Hantzsch ester triggered metal-free cascade approach to isoindolinones

Article abstract of DOI:10.1016/j.tetlet.2018.04.009

Disclosed herein is an expedient synthesis of biologically important isoindolinone derivatives from reactions of 2-formylbenzoic acids with various amines. This method operates via a deliberately designed catalyst-free tandem reductive amination/cyclization cascade event triggered by a transfer hydrogenation process with easily available Hantzsch ester as the organic hydride source. The ease of operation, mild reaction conditions, facile accessibility of the starting materials, and easy scalability of the current method distinguish it from the other precedent protocols, thus enable it a practical approach to the syntheses of valuable isoindolinone-incorporated drugs.

Full text of DOI:10.1016/j.tetlet.2018.04.009

Accepted Manuscript
Hantzsch ester triggered metal-free cascade approach to isoindolinones
Youping Tian, Junmei Wei, Meng Wang, Gaoqiang Li, Feng Xu
PII:
S0040-4039(18)30450-7
https://doi.org/10.1016/j.tetlet.2018.04.009
TETL 49872
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 February 2018
2 April 2018
3 April 2018
Please cite this article as: Tian, Y., Wei, J., Wang, M., Li, G., Xu, F., Hantzsch ester triggered metal-free cascade
approach to isoindolinones, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.009
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Tetrahedron Letters
Hantzsch ester triggered metal-free cascade approach to isoindolinones
Youping Tian, Junmei Wei, Meng Wang, Gaoqiang Li, and Feng Xu *
Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi
710062, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Disclosed herein is an expedient synthesis of biologically important isoindolinone derivatives
from reactions of 2-formylbenzoic acids with various amines. This method operates via a
deliberately designed catalyst-free tandem reductive amination/cyclization cascade event
triggered by a transfer hydrogenation process with easily available Hantzsch ester as the organic
hydride source. The ease of operation, mild reaction conditions, facile accessibility of the
starting materials, and easy scalability of the current method distinguish it from the other
precedent protocols, thus enable it a practical approach to the syntheses of valuable
isoindolinone-incorporated drugs.
Available online
Keywords:
Hantzsch ester
biomimetic synthesis
catalyst-free
2009 Elsevier Ltd. All rights reserved.
cyclization
isoindolinones
process,4c
Diels–Alder
reaction,4d
Wittig
reaction,4e
1. Introduction
rearrangement process4f and even photochemical reaction4g have
been historically documented.
Owing to the profound biological activities of this ubiquitous
isoindolinone motif found in a wide variety of natural products1
and synthetic drugs,2 i.e., the anti-inflammatory drug of
indoprofen, the anti-tumor agent of deoxythalldomide, the tumor
necrosis factor (TNF-α) production inhibitor of DWP201190, and
also the mouse glutathione reductase 1 (mGR-1) antagonist of
triazol-isoindolinone, (as shown in Figure 1),3 inspirred by this
unarguable fact, thus the construction of such a skeleton has
increasingly gained considerable momentum over the past
decades. As a consequence, an array of viable methods has been
developed toward the efficient syntheses of biologically relevant
isoindolinone-incorprated devatives. Traditional methods
including the Gabriel approach,4a Grignard procedure,4b lithiation
Apart from these stereotyped while practical methods, there
are also some modern synthetic approaches that have been
elegantly established. In 2005, Khan and co-workers5 achieved a
Heck/Michael addition cascade using 2-iodo-N-substituted
benzamides and acrylic esters as the qualified substrates with
palladium
catalysis,
a
series
of
N-substituted-3-
alkylisoindolinone esters were facilely synthesized. Undoubtedly,
the direct selective monoreduction of phthalimides (Scheme 1,
a),6 intramolecular amidation of 2-methyl-N-substituted
benzamides (Scheme 1, c)7 and intramolecular C(sp3)-H
activation of ortho-halogenated benzamides (Scheme 1, e)8
provide the most straightforward approaches to the isoindolinone
derivatives. Moreover, an intermolecular carbonylation of 2-halo-
N-alkylbenzylamines under transition metal catalysis also
provides an alternative method for the syntheses of such an
important motif (Scheme 1, b).9 Besides, the transition-/coinage-
metal-catalyzed reductive amination/condensation cascade
approaches from 2-formyl-benzoic acids and amines have also
been innovatively developed (Scheme 1, d).10 Among
aforementioned methods,11 either precious transition metals or
unavailability issue of the starting materials or toxic CO or
flammable H2 is indispensible for the transformations, which
greatly limit the practicality of these methods. Hence, the
development of a new method, of which the use of costly
transition metal catalysts and intractable reagents could be
circumvented, is still in high demand. To this end, we disclose
herein our most recent endeavor on the development of
Figure 1. Biologically active N-substituted isoindolinones.
* Corresponding Author. e-mail: fengxu@snnu.edu.cn

2
Tetrahedron Letters
Scheme 1 Strategies for the syntheses of biologically relevant isoindolinones
methodology towards the syntheses of biologically important
indolinone derivatives.
Table 1 Optimization of the reaction conditionsa
Nicotinamide adenine dinucleotide (NADH), as a coenzyme
found in all living cells, serves as a hydride co-factor for a broad
range of reductions.12 Among all the NADH-involved
transformations in nature, the glutamate dehydrogenase catalyzed
reductive amination of 2-ketoglutarate to form the amino acid
glutamate represents one of the most typical examples.13
Stimulated by this precisely established process by nature,
chemists have recently found that Hantzsch esters can undertake
the similar reductive process as that of the NADH.14 As a result,
numerous biomimetic transformations involving the Hantzsch
esters reduction have been impressively established.15 Given the
importance of this isoindolinone motif, we envisioned that a
similar biomimetic strategy could be applied in the syntheses of
isoindolinones from 2-formyl benzoic acids, amines and
Hantzsch ester under catalyst-free conditions, as showed in
Figure 2.
Entry
1
2
3
4
5
6
7
8
Solvent
DCM
CHCl3
DCE
Toluene
DMF
1,4-Dioxane
THF
MeCN
DMSO
MeOH
DCM
HEH (equiv)
Time (h)
Yield(%)b
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1
5
5
6
86
85
76
82
-
-
-
-
-
12
24
24
24
24
24
24
8
9
10
11
12
-
75
85
DCM
1.5
5
a
Unless otherwise noted, the reaction is performed using
phthalaldehydic acid 1a (1.0 mmol), amine 2a (1.1 mmol), and
b
Hantzsch ester in 3.0 mL of solvent at room temperature under N2.
Isolated yield.
yields (entries 2-4). However, to our surprise, other used solvents
delivered no desired product at all, even at an expense of a
prolonged reaction time (entries 5-10). Furthermore, reducing the
loading of HEH from 1.2 equiv to 1.0 equiv, a slight erosion of
the yield of product 3a was observed, whereas increasing the
amount of HEH loading to 1.5 equiv still failed to further
improve the yield (entries 11-12).
Figure 2 NAD(P)H-mediated reduction and our design
Results and discution
With optimized conditions in hand, the reactions of various
amines with phthalaldehydic acid (1a) were immediately
examined and the results were summarized in Table 2. Aromatic
amines bearing electron-donating groups at the para- or meta-
positions such as CH3-, CH3O- groups reacted smoothly to afford
the corresponding isoindolinone 3 in good to excellent yields
(Table 2, entries 2-5). The fluoro-, chloro-, bromo-, and iodo-
substitutions at the para-position of aromatic amines were all
well tolerated, giving the desired isoindolinone 3 in over 80%
yields (Table 2, entries 6-9). It should be noted that the aromatic
amines with halogen substitution at the meta-position generally
afforded better results than the ones with a para-substitution
pattern (Table 2, entries 10-12). And other electron-withdrawing
groups like CF3-, CF3O-, EtOOC- and NC- worked equally well
(Table 2, entries 13-16). However, a dramatically decreased yield
To prove the feasibility of our working hypothesis, we first
investigated
the
reductive
amination/cyclization
of
phthalaldehydic acid (1a) and aniline (2a) using HEH as the
hydride source under various conditions (Table 1). To our
delight, the direct reductive amination/cyclization reaction took
place under this catalyst-free condition and the desired
isoindolinone 3a was obtained in DCM at room temperature in
86% yield (Table 1, entry 1). Encouraged by this preliminary
result, several solvents, such as chloroform, DCE, toluene, DMF,
1, 4-Dioxane, THF, MeCN, DMSO and MeOH, were
systematically screened. As shown in Table 1, it was found that
the solvent exerted a significant effect on the reaction, only
commonly used chlorinated solvent or toluene used as the
reaction media can afford the desired product in satisfactory

from the above-mentioned aromatic amines, benzylic amine and
even aliphatic amine also participated in the reactions, delivering
the corresponding isoindolinones 3s and 3t (Table 2, entries 20-
21). Again, when 1-butylamine and the highly sterically
demanding tert-butylamine were adopted as the reaction partner,
no any desired product was detected. Furthermore, the functional
group tolerance on the phthalaldehydic acid moiety was also
investigated. As shown in entries 24 and 25, the tranformable
cyano groups on substrates 1 was perfectly compatible in the
optimized conditions, good yields of the isolated products were
obtained accordingly.
Table 2 Synthesis of isoindolin-1-onesa
Time（h
Entry
R1
R2
Product 3
Yield
(%)b
86
93
89
95
89
80
84
84
85
89
92
86
89
90
76
90
46
0
）
5
1
2
3
4
5
6
H
H
H
H
H
H
C6H5
3a
3b
3c
3d
3e
3f
4-CH3-C6H4
4-CH3O-C6H4
3-CH3-C6H4
3,4-(CH3)2-C6H3
4-F-C6H4
6
6
12
10
15
Scheme 2. Gram-scale synthesis of isoindolinone 3a.
7
H
4-Cl-C6H4
4-Br-C6H4
4-I-C6H4
16
15
13
20
20
16
14
15
24
10
24
24
24
24
24
24
24
10
3g
3h
3i
8
H
Scheme 2 Gram-scale synthesis of isoindolinone 3a.
9
H
10
11
12
13
14
15
16
17
18
19c
20c
21c
22c
23c
24
H
3-Cl-C6H4
3,4-Cl2-C6H3
3-Br-4-CH3-C6H3
4-CF3-C6H4
4-CF3O-C6H4
4-EtOOC-C6H4
4-NC-C6H4
2-naphthyl
2-CH3-C6H4
2-pyridinyl
benzyl
3j
3k
3l
To showcase the scalability of our current methodology, a
20.0 mmol scale synthesis using model substrates of 1a and 2a
was practiced under the optimized conditions. (Scheme 2)
Gratifyingly, 85% yield of the desired isoindolinone 3a was
afforded by a simple recrystallization of the crude reaction
mixture from CH2Cl2, obviating the tedious column
chromatography.
H
H
H
3m
3n
3o
3p
3q
-
H
H
H
H
H
H
3r
3s
3t
-
70
86
60
0
H
H
2-phenylethyl
1-butyl
H
H
tert-butyl
-
0
4-
CN
4-
CN
C6H5
3u
70
25
4-CH3O-C6H4
8
3v
77
a
Conditions: phthalaldehydic acid 1 (1.0 mmol), amine 2 (1.1 mmol),
and Hantzsch ester (1.2 mmol) and DCM (3.0 mL) at room temperature
under N2 for 5-24h. b Isolated yield. C at 50 oC
of 46% was observed when using 2-naphthylamine as the
substrate (Table 2, entry 17). This phenomenon could be
reasonably ascribed to the steric hindrance exerted by the amine
substrate. And such a notion has been subsequently reinforced by
the use of ortho-substituted aromatic amine as the substrate
(Table 2, entry 18). Interestingly, heteroaromatic amines like 2-
aminopyridine furnished the corresponding product 3r in 70%
yield, albeit a slightly higher temperature of 50 oC was a
prerequisite condition for the success (Table 2, entry 19). Apart
Scheme 3 Control experiments toward the mechanistic
elucidation
To shed light on the mechanism of this facile reductive
amination/cyclization cascade event, several control experiments
were performed accordingly (Scheme 3). It was found that
isobenzofuranone 5a’ was obtained when phthalaldehydic acid
1a reacted with aniline 2a in the absence of Hantzsch ester
16i, 16j
(Scheme 3, a).16e,
To our surprise, treatment of
isobenzofuranone 5a’ with Hantzsch ester in DCM for 24 h also
Scheme 4 Proposed mechanism of the synthesis of isoindolinone 3a

4
Tetrahedron Letters
Byeon, S. R.; Kim, Y. S.; Lim, S. J.; Oh, S. J.; Dae, K. H.; Moon, H.
C.; Chung, B. Y.; Kim, D. J. Bioorg. Med. Chem. Lett. 2008, 18, 5701.
(3) (a) Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem.
1996, 39, 149. (b) Lawrence, N. J.; Liddle, J.; Bushell, S.; Jackson, D.
A. J. Org. Chem. 2002, 67, 457. (c) Park, J. S.; Moon, S. C.; Baik, K.
U.; Cho, J. Y.; Yoo, E. S.; Byun, Y. S.; Park, M. H. Arch. Pharmacal
Res. 2002, 125, 137. (d) T. Libbers, P.Angehrn, H. Gminder, S.
Herzig, Bioorg. Med. Chem. Lett. 2007, 17, 4708. (e) Uno, M.; Ban,
H. S.; Nakamura, H. Bioorg. Med. Chem. Lett. 2009, 19, 3166.
(f) Ghosh, U.; Bhattacharyya, R.; Keche, A. Tetrahedron 2010, 66,
2148.
(4) For selected examples, see: (a) Hozl, J. Collect. Czech. Chem.
Commun. 1971, 35, 2775. (b) Ang, W. S.; Halton, B. Aust. J. Chem.
1971, 24, 851. (c) Ahmed, A.; Clayden, J.; Yasin, S. A. Chem.
Commun. 1999, 231. (d) Huang, X.; Xu, J. J. Org. Chem. 2009, 74,
8859. (e) Epsztajn, J.; Grzelak, R.; Jóźwiak, A. Synthesis 1996, 1212.
(f) Guillaumel, J.; Boccara, N.; Demersemann, P.; Royer, R. J. Chem.
Soc., Chem. Commun. 1988, 1604. (g) Griesbeck, A. G.; Hirt, J.;
Kramer, W.; Dallakian, P. Tetrahedron 1998, 54, 3169.
afforded 3a in 82% yield (Scheme 3, b). However, when methyl
2-formylbenzoate 4 was employed instead of 1a, no product 3a
was found and the imine 5b was obtained under the standard
conditions(Scheme 3, c). This result shows that the carboxylic
acid moiety functions as not only the crucial activator of
Hantzsch ester transfer hydrogenative process but also the
promoter of the following amide formation event.
On the basis of literature precedents16 and our present findings,
a plausible reaction mechanism for the formation of 3a is
depicted in Scheme 4. Initially, phthalaldehydic acid 1a reacts
with aniline 2a to afford the imine 5a with an intramolecular
hydrogen bond, which could be converted into isobenzofuranone
5a’,16e, 16j the imine 5a and isobenzofuranone 5a’ probably exist
as an equilibrium.16i Subsequent intramolecular activation of this
imine moiety by the carboxylic acid moiety via protonation,
followed by an intermolecular transfer hydrogenation with the
coming
Hantzsch
ester
to
form
the
2-
((phenylamino)methyl)benzoic acid 6, further intramolecular
cyclization takes place to furnish the final product 3a.
(5) Khan, M. W.; Reza, A. F. G. M. Tetrahedron 2005, 61, 11204.
(6) (a) Aoun, R.; Renaud, J.-L.; Dixneuf, P. H.; Bruneau, C. Angew.
Chem. Int. Ed. 2005, 44, 2021. (b) Das, S.; Addis, D.; Knöpke, L. R.;
Bentrup, U.; Junge, K.; Brückner, A.; Beller, M. Angew. Chem., Int.
Ed. 2011, 50, 9180. (c) Jóźwiak, A.; Zagórski, P. M.; Płotka, M. W.;
Cal, D. Tetrahedron Lett. 2014, 55, 2420.
Conclusions
In conclusion, we have developed an efficient catalyst-free
reductive amination/cyclization cascade of 2-formylbenzoic acids
with amines for the construction of biologically important
isoindolinone derivatives. This approach operates with a cheap
while widely accessible Hantzsch ester as the reductant,
providing a straightforward thus viable synthetic route toward
the syntheses of medicinally relevant isoindolinones.
Intriguingly, the robust scalability of this method renders the
potential application in industrial synthesis. Further development
of more methods by applying a similar strategy while aiming at
the efficient syntheses of biologically active compounds, is still
underway in our laboratory.
(7) (a) Nozawa-Kumada, K.; Kadokawa, J.; Kameyama, T.; Kondo,
Y. Org. Lett. 2015, 17, 4479. (b) Zhu, C.; Liang, Y.; Hong, X.; Sun,
H.; Sun, W.-Y.; Houk, K. N.; Shi, Z. J. Am. Chem. Soc. 2015, 137,
7564. (c) Verma, A.; Patel, S.; Meenakshi; Kumar, A.; Yadav, A.;
Kumar, S.; Jana, S.; Sharma, S.; Prasad, Ch. D.; Kumar, S. Chem.
Commun. 2015, 51, 1371. (d) Yamamoto, C.; Takamatsu, K.; Hirano,
K.; Miura, M. J. Org. Chem. 2016, 81, 7675. (e) Bedford, R. B.;
Bowen, J. G.; Méndez-Gálvez, C. J. Org. Chem. 2017, 82, 1719.
(8) (a) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 10692. (b) Wertjes, W.; Wolfe, L. C.;Waller, P.
J.; Kalyani, D. Org. Lett. 2013, 15, 5986. (c) Chen, W.; Jin, L.; Zhu,
Y.; Cao, X.; Zheng, L.; Mo, W. Synlett 2013, 24, 1856. (d) Bhakuni,
B. S.; Yadav, A.; Kumar, S.; Patel, S.; Sharma, S.; Kumar, S. J. Org.
Chem. 2014, 79, 2944.
Acknowledgments
(9) (a) Grigg, R.; Sridharan, V.; Suganthan, S.; Bridge, A. W.
Tetrahedron 1995, 51, 295. (b) Grigg, R.; MacLachlan, W. S.;
MacPherson, D. T.; Sridharan, V.; Suganthan, S.; Thornton-Pett, M.;
Zhang, J. Tetrahedron 2000, 56, 6585. (c) Grigg, R.; Zhang, L.;
Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 6979. (d) Grigg, R.;
Sridharan, V.; Thayaparan, A. Tetrahedron Lett. 2003, 44, 9017. (e)
Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004,
126, 14342. (f) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.;
Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.;
Tokuda, M. J. Org. Chem. 2006, 71, 5951. (g) Marosvölgyi-Haskó,
D.; Takács, A.; Riedl, Z.; Kollár, L. Tetrahedron 2011, 67, 1036.
(10) (a) Shi, L.; Hu, L.; Wang, J.; Cao, X.; Gu, H. Org. Lett. 2012, 14,
1876. (b) Kumar, V.; Sharma, S.; Sharma, U.; Singh, B.; Kumar, N.
Green Chem. 2012, 14, 3410. (c) Kumar, V.; Sharma, U.; Verma, P.
K.; Kumar, N.; Singh, B. Adv. Synth. Catal. 2012, 354, 870.
(d) Kumar, V.; Sharma, U.; Singh, B.; Kumar, N. Aust. J. Chem.
2012, 65, 1594. (e) Nayal, O. S.; Thakur, M. S.; Bhatt, V.; Kumar, M.;
Kumar, N.; Singh, B.; Sharma, U. Chem. Commun. 2016, 52, 9648. (f)
Mao, F.; Sui, D. j.; Qi, Z.; Fan, H.; Chen, R.; Huang, J. RSC Adv.
2016, 6, 94068. (g) Fasano, V.; Radcliffe, J. E.; Ingleson, M. J. ACS
Catal., 2016, 6, 1793. (h)Zhou, Y.; Chen, P.; Lv, X.; Niu, J.; Wang,
Y.; Lei, M.; Hu, L. Tetrahedron Lett. 2017, 58, 2232.
We are grateful for financial support from the National
Natural Science Foudation of China (No.21572123, 21172138
and 21302117), the Fundamental Research Funds for the Central
Universities (GK201601003 and GK201603047) and the
Distinguished Doctoral Research Funds from Shaanxi Normal
University (S2011YB04).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
References
(1) (a) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron
Lett. 1984, 25, 599. (b) Desai, S. J.; Chaturvedi, R.; Mulchandani, N.
B. J. Nat. Prod. 1990, 53, 496. (c) Speck, K.; Magauer, T. J. Org.
Chem. 2013, 9, 2048.
(2) (a) Xu, X.; de Guzman, F. S.; Gloer, J. B. J. Org. Chem. 1992, 57,
6700. (b) Egbertson, M. S.; Hartman, G. D.; Gould, R. J.; Bednar, R.
A.; Cook, J. J.; Gaul, S. L.; Holahan, M. A.; Libby, L. A.; Lynch, J. J.;
Sitko, G. R.; Stranieri, M. T.; Vassallo, L. M. Bioorg. Med. Chem.
Lett. 1996, 6, 2519. (c) Boger, D. L.; Lee, J. K.; Goldberg, J.; Jin, Q. J.
Org. Chem. 2000, 65, 1467. (d) Wehlan, H.; Jezek, E.; Lebrasseur, N.;
Pave, G.; Roulland, E.; White, A. J. P.; Burrows, J. N.; Barett, A. G.
M. J. Org. Chem. 2006, 71, 8151. (e) Lee, S.; Shinji, C.; Ogura, K.;
Shimizu, M.; Maeda, S.; Sato, M.; Yoshida, M.; Hashimotoa, Y.;
Miyachi, H. Bioorg. Med. Chem. Lett. 2007, 17, 4895. (f) Lee, J. H.;
(11) (a) Deguest, G.; Devineau, A.; Bischoff, L.; Fruit, C.; Marsais, F. Org.
Lett. 2006, 8, 5889. (b)Wan, J.; Zhou, J.; Mao, H.; Pan, Y.; Wu, A.
Tetrahedron 2008, 64, 11115. (c) Mamidyala, S. K.; Cooper, M. A.
Chem. Commun. 2013, 49, 8407. (d) Adachi, S.; Onozuka, M.;
Yoshida, Y.; Ide, M.; Saikawa, Y.; Nakata, M. Org. Lett. 2013, 16,
358. (e) Hong, X.; Wang, H.; Liu, B.; Xu, B.; Chem. Commun. 2014，
50, 14129. (f) Wang, P.-M.; Pu, F.; Liu, K.-Y.; Li, C.-J.; Liu, Z.-W.;
Shi, X.-Y.; Fan, J.; Yang, M.-Y.; Wei, J.-F. Chem. Eur. J. 2016, 22,

6262. (g) Liu, C.; Zhang, Q.; Li, H.; Guo, S.; Xiao, B.; Deng, W.; He,
W. Chem. Eur. J. 2016, 22, 6208.
(12) (a) Lin, H. Org. Biomol. Chem. 2007, 5, 2541. (b) Ying, W. H.
Antioxid. Redox Signal 2008, 10, 179. (c) Houtkooper, R. H.; antó,
C.; Wanders, R. J.; Auwerx, J. Endocr. Rev. 2010, 31, 194.
(13) (a) John, R. O. In Comprehensive Biological Catalysis; Sinnot, M.,
Ed.; Academic Press: London, UK, 1998; Vol. 2, 173. (b) Silverman,
R. B. The Organic Chemistry of Enzyme-Catalyzed Reactions;
Academic Press: London, UK, 2002; 428. (c) Rüping, M.; Sugiono, E.;
Schoepke, F. R. Synlett 2010, 852.
(14) For reviews on transfer hydrogenation reactions using Hantzsch esters,
see: (a) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem.
Res. 2007, 40, 1327. (b) You, S. L. Chem. Asian J. 2007, 2, 820. (c)
Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407. (d) Rueping, M.;
Dufour, J.; Schoepke, F. R. Green Chem. 2011, 13, 1084. (d) Zheng,
C.; You, S. -L. Chem. Soc. Rev. 2012, 41, 2498. (d) Faísca Phillips, A.
M.; Pombeiro, A. J. L. Org. Biomol. Chem. 2017, 15, 2307.
added, and was extracted with EtOAc (3×10 mL). The combined
organic layers were dried over anhydrous MgSO4 and concentrated to
give a residue that was purified by column chromatography with
EtOAc/petroleum (1:10-1:3) as an eluent.
2-(3,4-dichlorophenyl)isoindolin-1-one(3k): White solid; 285 mg,
yield: 92%; m.p.: 201-203℃. 1H NMR (400 MHz, Chloroform-d) δ 8.03
(d, J = 2.6 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.82 – 7.79 (m, 1H), 7.64
– 7.60 (m, 1H), 7.54 – 7.45 (m, 2H), 7.46 (d, J = 8.8 Hz, 1H), 4.82 (s,
2H). 13C NMR (101 MHz, Chloroform-d) δ 167.7, 139.8, 139.1, 133.0,
132.7, 132.6, 130.7, 128.7, 127.6, 124.4, 122.8, 120.6, 118.2, 50.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H1035Cl2NO: 278.0134; found:
278.0133.
2-(3-bromo-4-methylphenyl)isoindolin-1-one(3l): White solid; 256
mg, yield: 86%; m.p.: 178-180℃. 1H NMR (400 MHz, Chloroform-d) δ
7.90 (d, J = 8.0 Hz, 1H), 7.80 – 7.79 (m, 1H), 7.61 – 7.57 (m, 1H), 7.55
– 7.47 (m, 4H), 4.81 (s, 2H), 2.43 (s, 3H). 13C NMR (101 MHz,
Chloroform-d) δ 167.6, 140.0, 138.8, 138.7, 133.1, 132.8, 132.4, 128.6,
124.2, 122.7, 121.5, 119.9, 118.2, 50.8, 23.4. HRMS (ESI): m/z [M +
Na]+ calcd for C15H1279BrNNaO: 323.9994; found: 323.9992.
(15) (a) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637. (b) Hantzsch,
A. Justus Liebigs Ann. Chem. 1882, 215, 1.
(16) (a) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 84. (b) Menche, D.; Arikan, F. Synlett 2006,
841. (c) Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.;
Rudolph, S. Org. Lett. 2006, 8, 741. (d) Simón, L.; Goodman, J. M. J.
Am. Chem. Soc. 2008, 130, 8741. (e) Kubota, Y.; Tatsuno, T. Chem.
Pharm. Bull. 1971, 19, 1226. (f) Shen, S. C.; Sun, X. W.; Lin, G. Q.
Green Chem. 2013, 15, 896. (g) Chen, F.; Lei, M.; Hu, L. Green Chem.
2014, 16, 2472. (h) Nammalwar, B.; PrasadMuddala, N.; Murie, M.;
Bunce, R. A. Green Chem. 2015, 17, 2495. (i) Muddala,
N.P.; Nammalwar, B.; Bunce, R. A. RSC Adv. 2015, 5, 28389. (j)
Zhang, Y.; Ao, Y. F.; Huang, Z. T.; Wang, D. X.; Wang, M. X.; Zhu, J.
Angew. Chem. Int. Ed. 2016, 55, 5282. (k) Chen, T.; Cai, C. New J.
Chem. 2017, 41, 2519.
2-(4-(trifluoromethoxy)phenyl)isoindolin-1-one(3n): White solid;
263 mg, yield: 90%; m.p.: 184-186℃. 1H NMR (400 MHz, Chloroform-
d) δ 7.93 – 7.88 (m, 3H), 7.63 – 7.58 (m, 1H), 7.53 – 7.49 (m, 2H), 7.28
– 7.25 (m, 2H), 4.84 (s, 2H). 13C NMR (101 MHz, Chloroform-d) δ
167.7, 145.4, 134.0, 138.2, 132.9, 132.5, 128.6, 124.3, 122.8, 122.0,
120.5(q, JC-F = 255.5Hz), 120.4, 50.7. HRMS (ESI): m/z [M + Na]+
calcd for C15H10F3NNaO2: 316.0556; found: 316.0553.
2-(naphthalen-2-yl)isoindolin-1-one(3q): White solid; 119 mg, yield:
46%; m.p.: 184 -185℃. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (dd, J
= 8.9, 2.3 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H),
7.90 (d, J = 9.0 Hz, 1H), 7.83 (t, J = 8.8 Hz, 2H), 7.63 – 7.60 (m, 1H),
7.55 – 7.41 (m, 4H), 4.98 (s, 2H). 13C NMR (101 MHz, Chloroform-d) δ
167.8, 140.2, 137.3, 133.8, 133.3, 132.3, 130.7, 129.0, 128.5, 127.8,
127.7, 126.6, 125.3, 124.3, 122.7, 119.3, 116.3, 51.1. HRMS (ESI): m/z
[M + Na]+ calcd for C18H13NNaO: 282.0889; found: 282.0887.
(17) Typical procedure for the synthesis of N-substituted
isoindolinones(3a-v): A mixture of 2-formylbenzoic acid (1.0 mmol),
amine (1.1 mmol), and Hantzsch ester (1.2 mmol) was stirred in
CH2Cl2 (3 mL) at room temperature under N2 until the reaction was
complete (TLC analysis). A solution of saturated NaHCO3 (5 mL) was
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Hantzsch ester triggered metal-free cascade
approach to isoindolinones
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Youping Tian, Junmei Wei, Meng Wang, Gaoqiang Li, and Feng Xu *
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Highlights
 Transition-metal-free, highly efficient, and
mild approach for the synthesis of N-
substituted isoindolinones .
 An intramolecular hydrogen-bond-catalyzed
tandem reductive amination/ cyclization of 2-
formylbenzoic acids is described.
 Up to 95% yield.
 This protocol could be readily scaled up to
gram scale.