One-pot facile synthesis of substituted isoindolinones via an Ugi four-component condensation/Diels-Alder cycloaddition/deselenization- aromatization sequence

Article abstract of DOI:10.1021/jo901628a

(Chemical Equation Presented) A versatile one-pot synthesis of substituted isoindolinones from 2-furaldehydes, amines, 2-(phenylselanyl)-acrylic acids, and isocyanides is described. The tandem process involves the Ugi four-component condensation, intramol

Full text of DOI:10.1021/jo901628a

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One-Pot Facile Synthesis of Substituted
Isoindolinones via an Ugi Four-Component
Condensation/Diels-Alder Cycloaddition/
Deselenization-Aromatization Sequence
Xian Huang*,†,‡ and Jianfeng Xu†
†Department of Chemistry, Zhejiang University (Xixi
Campus), Hangzhou 310028, People’s Republic of China, and
‡State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, People’s Republic of China
huangx@mail.hz.zj.cn
Received July 27, 2009
FIGURE 1. Structures of some biological and medical active com-
pounds containing the isoindolinone scaffold.
show biological and medical activities.2 For example
(Figure 1), isoindolinone 1 is found to be a potent Cdk4
inhibitor,2a isoindolinone 2 displays modest antiproliferative
effect against HT-29 and L1210 cell lines,2b isoindolinone 3
exhibits strong sedative-hypnotic effects in mice after intra-
venous administration,2c and isoindolinone 4 is a potent
inhibitor of DNA gyrase, which shows promising anti-
bacterial activity against Gram-positive bacterial strains.2d
Traditionally, the preparation of substituted isoindoli-
nones has been carried out by the nucleophilic attack-
reduction sequence on phthalimide.3 More modern achieve-
ments in the construction of substituted isoindolinones in-
clude rhenium-catalyzed reaction of aromatic aldimines with
isocyanates,4 superacid-catalyzed aza-Nazarov reaction of
N-acyliminium ion salts,5 palladium-catalyzed aromatic
carbonylation of benzylic amines,6 and iodoamination of
R-substituted secondary 2-vinylbenzamides.7 However, these
methods involve either expensive transition metal catalysts or
multistep procedures. Therefore, alternative protocols with
mild conditions, low cost, and simple operation are desirable.
Multicomponent reactions (MCRs) have emerged as
powerful synthetic strategies for the construction of biolo-
gically interesting compounds based on their high efficiency,
rich diversity, and easy operation.8 Among them, the Ugi
four-component reaction (Ugi-4CR) has been extensively
A versatile one-pot synthesis of substituted isoindoli-
nones from 2-furaldehydes, amines, 2-(phenylselanyl)-
acrylic acids, and isocyanides is described. The tandem
process involves the Ugi four-component condensation,
intramolecular Diels-Alder cycloaddition, and sub-
sequent deselenization-aromatization promoted by
BF3-OEt2. The procedure is general and efficient and
the substrates are easily available.
Isoindolinone represents a core skeleton in a large number
of natural products and pharmacophores.1 Experience has
shown that compounds with the isoindolinone scaffold often
(1) (a) Link, J. T.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 1995,
117, 552. (b) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J.-N. Org.
Lett. 2008, 10, 3543. (c) Wehlan, H.; Jezek, E.; Lebrasseur, N.; Pave, G.;
Roulland, E.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M. J. Org. Chem.
2006, 71, 8151. (d) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95.
(e) Yoon, U. C.; Jin, Y. X.; Oh, S. W.; Park, C. H.; Park, J. H.; Campana, C. F.;
Cai, X.; Duesler, E. N.; Mariano, P. S. J. Am. Chem. Soc. 2003, 125, 10664.
(2) (a) Honma, T.; Hayashi, K.; Aoyama, T.; Hashimoto, N.; Machida, T.;
Fukasawa, K.; Iwama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.;
Iwasawa, Y.; Hayama, T.; Nishimura, S.; Morishima, H. J. Med. Chem.
(3) (a) Beak, P.; Kerrick, S. T.; Donald, J. G. J. Am. Chem. Soc. 1993, 115,
10628. (b) Bousquet, T.; Fleury, J.-F.; Daich, A.; Netchitailo, P. Tetrahedron
2006, 62, 706. (c) Pearson, W. H.; Dietz, A.; Stoy, P. Org. Lett. 2004, 6, 1005.
(4) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Taka, K. J. Am. Chem.
Soc. 2006, 128, 202.
(5) Klumpp, D. A.; Zhang, Y.; O’Connor, M. J.; Esteves, P. M.; Almeid,
L. S. Org. Lett. 2007, 9, 3085.
(6) 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.
ꢀ
ꢀ
2001, 44, 4615. (b) Guillaumel, J.; Leonce, S.; Pierre, A.; Renard, P.; Pfeiffer,
B.; Arimondo, P. B.; Monneret, C. Eur. J. Med. Chem. 2006, 41, 379. (c)
Kanamitsu, N.; Osaki, T.; Itsuji, Y.; Yoshimura, M.; Tsujimoto, H.; Soga, M.
Chem. Pharm. Bull. 2007, 55, 1682. (d) Lubbers, T.; Angehrn, P.; Gmunderb,
H.; Herzig, S. Bioorg. Med. Chem. Lett. 2007, 17, 4708. (e) Hamprecht, D.;
Micheli, F.; Tedesco, G.; Checchia, A.; Donati, D.; Petrone, M.; Terrenia, S.;
Wood, M. Bioorg. Med. Chem. Lett. 2007, 17, 428. (f) 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. (g) Lee, J. H.; Byeon,
S. R.; Kim, Y. S.; Lim, S. J.; Oh, S. J.; Dae Hyuk Moon c; Yoo, K, H.; Chung,
B. Y.; Kim, D. J. Bioorg. Med. Chem. Lett. 2008, 18, 5701.
(7) Kobayashi, K.; Hase, M.; Hashimoto, K.; Fujita, S.; Tanmatsu, M.;
Morikawa, O.; Konishi, H. Synthesis 2006, 15, 2493.
(8) (a) Zhu, J., Bienayme, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, Germany, 2005. (b) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899. (c)
D'Souza, D. M.; M€uller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095. (d) Murakami,
M. Angew. Chem., Int. Ed. 2003, 42, 718.
DOI: 10.1021/jo901628a
r
Published on Web 10/27/2009
J. Org. Chem. 2009, 74, 8859–8861 8859
2009 American Chemical Society

Huang and Xu
JOCNote
SCHEME 1
TABLE 1. Effects of Reaction Conditions on the Ugi/Diels-Alder
Reactiona
investigated for the generation of small molecule libraries.9
Recently, efforts have been made to synthesize more com-
plex structures with the tandem Ugi/Diels-Alder reaction.10
2-(Phenylselanyl)acrylic acid 7a is a useful multifunctionali-
zed building block, since it has an acid group with an
R,β-unsaturated system, and we believe that it could react
smoothly in the Ugi/Diels-Alder reaction. Organoselenium
compounds have been widely used in organic synthesis due
to its various reactivities.11 Herein we envisioned that the
cycloadduct 9 formed from 7a via Ugi/Diels-Alder reaction
may go further deselenization-aromatization to afford the
desired product, isoindolinone 10 (Scheme 1).
Initially, the Ugi/Diels-Alder tandem reaction was per-
formed in CH2Cl2 with 2-furaldehyde 5a, benzylamine 6a,
2-(phenylselanyl)acrylic acid 7a, and benzyl isocyanide 8a as
the substrates; the yield was 28% (Table 1, entry 1). A solvent
screen found that protic solvent MeOH was the best (Table 1,
entries 1-4). Upon adjusting the amount of each compo-
nent, the highest yield was obtained with 1.2 equiv of 6a and
1.0 equiv of the other three components (Table 1, entries
5-10). Although heating the reaction could shorten the
reaction time, it gave a lower yield (Table 1, entries 6, 11,
and 12). Generally, the optimized condition of the Ugi/
Diels-Alder reaction used 1.0 equiv of 5a, 1.2 equiv of 6a,
1.0 equiv of 7a, and 1.0 equiv of 8a in MeOH at 25 °C for 16 h
(Table 1, entry 6).
entry 5a:6a:7a:8a (equiv) solvent temp (°C) time (h)b yield (%)c
1
2
3
4
5
6
7
8
9
1.0:1.0:1.0:1.0
1.0:1.0:1.0:1.0
1.0:1.0:1.0:1.0
1.0:1.0:1.0:1.0
1.2:1.0:1.0:1.0
1.0:1.2:1.0:1.0
1.0:1.0:1.2:1.0
1.0:1.0:1.0:1.2
1.0:1.2:1.2:1.0
CH2Cl2
toluene
CH3CN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
25
25
25
25
25
25
25
25
30
36
24
16
16
16
16
16
16
16
12
8
28
32
54
76
72
83
80
74
79
82
76
60
25
25
10 1.0:1.4:1.0:1.0
11 1.0:1.2:1.0:1.0
12 1.0:1.2:1.0:1.0
40
reflux
aUnless otherwise specified, the reaction was carried out with 5a
(1.0 mmol), 6a (1.0 mmol), 7a (1.0 mmol), and 8a (1.0 mmol) in 4 mL of
solvent under an air atmosphere. bThe reaction was monitored by TLC.
cIsolated yields.
SCHEME 2
We then tested the deselenization of product 9a to afford
isoindolinone 10a. Traditional methods applied to deseleniza-
tion such as oxidation-elimination with H2O2, NaIO4 did not
give isoindolinone 10a. We already knew that Lewis acids
could be used to open the oxo-bridge to afford a carbonca-
tion12 and the β-phenylselenyl cation could be easily eliminated
to form a carbon-carbon double bond.13 So we proposed that
when Lewis acid was added to9a, a new β-phenylselenyl cation
would form, and elimination of this β-phenylselenyl cation
followed by aromatization would produce isoindolinone 10a
(Scheme 2). A variety of Lewis acids were investigated, as
TABLE 2. Effects of Lewis Acids on the Deselenization and Aromati-
zation Reactiona
entry
Lewis acid (equiv)
time (h)b
yield (%)c
1
2
3
4
5
6
7
8
ZnCl2 (1.0)
AlCl3 (1.0)
FeCl3 (1.0)
10
6
1.5
0.5
2
40
20
2
50
56
73
77
86
0
€
(9) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632–639. (c) Domling, A.
Chem. Rev. 2006, 106, 17.
€
(10) (a) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1581. (b) Lee, D.;
Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709. (c) Wright, D. L.;
Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002, 43, 943. (d) Sello, J. K.;
Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003, 5, 4125. (e)
Oikawa, M.; Ikoma, M.; Sasaki, M. Tetrahedron Lett. 2005, 46, 415.
(11) (a) Wirth, T., Ed. Organoselenium Chemistry: Modern Developments in
Organic Synthesis. In Topics in Current Chemistry; Springer: Berlin, Germany,
2000; Vol. 208. (b) Wirth, T. Angew. Chem. 2000, 112, 3890. Angew. Chem., Int.
Ed. 2000, 39, 3740. (c) Uehlin, L.; Wirth, T. Org. Lett. 2001, 3, 2931. (d) Tiecco,
M. Top. Curr. Chem. 2000, 208, 7. (e) Tiecco, M.; Testaferri, L.; Santi, C.;
Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A. Angew. Chem. 2003, 115,
3239. Angew. Chem., Int. Ed. 2003, 42, 3131. (f) Santi, C.; Santoro, S.;
Battistelli, B.; Testaferri, L.; Tiecco, M. Eur. J. Org. Chem. 2008, 5387. (g)
Fujiwara, S.; Asanuma, Y.; Shin-ike, T.; Kambe, N. J. Org. Chem. 2007, 72, 8087.
(12) Liu, L.; Gao, Y.; Che, C.; Wu, N.; Wang, D. Z.; Li, C.-C.; Yang, Z.
Chem. Commun. 2009, 662.
TiCl4 (1.0)
BF3-OEt2 (1.0)
AgOTf (1.0)
ZrCl4 (1.0)
38
84
BF3-OEt2 (2.0)
aUnless otherwise specified, the reaction was carried out with 9a
(1.0 mmol) and Lewis acid (1.0 mmol) in 4 mL of CH2Cl2 under an air
atmosphere at room temperature. bThe reaction was monitored by TLC.
cIsolated yields.
shown in Table 2, and the results indicated that BF3-OEt2 was
the optimum Lewis acid (Table 2, entry 5).
With the above two optimized conditions in hand, we tried
to combine these two steps in one pot, without the isolation
(13) Yoshimatsu, M.; Murase, Y.; Itoh, A.; Tanabe, G.; Muraoka, O.
Chem. Lett. 2005, 34, 998.
8860 J. Org. Chem. Vol. 74, No. 22, 2009

Huang and Xu
JOCNote
TABLE 3. Synthesis of Various Isoindolinones 10a
entry
5
6
7
8
yield (%)d
1
R1 = H (5a)
R2 = Bn (6a)
6a
R3 = H (7a)
7a
7a
7a
7a
7a
R4 = Bn (8a)
8a
8a
8a
8a
8a
8a
8a
10a, 65
10b, 47
10c, 56
10d, 42
10e, 58
10f, 61
10g, 69
10h, 49
10i, 40
10j, 47
10k, 53
10l, 40
10m, 35
10n, 43
10o, 42
2b
3
R1 = Me (5b)
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5a
5a
R2 = Pr (6b)
4
R2 = Cy (6c)
5c
R2 = Ph (6d)
6c
R2 = p-CH3OC6H4 (6e)
7c
R2 = p-ClC6H4 (6f)
7a
R3 = Me (7b)
8c
6a
6a
6a
6a
6a
6a
6b
6a
9b
10b
11
12
13b
14c
15c
R3 = Pr (7c)
8a
8a
R3 = Ph (7d)
7a
7a
7b
7b
7b
R4 = p-CH3C6H4 (8b)
R4 = CH2COOEt (8c)
8a
8a
8b
aThe reaction was carried out with 5 (1.0 mmol), 6 (1.2 mmol), 7 (1.0 mmol), and 8 (1.0 mmol) in 4 mL of MeOH under an air atmosphere at room
temperature for 16 h. bThe reaction was carried out with 5 (1.0 mmol), 6 (1.2 mmol), 7 (1.0 mmol), and 8 (1.0 mmol) in 4 mL of MeOH under an air
atmosphere at room temperature for 12 h then reflux for 24 h. cThe reaction was carried out with 5 (1.0 mmol), 6 (1.2 mmol), 7 (1.0 mmol), and 8 (1.0
mmol) in 4 mL of MeOH under an air atmosphere at room temperature for 12 h then reflux for 8 h. dIsolated yields.
of cycloadduct 9a. When the Diels-Alder reaction was
complete, MeOH was removed and the solvent was replaced
with anhydrous CH2Cl2. Then 2.0 equiv of BF3-OEt2 was
added and, after 2 h, the isoindolinone 10a was obtained
in 65% overall yield. By using the established reaction
conditions, a variety of 2-furaldehydes 5, amines 6,
2-(phenylselanyl)acrylic acids 7, and isocyanides 8 were
investigated. As shown in Table 3, the yields of isoindo-
linones 10 ranged from 35% to 69%. When substituted
2-furaldehydes, arylamines, and substituted 2-(phenylsela-
nyl)acrylic acids were used, the cycloaddtion step proceeded
under reflux conditions. The substituent on 2-furaldehyde
made the reaction take place under a more forceful condi-
tion, and the yields were lower (Table 3, entries 1, 2 and
entries 8, 13). Arylamines gave higher yields than alkyla-
mines (Table 3, entries 1 and 3-7), and the substituents on
the aryl group did not influence the reaction much (Table 3,
entries 5-7). Both alkyl and aryl subtituents on 2-(phenyl-
selanyl)acrylic acid can be used in this reaction smoothly,
and the yields were moderate (Table 3, entries 1, 8-10 and
entries 13-15). Substituents on isocyanides also affected this
reaction where alkyl isocyanides were generally better than
aryl isocyanide and isocyanide with an electron-withdrawing
group (Table 3, entries 1, 11, and 12).
Experimental Section
General Procedure for Synthesis of Isoindolinones 10. A 2-
furaldehyde 5 (1.0 mmol), a primary amine 6 (1.2 mmol), a
2-(phenylselanyl)acrylic acid 7 (1.0 mmol), and an isocyanide 8
(1.0 mmol) were combined in methanol (4 mL), and the reaction
mixture was stirred at 25 °C for 16 h. Then methanol was
evaporated and anhydrous CH2Cl2 (5 mL) and BF3-OEt2 (2.0
mmol) were added, then stirring was continued at 25 °C for an
additional 2 h before the reaction was quenched by adding sat. aq
NaHCO3 (20 mL). The layers were separated and the aqueous
layer was extracted with CH2Cl2 (2 ꢀ 15 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and
evaporated. The residue was purified by flash chromatography
(petroleum ether/ethyl acetate 2:1 v/v) to give the product 10.
N,2-Dibenzyl-3-oxoisoindoline-1-carboxamide (10a): pale
solid, mp 169-171 °C; 1H NMR (400 MHz, CDCl3) δ 7.59
(1H, d, J=7.2 Hz), 7.48-7.51 (1H, m), 7.40 (1H, br, 1H of NH),
7.15-7.34 (12H, m), 5.24 (1H, d, J=14.8 Hz, 1H of CH2), 4.88
(1H, s, 1H of CH), 4.44 (1H, dd, J1=14.8 Hz, J2=6.0 Hz, 1H of
CH2), 4.38 (1H, dd, J1=14.8 Hz, J2=6.0 Hz, 1H of CH2), 4.17
(1H, d, J=14.8 Hz, 1H of CH2); 13C NMR (100 MHz, CDCl3) δ
169.5, 167.5, 141.2, 138.0, 135.9, 132.2, 130.4, 128.9, 128.6,
128.4, 128.0, 127.7, 127.4, 123.7, 112.7, 64.1, 45.6, 43.4; MS
(EI) m/z 356 (Mþ); IR νmax (cm-1) 1695, 1664, 1541, 1397, 1241,
740, 699; HRMS (EI) m/z calcd for C23H20N2O2 (Mþ) 356.1525,
found 356.1522.
In summary, we have developed a one-pot synthesis of
substituted isoindolinones from 2-furaldehydes, amines,
2-(phenylselanyl)acrylic acids, and isocyanides. The tandem
process involves the Ugi four-component condensation,
intramolecular Diels-Alder cycloaddition, and subsequent
deselenization-aromatization promoted by BF3-OEt2. The
procedure is general and efficient and the substrates are
easily available. Considering the importance of isoindoli-
none derivatives, this method may find wide application in
the synthesis of more complex polycyclic heterocycles.
Acknowledgment. We are grateful to the National Natur-
al Science Foundation of China (Project Nos. 20672095 and
20732005) and National Basic Research Program of China
(973 Program, 2009CB825300) for financial support.
Supporting Information Available: General experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 74, No. 22, 2009 8861