Sc(OTf)3-catalyzed three-component cascade reaction: One-pot synthesis of substituted 3-oxoisoindoline-1-carbonitrile derivatives

Article abstract of DOI:10.1016/j.catcom.2015.11.011

A facile and efficient approach for the synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile derivatives has been developed, with a Sc(OTf)₃-catalyzed three-component Strecker/Lactamization cascade reaction involving methyl 2-formylbenzoate, TMSCN and amines in ethanol at room temperature. Good to excellent yields for a broad scope of amine substrates were achieved.

Full text of DOI:10.1016/j.catcom.2015.11.011

Catalysis Communications 74 (2016) 119–121
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Catalysis Communications
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Short communication
Sc(OTf)3-catalyzed three-component cascade reaction: One-pot
synthesis of substituted 3-oxoisoindoline-1-carbonitrile derivatives
⁎
Tingting Chen, Chun Cai
Chemical Engineering College, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing 210094, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient approach for the synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile derivatives has
been developed, with a Sc(OTf)3-catalyzed three-component Strecker/Lactamization cascade reaction involving
methyl 2-formylbenzoate, TMSCN and amines in ethanol at room temperature. Good to excellent yields for a
broad scope of amine substrates were achieved.
Received 21 September 2015
Received in revised form 10 November 2015
Accepted 13 November 2015
Available online 15 November 2015
© 2015 Published by Elsevier B.V.
Keywords:
Isoindolinones
Cascade reaction
Amines
Sc(OTf)3
1. Introduction
such as the intramolecular reactions that form the nitrogen heterocycles
in the presence of a neighboring reactive site [31].
Isoindolinone derivatives are important building blocks for the
synthesis of a variety of natural products [1–3]. Due to their biological
properties, such as antihypertensive [4], antipsychotic [5], anxiolytic
[6], anticonvulsant [7], antiviral [8] and antileukemic [9] activities,
isoindolinone derivatives extensively exist in the core structures of
many commercial drugs (Fig. 1). Owing to the significant importance
of this structural motif, the development of efficient routes for the syn-
thesis of the isoindolinone derivatives is highly valuable. Conventional
approaches for the synthesis of isoindolinone derivatives are usually
unsatisfactory because of the requirement of harsh reaction conditions,
complex starting materials and multistep synthesis [10–15]. In recent
years, attribute to their ability to generate diverse and complex targets
in fewer steps from readily available starting materials, multicompo-
nent reactions (MCRs) have attracted extensive attention and emerged
as powerful tools for the synthesis of complex compounds [16–17], like
the construction of isoindolinone skeletons [18–25].
The Strecker reaction is regarded as one of the first multicomponent
reactions and has been widely employed in the synthesis of α-
aminonitrile by the condensation of aldehyde, amine and hydrogen cy-
anide [26–27]. Bifunctional α-aminonitrile compounds are versatile
intermediates in a number of synthetic applications [28]. The cyano
group can be transformed into primary amine [29], aldehyde [30] or
carboxylic acid [26]. On the other hand, the amine function is nucleo-
philic and can undergo well-known reactions with electrophilic agents,
The Strecker reaction has been applied to the multicomponent
synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile derivatives
using 2-carbonyl benzaldehyde as the neighboring functionalized
substrate. The Baum group first employed this method by reacting
potassium cyanide with the 2-carbomethoxybenzylideneanilines in
refluxing ethanol using equivalent acetic acid as the catalyst [18]. Subse-
quently, the Opatz group reported a similar route using methylamine
hydrochloride as the substrate [32]. Both of these methods exhibited
several shortages, such as the use of toxic cyanides and unsatisfied
yields. Then Hu and co-workers developed a safer method for the
synthesis of the isoindolinone derivatives utilizing trimethylsilyl cya-
nide (TMSCN) as the cyano source under acidic medium [33]. Though
the yields have been improved, high temperature is still required in
this protocol. And the substrates are limited to the benzyl and aliphatic
amines. Recently, Bunce reported a mild and green approach for the
synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile derivatives
employing 5 mol% OSU-6, a MCM-41 type hexagonal mesoporous silica
with high Lewis acid, as the catalyst. Both benzyl and aliphatic amines
were suitable substrates and resulted in good to excellent yields at
room temperature. However, aniline substrates failed to give the
expected isoindolinones [24]. Thus, a more efficient method to facilitate
the synthesis of N-substituted 3-oxoisoindoline-1-carbonitrile deriva-
tives is still needed.
Herein, we reported an improved Sc(OTf)3-catalyzed three-
component cascade reaction for one-pot synthesis of N-substituted
3-oxoisoindoline-1-carbonitrile derivatives from methyl 2-
formylbenzoate, TMSCN and amines in ethanol at room temperature
(Scheme 1).
⁎
Corresponding author.
E-mail address: c.cai@njust.edu.cn (C. Cai).
http://dx.doi.org/10.1016/j.catcom.2015.11.011
1566-7367/© 2015 Published by Elsevier B.V.

120
T. Chen, C. Cai / Catalysis Communications 74 (2016) 119–121
Table 1
Optimization of the reaction conditionsa.
Entry
Catalyst (mol %)
Solvent
t (h)
Yield (%)b
1
2
3
4
5
6
7
8
/
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
THF
4
4
4
4
4
4
4
4
4
4
7
7
7
7
7
7
7
7
48
Trace
95
21
25
Trace
30
Trace
91
76
37
89
43
18
65
85
94
57
50
32
Sc(OTf)3 (10)
Zn(OAc)2 (10)
Zn(OTf)2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
NiCl2 (10)
Sc(OTf)3 (7.5)
Sc(OTf)3 (5.0)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (1.0)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
Sc(OTf)3 (2.5)
9
10
11
12
13
14
15
16
17
18
19c
Fig. 1. Examples of biologically isoindolinone derivatives.
MeOH
EtOH
1,4-Dioxane
DMF
2. Experimental
2.1. General
EtOH
All reagents were purchased from commercial sources and used
without treatment. All known compounds were identified by appropri-
ate technique such as 1H NMR, 13C NMR and compared with previously
reported data. The products were purified by column chromatography
over silica gel (100–200 mesh). 1H NMR and 13C NMR spectra were
recorded on a Bruker AVANCE III 500 (500 MHz and 125 MHz)
spectrometer, and tetramethylsilane (TMS) was used as a reference.
a
Reaction conditions: methyl 2-formylbenzoate (0.5 mmol), aniline (0.5 mmol),
TMSCN (1 mmol), catalyst and solvent (1 mL) were stirred at room temperature.
b
Isolated yield.
c
2-Formylbenzoic acid was utilized as the starting material.
entries 11, 13–18), such as MeCN, CH2Cl2, MeOH, THF, 1,4-dioxane
and DMF. At last, in contrast to methyl 2-formylbenzoate, a cheaper
starting material, 2-formylbenzoic acid was utilized and resulted in a
lower yield (32% vs. 94%), even the reaction time prolonged to 48 h
(Table 1, entries 16 vs. 19).
2.2. General procedure to prepare N-substituted 3-oxoisoindoline-1-
carbonitrile derivatives
After the establishment of the optimal reaction conditions, a
broad range of amines were applied to define the substrate scope
(Table 2). Initially, various anilines were evaluated. In the previous
work reported by Bunce, anilines failed to give the expected
isoindolinones, but instead, gave the isobenzofuranone derivatives
[24]. Gratifyingly, in this protocol, almost all of the para- or meta-
substituted anilines, including electron-rich and electron-deficient
ones, afforded isoindolinones 3a–e, 3g–h in up to 97% isolated yields.
It is worth noting that the anilines with electron-donating groups
afforded relatively higher yields than the ones with electron-
withdrawing groups. Unfortunately, when p-nitroaniline was
employed in the cascade reaction, the yield of 3f dramatically de-
creased and only trace product was obtained. Subsequently the
ortho-substituted anilines were examined. Due to the steric hin-
drance effect, o-methoxyaniline resulted in lower yield than p-
methoxyaniline and afforded isoindolinone 3i in 82% yield. On the
other hand, ortho-substituted anilines, such as o-methylaniline, o-
chloroaniline, o-iodoaniline and o-nitroaniline, all resulted the sole
uncyclized Strecker products in good yields, except that o-
methoxyaniline and 2-fluoro-4-methylaniline afforded the cyclized
products 3i and 3j in yields of 82% and 85% respectively, probably
indicating that the increase of the size or electron-withdrawing
ability of the ortho-substituents both have negative impact on the
reactivity of anilines.
Methyl 2-formylbenzoate (0.5 mmol), amine (0.5 mmol), TMSCN
(1.0 mmol) and 2.5 mol% Sc(OTf)3 were dissolved in EtOH (1 mL), and
the homogeneous solution was stirred at room temperature for 7 h.
After completing the reaction (judged by running TLC), the mixture
was concentrated in vacuo and the crude product was purified over
silica gel by column chromatography (20–30% EtOAc in hexane).
3. Results and discussion
Our studies began by selecting the three-component cascade
reaction of methyl 2-formylbenzoate, TMSCN and aniline as a platform
for the identification of optimal reaction conditions (Table 1). Initially,
the control experimental was conducted without catalyst and only
trace mount of the target product was obtained (Table 1, entry 1).
Then several transition-metal salts were screened as the catalysts, and
10 mol% Sc(OTf)3 gave the product in excellent yield in 4 h, whereas
all other Lewis acids investigated afforded only low yields (Table 1,
entries 2–7). Given that Sc(OTf)3 has been proven to be the most
effective catalyst for the cascade reaction, we then turned our attention
to examine catalyst loading. When the catalyst loading was decreased
from 10 to 2.5 mol%, high yield (89%) still obtained, although long
reaction times were necessary (Table 1, entries 2, 8–12). To further
explore this reaction, the reaction medium was then screened, and
EtOH afforded relatively higher yield than other solvents (Table 1,
The protocol was then applied to the benzylamines. In all of the
studied examples, benzylamines with electron-donating groups or
electron-withdrawing ones were both well tolerated and could react
smoothly to give the corresponding products 3k–3p in good to
excellent yields (87–93%). Furthermore, the heteroaromatic amines
furan-2-ylmethanamine and pyridin-3-ylmethanamine both reacted
efficiently to give products 3q and 3r in 86% and 90% yields, respectively.
Some alkylamines, including phenethylamines and some aliphatic
amines were also subjected to the conditions of this multicomponent
Scheme 1. Sc(OTf)3-catalyzed Strecker/Lactamization cascade reaction.

T. Chen, C. Cai / Catalysis Communications 74 (2016) 119–121
121
Table 2
Appendix A. Supplementary data
Scope of substratesa.
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.catcom.2015.11.011.
Reference
Entry
R
Product
Yield (%)b
[1] J.S. Park, S.C. Moon, K.U. Baik, J.Y. Cho, E.S. Yoo, Y.S. Byun, M.H. Park, Arch. Pharm.
Res. 25 (2002) 137–142.
[2] S. Lee, C. Shinji, K. Ogura, M. Shimizu, S. Maeda, M. Sato, M. Yoshida, Y. Hashimoto,
H. Miyachi, Bioorg. Med. Chem. Lett. 17 (2007) 4895–4900.
[3] T.V. Hughes, S.L. Emanuel, H.R. O'Grady, P.J. Connolly, C. Rugg, A.R. Fuentes-
Pesquera, P. Karnachi, R. Alexander, S.A. Middleton, Bioorg. Med. Chem. Lett. 18
(2008) 5130–5133.
[4] J.M. Ferland, C.A. Demerson, L.G. Humber, Can. J. Chem. 63 (1985) 361–365.
[5] Z.P. Zhuang, M.P. Kung, M. Mu, H.F. Kung, J. Med. Chem. 41 (1998) 157–166.
[6] M. Anzini, A. Cappelli, S. Vomero, G. Giorgi, T. Langer, G. Bruni, M.R. Romeo, A.S.
Basile, J. Med. Chem. 39 (1996) 4275–4284.
1
2
3
4
5
6
7
8
C6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
94
97
96
92
91
Trace
84
87
82
85
92
93
87
91
90
89
86
90
91
87
88
86
82
Trace
4-OMeC6H4
4-MeC6H4
4-FC6H4
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
3-ClC6H4
2-OMeC6H4
2-F-4-MeC6H3
C6H5CH2
4-OMeC6H4CH2
4-ClC6H4CH2
3-MeC6H4CH2
2-MeC6H4CH2
2-FC6H4CH2
2-FurylCH2
3-PyridylCH2
C6H5CH2CH2
CH3(CH2)3
CH3(CH2)11
Cyclopropyl
Cyclohexyl
(CH3)3C
9
[7] V. Gotor, F. Limeres, R. García, M. Bayod, R. Brieva, Tetrahedron Asymmetry 8 (1997)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
995–997.
[8] E.D. Clercq, J. Med. Chem. 38 (1995) 2491–2517.
[9] E.C. Taylor, P. Zhou, L.D. Jennings, Z. Mao, B. Hu, J.G. Jun, Tetrahedron Lett. 38 (1997)
521–524.
[10] D. Enders, V. Braig, G. Raabe, Can. J. Chem. 79 (2001) 1528–1535.
[11] A. Moreau, A. Couture, E. Deniau, P. Grandclaudon, S. Lebrun, Tetrahedron 60 (2004)
6169–6176.
[12] D.L. Comins, S. Schilling, Y. Zhang, Org. Lett. 7 (2005) 95–98.
[13] C. Zhu, J.R. Falck, Org. Lett. 13 (2011) 1214–1217.
[14] S. Adachi, M. Onozuka, Y. Yoshida, M. Ide, Y. Saikawa, M. Nakata, Org. Lett. 16 (2014)
358–361.
3s
3t
3u
3v
3w
3x
[15] H.L. Wang, M. Shang, S.Z. Sun, Z.L. Zhou, B.N. Laforteza, H.X. Dai, J.Q. Yu, Org. Lett. 17
(2015) 1228–1231.
[16] J. Zhu, H. Bienayme′, Multicomponent Reactions, Wiley-VCH, Weinheim, 2005.
[17] A. Domling, Chem. Rev. 106 (2006) 17–89.
[18] J.S. Bauma, M.M. StaveskiaL, Synth. Commun. 19 (1989) 2283–2291.
[19] X.T. Sun, T.Q. Zeng, D. Jiang, L.Y. Dai, C.J. Li, Can. J. Chem. 90 (2012) 92–99.
[20] H.Y. Zhang, Y.X. Leng, W.J. Liu, W.H. Duan, Synth. Commun. 42 (2012) 1115–1127.
[21] V. Bisai, A. Suneja, V.K. Singh, Angew. Chem. Int. Ed. 53 (2014) 10737–10741.
[22] S. Dhanasekaran, V. Bisai, R.A. Unhale, A. Suneja, V.K. Singh, Org. Lett. 16 (2014)
6068–6071.
a
Reaction conditions: methyl 2-formylbenzoate (0.5 mmol), amines (0.5 mmol), TMSCN
(1 mmol), Sc(OTf)3 (2.5 mol%) and EtOH (1 mL) were stirred at room temperature.
b
Isolated yield.
[23] V. Bisai, R.A. Unhale, A. Suneja, S. Dhanasekaran, V.K. Singh, Org. Lett. 17 (2015)
2102–2105.
cascade reaction. The results revealed that most of the alkylamines
could work well to afford the cyclized products 3s–3w in 82–91%
isolated yields. Unfortunately, due to the bulky substituent, only trace
yield of the desired product 3x was obtained when tert-butylamine
was utilized as the starting material.
[24] B. Nammalwar, N. Prasad Muddala, M. Murie, R.A. Bunce, Green Chem. 17 (2015)
2495–2503.
[25] A. Rayatzadeh, M. Saeedi, M. Mahdavi, Z. Rezaei, R. Sabourian, M.H. Mosslemin, T.
Akbarzadeh, A. Foroumadi, A. Shafiee, Monatsh. Chem 146 (2015) 637–643.
[26] A. Strecker, Liebigs Ann. Chem. 75 (1850) 27–45.
[27] D. Enders, J.P. Shilvock, Chem. Soc. Rev. 29 (2000) 359–373.
[28] A. Sacchetti, A. Silvani, F.G. Gatti, G. Lesma, T. Pilatic, B. Trucchi, Org. Biomol. Chem. 9
(2011) 5515–5522.
4. Conclusions
[29] B.M. Trost, I. Fleming, Comprehensive Organic Synthesis, Pergamon, Oxford, 1991
251–254;
S. Satoh, S. Suzuki, Tetrahedron Lett. 10 (1969) 4555–4558.
[30] R.C. Larock, Comprehensive Organic Transformations, 2nd edn. Wiley-VCH, 1999
1271–1272.
[31] N. Otto, T. Opatz, Chem. Eur. J. 20 (2014) 13064–13077.
[32] T. Opatz, D. Ferenc, J. Org. Chem. 69 (2004) 8496–8499.
[33] L.J. Hu, Z.J. Zhan, M. Lei, L.H. Hu, ARKIVOC (2013) 189–198.
In summary, we have developed a highly practical and efficient
method for the synthesis of N-substituted 3-oxoisoindoline-1-
carbonitrile derivatives from methyl 2-formylbenzoate, TMSCN and
amines in the presence of 2.5 mol% Sc(OTf)3 in ethanol. This green
procedure was conducted in a benign solvent at room temperature.
Various amines, including anilines, benzylamines and aliphatic amines,
were investigated and good to excellent yields (up to 97%) were
obtained in most cases.