, 697 cm–1; HRMS (ESI, [M+Na]+) for
C31H30N2O2Na+ calcd 485.2199, found 485.2188.
Keywords: Multicomponent reactions • Cycloaddition • Domino
reactions • Ugi reaction • Diels-Alder reaction
7-(4-Acetylphenyl)-2-benzyl-N-butyl-4-methyl-3-oxo-2,3-dihydro-1H-
benzo[f]isoindole-1-carboxamide (15b). Yield: 59%; pale yellow solid;
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700747
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
One-pot synthesis
Jianjun Huang, Xiaochen Du, Kristof
Van Hecke, Erik V. Van der Eycken,
Olga P. Pereshivko, * Vsevolod A.
Peshkov*
Page No. – Page No.
A one-pot procedure involving a four-component Ugi reaction followed by an
intramolecular Diels-Alder/HCl-elimination cascade has been developed to provide
rapid access to the isoindolinone framework in a diversity-oriented fashion.
Ugi Reaction Followed by the
Intramolecular Diels-Alder and HCl-
Elimination: a One-Pot Approach
towards Arene-Fused Isoindolinones
This article is protected by copyright. All rights reserved.