TfOH-catalyzed synthesis of 3-aryl isoindolinones via a tandem reaction

Article abstract of DOI:10.1039/c4cc06653g

A convenient metal-free method for the synthesis of 3-aryl isoindolinones via TfOH catalyzed aromatic C-H functionalization of electron-rich arenes with 2-formylbenzonitriles is developed. This process provided a new efficient strategy for the synthesis of isoindolinone derivatives in good to high yields and regioselectivities by forming two bonds.

Full text of DOI:10.1039/c4cc06653g

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TfOH-catalyzed synthesis of 3-aryl isoindolinones via tandem reaction
Jiaxing Hu, Hua-Li Qin, Wengang Xu, Junli Li, Fanglin Zhang* and Hua Zheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Previous Work
5
A convenient metal-free method for the synthesis of 3-aryl
isoindolinones via TfOH catalyzed aromatic C−H
functionalization of electron-rich arenes with 2-
formylbenzonitriles is developed. This process provided a new
efficient synthetic strategy to isoindolinone derivatives by
O
O
LDA, Et3N
N
R1
NH
R1
Ph
Ph
O
10 forming two bonds in good to high yields and
regioselectivities.
Me
O
CHO
N
MeNH2, AcOH
Pd(OAc)2
Ph
Ph
Isoindolinones can be found in natural products including
stachybotrin C,1 indoprofen,2 Lennoxamineand,3 and also in some
pharmacologically important synthetic compounds, such as
15 zopiclone4 and pagoclone.5 Numerous synthetic and natural
molecules containing the isoidolinone skeleton have been
reported to display significant biological activities including
antimicrobials,6 antiviras,7 HIV-1 inhibitors,8 TACE inhibitors,9
antitumor activities,2,10 hypnotic agents,11 antidopaminergic
20 agents and also protein kinase inhibiting activities.12 Some
isoindoline derivatives were also reported to exhibit local
anesthetic activity superior to that of procaine.13 Furthermore,
these heterocyclic scaffolds have been found to have special
fluorescent properties recently.14
NHR
R1
R1
NH
CO
+
C
O
50
This Work
Scheme 1 Synthetic approaches for isoindolinones.
25
Numerous methods for the construction of the isoindolinone
ring system have been reported, among which. the more
commonly used approaches are those from aromatic mono-
carbonyl compounds, from 1,2-dicarbonyl compounds, and from
the transformations of heterocycles, via the Diels–Alder reaction,
requirements, and are not suitable for the preparation of
55 compound libraries. Therefore, there remains considerable scope
for improvement, such as a more versatile catalyst and reaction
conditions which prevent catalyst leakage, a voiding the use of
highly toxic CO, and obtaining higher yields.
It was known that several classes of catalysts have been
60 successfully applied to the FC reaction of aldehydes with
nucleophiles, including brφnsted acids, conventional lewis acids,
and transition metals.19 Keeping the proposed intermediates of
the FC reaction in view, we wished to construct the isoindolinone
core from corresponding 2-formylbenzonitrile with arenes via the
65 Friedel-Crafts reaction followed by assisted ring closing reaction
route.
Our recent studies have been focusing on the development of
new synthetic pathways for the preparation of heterocyclic
compounds.20 Herein, we report a novel and efficient route to
70 isoindolinones through tandem reaction of 2-formylbenzonitriles
with benzene derivatives catalysed by TfOH. To the best of our
knowledge, this process was established for the first time as the
tandem construction of isoindolinones.
For the synthesis of isoindolinones 3 via FC-ring closing
75 reaction, 2-formylbenzonitriles 1a and mesitylene 2a was chosen
as the model starting material. Accordingly different lewis acid21
such as FeCl3, CuCl, CuBr, CuI, BF3•Et2O and proton acid22 such
30 and through the Wittig reaction.7,15 Cyclizations of aryl lithium
species of different N-acyl-benzylamine derivatives such as N-
benzyl-N,N-dimethylureas were also reported in the literature
with the using of strong basic organo-lithium regents, which are
normally incompatible with functional groups sensitive to
35 nucleophilic attack.16 More recently, several metal-catalyzed
approaches have been described for the synthesis of
isoindolinones including carbonylation of benzylamines under
CO atmosphere using the catalytic system Pd(OAc)2-Cu(OAc)2, a
tandem limination-cyclization-Suzuki approach, Heck-Suzuki-
40 Miyaura domino reaction involving ynamides, a Sonogashira
reaction of 2-halobenzamides with terminal alkynes and
alkynylation/lactamization cascade of available o-formyl methyl
benzoates and o-formyl methyl arylacetates.17 Other approaches
to the isoindolinone system generally involved electrophilic
45 cyclization, and an intramolecular cyclization of acyl radicals
onto an azide group.18
Above all, most of the existing methods suffer from certain
limitations with respect to yield, substrate scope, or apparative
This journal is © The Royal Society of Chemistry [year]
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Page 2 of 5
as H2SO4, CF3COOH, TfOH, was selected as the catalyst. As
transformation.
anticipated in the previous section, the nature of the acid plays an
important role in the efficiency of the process (Table 1). In fact,
as reported in Table 1, it can be seen that the use of lewis acid
(0.2 equiv) in 1, 2-dichloroethane (Table 1, entries 1-5) led to
only less than 10% yields after 24 h. To our delight, a slight
Table 2 Reaction of substituted isoindolinones under optimized
View Article Online
conditionsa
DOI: 10.1039/C4CC06653G
5
Table 1 Optimization of the reaction conditions screening for the
synthesis of isoindolinonea
F
Cl
NH
NH
NH
NH
F
O
O
O
O
3a (87%)
3c (79%)
3b (82%)
3d (74%)
Entry
1
2
3
4
5
6
7
8
Catalyst (eq.)
FeCl3 (0.2 eq)
CuCl (0.2 eq)
CuBr (0.2 eq)
CuI (0.2 eq)
Solvent
Yieldb (%)
<10
Br
Ph
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH3OH
C2H5OH
H2O
acetone
THF
CH2Cl2
CH3CN
EtOAc
CH3NO2
CH3NO2
NH
NH
NH
NH
<10
<10
<10
<10
25
27
39
nr
nr
nr
<10
<10
33
45
55
87
88
Cl
Br
O
O
O
O
3e (72%)
3f (76%)
3g (75%)
3h (97%)
BF3·Et2O (0.2 eq)
H2SO4 (0.2 eq)
CF3COOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.2 eq)
TfOH (0.3 eq)
H3CO
H3CO
NH
O
NH
O
NH
NH
O
9
O
3i (73%)
3j (33%)
10
11
12
13
14
15
16
17
18
3k (82%)
3l (77%)
OMe
MeO
NH
NH
NH
O
NH
O
O
O
3n (93%)
3o (61%)
3p (71%)
3m (82%)
(p/o = 77/23)
aReaction condition: Corresponding catalyst (0.2 mmol) was added to a
stirred 5 mL solvent of 2-formylbenzonitrile (132 mg, 1 mmol) and
mesitylene (601 mg, 5 mmol), The solution was stirred and heated to
reflux, after reaction was completed (as indicated by TLC), the mixture
was purified by flash chromatography on silica gel eluting with
petroleum ether/ethyl acetate. bYield of the isolated product after
chromatography on silica gel.
OMe
NH
NH
O
NH
NH
NH
O
O
O
O
3q (72%)
(p/o > 98/2)
3r (82%)
(p/o > 98/2)
3u (84%)
(p/o > 98/2)
3s (62%)
(p/o > 98/2)
3t (80%)
(p/o > 98/2)
35
aReaction condition: 20% equiv TfOH was added to a stirred 5 mL
CH3NO2 of 2-formylbenzonitrile derivatives (1 mmol) and benzene
derivatives (5 mmol), The solution was stirred and heated to reflux, after
reaction was completed (as indicated by TLC), the mixture was purified
10
improvement in the yield of the desired product was observed
when the reaction was carried out in protonic acid (Table 1,
entries 6-8). The yields increased to 25% and 27% respectively
when H2SO4, CF3COOH were used as catalyst (entries 6-7). In
40 by flash chromatography on silica gel eluting with petroleum ether/ethyl
acetate. bYield of the isolated product after chromatography on silica gel.
The para/ortho ratio was determined by 1H NMR of the crude products.
c
15 addition, the reaction catalysed with TfOH provided 39% of the
desired product (entry 8). In order to further improve the
efficiency of this procedure, we screened the reaction in the
presence of different solvents,23 when the reaction was performed
in the presence of protic solvent such as methanol, ethanol and
20 water, the desired product was not detected and the reaction did
not proceed (Table 1, entries 9-11), similar results were observed
in the case of THF and acetone (Table 1, entries 12-13); To our
delight, this reaction proceeded smoothly in CH2Cl2, CH3CN,
EtOAc and CH3NO2 (Table 1, entries 14-17), providing 3a in
25 moderate to good yields. On the basis of the above observations,
CH3NO2 was chosen as the most promising solvent to optimize
the reaction media, it gave the best isolated yield in 87%. The
reaction was also performed in the presence of 0.3 eq. of TfOH,
the yield of 3a was only increased to 88% (entry 18), which
30 indicated that additional amount of TfOH is not required for this
With the optimum reaction conditions in hand, the scope and
generality of this reaction were explored by treating different 2-
45 formylbenzonitriles and benzene derivatives to generate various
substituted isoindolinone products. The results showed that the
reaction is quite general. First, the scope of 2-
formylbenzonitriles24 was investigated under the optimized
reaction conditions. Substrates with F, Cl or Br groups on
50 aromatic ring gave the desired products 3b-3g in good yields
(72%-82%). It is noteworthy that position of substituted groups
and electron-withdrawing ability on the phenyl ring
had less influence on the reaction. substrates with electron-
donating group such as phenyl and 4,5-dimethoxy were also
55 investigated under the optimum conditions, which proceeded
smoothly to generate the products in good to excellent yields (3h
and 3i).
2
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Next, different benzene derivatives in the reaction were
addition type of reaction, the imine is then converted to amide
after rearrangement, the final product is finally generated through
the conjugate addition of amide (Path B)..DOI: 10.1039/C4CC06653G
examined. Benzene reacted with 2-formylbenzonitriles to give the
corresponding products 3j in 33% yield. Then, the treatment of
1a with p-xylene and 1,4-diethylbenzene furnished the desired
products 3k and 3l in good yield (82% and 77%) which might be
due to strong electron-donating ability. To evaluate the reactivity
of methoxy group on the benzene ring, 1,4-dimethoxybenzene
was examined with 1a, the desired product 3-(2,5-
dimethoxyphenyl)isoindolin-1-one (3m) was finally produced in
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5
10 82% yield under optimized conditions. We also tried the reaction
of m-xylene and o-xylene with 1a, it was pleased to find that high
regioselectivity was observed in this reaction. The desired
products 3n and 3o were afforded as single regioisomers
exclusively and with the yield of 93% and 61% respectively. In
15 order to further study the applicability and regioselectivity of this
procedure, various mono-substituted benzene derivatives,
including toluene, ethylbenzene, cumene, butylbenzene, tert-
butylbenzene were investigated for the tandem reaction. From
these results, it is concluded that the different electron-donating
20 substituents on benzene has almost insignificant effect on the
reaction yields. Major goal products (3p–3t) were gained as
reaction occurred on the para position of benzene derivatives.
When starting from toluene, the desired product was obtained as
a mixture of regioisomers (para/ortho = 77/23), greater ratios
25 (para/ortho > 98/2) were observed when benzene with an increase
in alkyl group chain were tested, it could be due to
the increasing steric hindrance effect. Finally, we tried the
reaction of anisole with 1a and produced the para-substituted
desired product 3-(4-methoxyphenyl)isoindolin-1-one (3u) under
30 optimized reaction conditions in 84% yield. Unfortunately, no
products were obtained while electron-defcient benzenes such as
chlorobenzene, nitrobenzene were investigated for this reaction, it
proved that electron-withdrawing benzene derivatives couldn't
proceed smoothly for this process.
55
Scheme 3 Proposed Mechanism for the Synthesis of isoindolinones.
In conclusion, we have developed an efficient and facile
procedure for the synthesis of isoindolinones in good to excellent
yields. The sequential reaction has been successfully applied with
60 a wide scope of substituents on the 2-formylbenzonitrile and
electron-rich arenes. The broad scope of this tandem reaction
makes this procedure promising for practical usages. The
investigation of the applications and the design of new synthetic
crafts for these products are ongoing in our laboratory.
65
This work was supported by National Natural Science
Foundation of China (51273156, 31301735).
Notes and references
COOH
TfOH
Department of Pharmaceutical Engineering, Wuhan University of
Technology, Wuhan, 430070, China. Fax: +86 27 87749300; Tel: +86 27
70 87749300;
+
O
CH3NO2, reflux
CHO
E-mail:fanglinzhang0210@gmail.com, zhenghua.whut@126.com
O
† Electronic Supplementary Information (ESI) available:See
DOI: 10.1039/b000000x/
4a
35
Scheme 2 Synthesis of 3-(2,5-dimethylphenyl)isobenzofuran-1(3H)-one.
75 1. Y. Nozawa, K. Yamamoto, M. Ito, N. Sakai, K. Mizoue, F. Mizobe
and K. Hanada, J. Antibiot., 1997, 50, 635.
2. a) U. Ghosh, R. Bhattacharyya and A. Keche, Tetrahedron, 2010, 66,
2148; b) I. Takahashi, E. Hirano, T. Kawakami and H. Kitajima,
Heterocycles, 1996, 43, 2343.
80 3. D. L. Comins, S. Schilling and Y. Zhang, Org. Lett., 2004, 7, 95.
4. a) V. Gotor, F. Limeres, R. García, M. Bayod and R. Brieva,
Tetrahedron: Asymmetry, 1997, 8, 995; b) M. Anzini, A. Cappelli, S.
Vomero, G. Giorgi, T. Langer, G. Bruni, M. R. Romeo and A. S.
Basile, J. Med. Chem., 1996, 39, 4275.
85 5. a) M.-D. Chen, M.-Z. He, X. Zhou, L.-Q. Huang, Y.-P. Ruan and P.-
Q. Huang, Tetrahedron, 2005, 61, 1335; b) T. L. Stuk, B. K. Assink,
R. C. Bates, D. T. Erdman, V. Fedij, S. M. Jennings, J. A. Lassig, R.
J. Smith and T. L. Smith, Org. Process Res. Dev., 2003, 7, 851.
6. J. C. Breytenbach, S. van Dyk, I. van Den Heever, S. M. Allin, C. C.
Furthermore, to explore the scope and application of the
method, we examined the reaction of 2-formylbenzoic acid with
p-xylene to generate isobenzofuranone derivative, it was found
40 that the tandem reaction proceeded excellently to generate the
product 4a in 95% yield (Scheme 2).
The proposed reaction mechanism of the reaction between 2-
formylbenzonitriles and arenes is shown in Scheme 3.25 Arenes
first couple with the aldehyde groups through Friedel-Crafts
45 reaction to generate alcohol, which would then undergo a
dehydration to afford intermediate carbocation, cyano group is
subsequently converted to amide through hydrolysis reaction
under strong acidic condition, finally an intramolecular aza-
Michael addition process occurred to produce the isoindolinone
50 framework (Path A); Moreover, intermediate alcohol also can be
converted to imine through an intramolecular aza-Michael
90
Hodkinson, C. J. Northfield and M. I. Page, Bioorg. Med. Chem. Lett.,
2000, 10, 1629.
7. C. Maugeri, M. A. Alisi, C. Apicella, L. Cellai, P. Dragone, E.
Fioravanzo, S. Florio, G. Furlotti, G. Mangano, R. Ombrato, R. Luisi,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

ChemComm
Page 4 of 5
R. Pompei, V. Rincicotti, V. Russo, M. Vitiello and N. Cazzolla,
Bioorg. Med. Chem., 2008, 16, 3091.
8. X. Z. Zhao, K. Maddali, C. Marchand, Y. Pommier and T. R. Burke
Jr, Bioorg. Med. Chem., 2009, 17, 5318.
View Article Online
DOI: 10.1039/C4CC06653G
5 9. W. Yu, Z. Guo, P. Orth, V. Madison, L. Chen, C. Dai, R. J. Feltz, V.
M. Girijavallabhan, S. H. Kim, J. A. Kozlowski, B. J. Lavey, D. Li,
D. Lundell, X. Niu, J. J. Piwinski, J. Popovici-Muller, R. Rizvi, K. E.
Rosner, B. B. Shankar, N.-Y. Shih, M. Arshad Siddiqui, J. Sun, L.
Tong, S. Umland, M. K. C. Wong, D.-y. Yang and G. Zhou, Bioorg.
10
Med. Chem. Lett., 2010, 20, 1877.
10. a) M. Lamblin, A. Couture, E. Deniau and P. Grandclaudon,
Tetrahedron, 2007, 63, 2664; b) G. W. Muller, R. Chen, S.-Y. Huang,
L. G. Corral, L. M. Wong, R. T. Patterson, Y. Chen, G. Kaplan and D.
I. Stirling, Bioorg. Med. Chem. Lett., 1999, 9, 1625; c) C. Shinji, S.
Maeda, K. Imai, M. Yoshida, Y. Hashimoto and H. Miyachi, Bioorg.
Med. Chem., 2006, 14, 7625.
15
20
25
30
35
40
45
50
11. T. Shirasaka, T. Kunitake and I. Tsuneyoshi, Brain Res., 2009, 1300,
105.
12. a) J. Wrobel, A. Dietrich, S. A. Woolson, J. Millen, M. McCaleb, M.
C. Harrison, T. C. Hohman, J. Sredy and D. Sullivan, J. Med. Chem.,
1992, 35, 4613; b) H. Sugimoto, Y. Tsuchiya, H. Sugumi, K.
Higurashi, N. Karibe, Y. Iimura, A. Sasaki, S. Araki, Y. Yamanishi
and K. Yamatsu, J. Med. Chem., 1992, 35, 4542.
13. Benzylidenephthalimidines. Jpn. Kokai Tokkyo Koho JP 59046268,
1984.
14. a) S. Das, R. Fröhlich and A. Pramanik, Org. Lett., 2006, 8, 4263-
4266; b) Y. Zhou, Y. Xiao, D. Li, M. Fu and X. Qian, J. Org. Chem.,
2008, 73, 1571.
15. T. Do Minh, A. L. Johnson, J. E. Jones and P. P. Senise, J. Org.
Chem., 1977, 42, 4217.
16. K. Smith, G. A. El-Hiti and A. S. Hegazy, Chem. Commun., 2010, 46,
2790.
17. a) S. Couty, B. Liégault, C. Meyer and J. Cossy, Org. Lett., 2004, 6,
2511; b) C. Sun and B. Xu, J. Org. Chem., 2008, 73, 7361; c) K.
Orito, M. Miyazawa, T. Nakamura, A. Horibata, H. Ushito, H.
Nagasaki, M. Yuguchi, S. Yamashita, T. Yamazaki and M. Tokuda, J.
Org. Chem., 2006, 71, 5951. d) V. Bisai, A. Suneja and V. K. Singh,
Angew. Chem. Int. Ed., 2014, 53, 1.
18. a) R. P. Hsung, Tetrahedron, 2006, 62, 3781; b) L. Benati, R.
Leardini, M. Minozzi, D. Nanni, P. Spagnolo, S. Strazzari and G.
Zanardi, Org. Lett., 2002, 4, 3079.
19. a) C. Li, F. Guo, K. Xu, S. Zhang, Y. Hu, Z. Zha and Z. Wang, Org.
Lett., 2014, 16, 3192; b) M. Abid, L. Teixeira and B. Torok, Org.
Lett., 2008, 10, 933; c) S. Yamazaki, S. Morikawa, Y. Iwata, M.
Yamamoto and K. Kuramoto, Org. Biomol. Chem., 2004, 2, 3134; d)
J. A. McCubbin, H. Hosseini and O. V. Krokhin, J. Org. Chem., 2010,
75, 959; e) M. Wilsdorf, D. Leichnitz and H. U. Reissig, Org. Lett.,
2013, 15, 2494-2497.
20. J. Hu, Z. Deng, X. Zhang, F. Zhang and H. Zheng, Org. Biomol.
Chem., 2014, 12, 4885.
21. a) Q. Wu, Y. Zhang and S. Cui, Org. Lett., 2014, 16, 1350; b) A. G.
Smith and J. S. Johnson, Org. Lett., 2010, 12, 1784; c) Z. Li, F. Fan, J.
Yang and Z. Q. Liu, Org. Lett., 2014, 16, 3396; d) R. T. Naganaboina
and R. K. Peddinti, J. Org. Chem., 2013, 78, 12819.
55 22. a) B. Wen, J. L. Petersen and K. K. Wang, Org. Lett., 2011, 13, 168;
b) A. Varadi, T. C. Palmer, P. R. Notis, G. N. Redel-Traub, D.
Afonin, J. J. Subrath, G. W. Pasternak, C. Hu, I. Sharma and S.
Majumdar, Org. Lett., 2014, 16, 1668; c) X. Zhou, H. Zhang, X. Xie
and Y. Li, J. Org. Chem., 2008, 73, 3958.
60 23. X. B. Shen, Y. Zhang, W. X. Chen, Z. K. Xiao, T. T. Hu and L. X.
Shao, Org. Lett., 2014, 16, 1984.
24. C. Sun and B. Xu, J. Org. Chem., 2008, 73, 7361.
25. a) M. Angelin, P. Vongvilai, A. Fischer and O. Ramstrom, Chem.
Commun., 2008, 768; b) M. Angelin, M. Rahm, A. Fischer, T. Brinck
65
70
and O. Ramstrom, J. Org. Chem., 2010, 75, 5882; c) C. Petronzi, S.
Collarile, G. Croce, R. Filosa, P. De Caprariis, A. Peduto, L. Palombi,
V. Intintoli, A. Di Mola and A. Massa, Eur. J. Org. Chem., 2012,
5357; d) F. Qi, L. Hu, S. Lu, X. Cao and H. Gu, Chem. Commun.,
2012, 48, 9631-9633; e) S. Lu, J. Wang, X. Cao, X. Li and H. Gu,
Chem. Commun., 2014, 50, 3512-3515.
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DOI: 10.1039/C4CC06653G
Table of Contents Entry
A convenient method for the synthesis of 3ꢀarylisoindolinones via
TfOH catalyzed C−H functionalization of arenes with
2ꢀformylbenzonitriles is developed.