A New and Convenient Synthesis of Amino-phthalimide (1 H -Isoindole-1,3(2 H )-dione) Derivatives and...

A New and Convenient Synthesis of Amino-phthalimide (1H-Isoindole-1,3(2H)-dione) Derivatives and Their Photoluminescent Properties

by Ayse Tan, Ebru Bozkurt, Nurhan Kishali, and Yunus Kara*

Department of Chemistry, Faculty of Sciences, Atat�rk University, TR-25240 Erzurum(phone: þ 90-442-2314424; fax: þ 90-442-2360948; e-mail: [email protected] (Y. Kara);

[email protected] (N. Kishalı))

A new and convenient synthesis for amino-phthalimide (1H-isoindole-1,3(2H)-dione) derivativeshas been developed starting from an a,b-unsaturated ketone. The ketones were reacted with amines togive aromatic amine products. This is the first time that substituted amine groups have been incorporatedin aromatic rings. The mechanism of the product formation is rationalized by the 1,2-addition of aminesto ketones. All aromatic compounds exhibited high fluorescence properties at the blue-green region.

Introduction. – Phthalimides (1H-isoindole-1,3(2H)-diones), and their derivativesare protean building stones in organic synthesis; in particular, they have been a focus ofinterest as an important class of organic compounds with medicinal and biologicalimportance [1]. 1H-Isoindole-1,3(2H)-dione has attracted attention due to its recentlydiscovered action against inflammatory diseases and cancer [2].

1H-Isoindole-1,3(2H)-dione and its N-substituted derivatives of type 1 (Fig. 1) arewell-known for their biological features such as anti-inflammatory [3], anticonvulsant[4a], anticancer [4], and antimicrobial activities [5]. Further, structural modificationshave led to great improvements in activity, e.g., the remarketed drug thalidomide (21))and pomalidomide (3 ; ActimidTM; Fig. 1) [6]. These two compounds have beenmarketed as immune modulatory drugs. Studies of Malawska and co-workers on thedevelopment of cholinesterase inhibitors as a potential means of treating Alzheimer�sdisease indicated that 2-(3-diethylaminoalkyl)-1H-isoindoline-1,3(2H)-dione deriva-tives could be described as selective acetylcholine esterase inhibitors [7]. 2-Methyl-5-(pyrrolidine-1-yl)-1H-isoindole-1,3(2H)-dione (4a) [8], 5-(dimethylamino)-2-methyl-1H-isoindole-1,3(2H)-dione (4b) [9], and 5-(ethylamino)-2-methyl-1H-isoindole-1,3(2H)-dione (4c) [10], synthesized from 6-amino-2,3-dihydrophthalazine-1,4-dione,have been reported to have some biological activities and chemiluminescent properties(Fig. 2).

Recently, we have developed a versatile approach to the synthesis of the newnorcantharimide derivative 2-ethyl-3a,7a-dihydro-4H-isoindole-1,3,5-trione (11) from2-ethyl-3a,4,7,7a-tetrahydroisoindole-1,3-dione (5) [11a] (Scheme 1).

Helvetica Chimica Acta – Vol. 97 (2014) 1107

� 2014 Verlag Helvetica Chimica Acta AG, Z�rich

1) The pharmaceutical company Celgene [6a] has remarketed thalidomide (ThalomidTM) asimmunomodulatory drug (IMiDTM).

Herein, we describe a novel, and efficient synthesis of 5-aminophthalimide (1H-isoindole-1,3(2H)-diones) derivatives 4a – 4c and 13a – 13c from a,b-unsaturatedketones 11 and 12, and their fluorescence properties.

Results and Discussion. – a,b-Unsaturated ketones were the key compounds for thesynthesis of our target molecules 4a – 4c and 13a – 13c. Unsaturated ketone 11 wasprepared starting from 3-sulfolene [11a]. Ketone 12 [12] can also be synthesized indifferent ways; however, by our method [11a], we also obtained 12 (Scheme 1).

The compounds 5 – 12, formed from these reactions, are derivatives of norcanthar-imide. To synthesize new amino norcantharimide derivatives, we investigated thereaction of ketones 11 and 12 with amines. We first studied the reaction of 11 withpyrrolidine in CH2Cl2 at room temperature. This reaction gave a highly interestingproduct 13a, including an aromatic ring (Scheme 2).

The structure of 13a was assigned on the basis of its 1H- and 13C-NMR spectra,which revealed the presence of three different aromatic H-atoms, five CH2 groups, andone Me group. The most remarkable features deduced from the 1H-NMR spectrum of13a were the presence of the aromatic H-atoms and incorporation of the aminofunctionality in the molecule. The aromatic H-atom signals appeared as two doublets at7.60 (J¼ 8.4) and 6.93 ppm (J¼ 2.2) and a dd at 6.62 ppm (J¼ 8.4, 2.2). The 13C-NMRspectrum exhibited signals of two C¼O groups, and, six aromatic and six aliphatic C-atoms.

Helvetica Chimica Acta – Vol. 97 (2014)1108

Fig. 1. Phthalimide (1H-isoindole-1,3(2H)-dione) derivatives

Scheme 1. Synthesis of a,b-Unsaturated Ketones. TPP, Tetraphenylporphyrin; PCC, pyridinium chloro-chromate

Fig. 2. 5-Aminophthalimide (5-amino-1H-isoindole-1,3(2H)-dione) derivatives

To probe the general applicability of this method, we reacted ketones 11 and 12 withamines such as pyrrolidine, EtNH2, and Me2NH. Analogous results were obtained withall these amines (Scheme 2). Chemical-shift and double resonance experiments clearlyindicated that the amine has been added directly to the C¼O group (1,2-addition;Route B). 1H-NMR Analysis of the crude products did not indicate any 1,4-additionproduct (Route A). Based on the structure of the products, we propose a reactionmechanism in Scheme 3. First, product 15 is formed by the 1,2-addition reaction of theamine to the ketone to give 14, followed by H2O elimination. Compound 15 is thenconverted into an aromatic ring by dehydrogenation. This aromatization is assumed totake place through oxidation by O2 in the air atmosphere.

In these experiments, we observed that 2 equiv. of amine led to a low yield of theproduct (14 to 56%). This was attributed to the formations of uncharacterized products.However, with 1 equiv. of amine better yields between 44 and 68% were obtained. Onthe other hand, Hegde et al. [12] transformed a,b-unsaturated cyclohexanones to thecorresponding iodophenolic compounds using several equivalents of base and I2 at lowtemperatures (6 equiv. of EtONa, 2 equiv. of I2, � 788). In our study, we could proceedwith the aromatization process under very mild conditions (1 equiv. of amine at room


Scheme 3. Proposed Mechanism for the Formation of 5-Aminophthalimide Derivatives

Scheme 2. Synthesis of 5-Aminophthalimide Derivatives

temperature) to obtain new 5-aminophthalimide derivatives. With this protocol, weoffer a new method for the syntheses of aromatic amines under easily reproduciblereaction conditions.

We also investigated the photoluminescence properties of the 5-aminophthalimidederivatives. Several studies have been reported on the effects of various protic andpolar solvents on their luminescence properties [9] [10] [13] [14]. We studied thephotophysical properties of 5-aminophthalimide derivatives 4 and 13 in CH2Cl2 as anonpolar solvent. Normalized fluorescence spectra of all 5-aminophthalimide deriv-atives in CH2Cl2 were shown in Fig. 3. UV/VIS Absorption data (Table 1) have shownthat all derivatives 4 and 13 have three different absorption peaks in CH2Cl2.Fluorescence spectra revealed that these compounds exhibit high fluorescence in theblue-green region, indicating that aminophthalimide derivatives displaying differentwavelengths of fluorescence can be obtained by varying the substituents [13].

The fluorescence quantum yields and fluorescence lifetime values of amino-phthalimide derivatives 4 and 13 are compiled in Table 1. Compounds 4c and 13c hadthe highest fluorescence quantum yields. The quantum yields also varied depending onthe substituents of the amino group at C(5) of compounds 4 and 13. These changes canbe attributed to the substituent effect on conjugation. However, the fluorescence


Fig. 3. Normalized fluorescence spectra of 5-aminophthalimide derivatives a) 4a, 4b, and 4c and b) 13a,13b, and 13c in CH2Cl2 (lexc 350 nm)

Table 1. Maximum-Fuorescence Emission Wavelength, Fluorescence Quantum Yields, and Lifetimes of 5-Aminophthalimide Derivatives in CH2Cl2 at Room Temperature

Compound labs [nm] lems [nm] Ff t [ns]

4a 269, 327, 400 481 0.29 13.714b 268, 324, 394 478 0.75 14.574c 263, 317, 379 465 0.90 16.62

13a 269, 327, 400 481 0.17 13.9213b 268, 324, 393 477 0.72 13.7613c 263, 317, 378 463 0.89 15.83

quantum yields of 4b and 13b were quite high as well. The rate constants of theradiative (kr) and non-radiative (knr) deactivation were calculated by Eqns. 1 and 2[15].

kr ¼Ff

tfð1Þ

1tf¼ kr þ knr ð2Þ

The values for kr and knr are collected in Table 2. The non-radiative deactivationrate constants (knr) for 4 and 13 decrease with increasing electron-donating property ofthe amino group at C(5). Therefore, the radiative transitions for these types ofcompounds become more favorable due to the effect of the N-substituents in an apolarsolvent such as CH2Cl2.

5-Aminophthalimide derivatives have electron-donor and -acceptor groups. So,when these molecules are electronically excited in a polar solvent, intramolecularcharge transfer (ICT) occurs from the amino group to one of the C¼O groups in thephthalimide ring, and, therefore, the ICT state displays a fluorescence property. Withincreasing solvent polarity, nonfluorescent twisted intramolecular charge transfer(TICT) takes place by rotation of the amino group [14].

We have determined the photophysical parameters of 5-amino phthalimidederivatives with different alkyl substituents of the amino group in a nonpolar solvent.The values indicated that these compounds returned from the excited structure of ICTto the ground-state by a radiative process in CH2Cl2, which is much less polar than H2O.In CH2Cl2, the lifetime values are smaller than those in polar solvents. However,different electron-donating properties of these amino groups cause an increase in thefluorescence quantum yield and lifetime values for 5-aminophthalimide derivatives[16].

In conclusion, we reported an efficient synthesis of new 5-aminophthalimidederivatives, incorporating amine groups in the aromatic ring. This method has thepotential to be widely used in organic synthesis. We assume that the amount of amine


Table 2. Radiative and Non-radiative Deactivation Rate Constants of 5-Aminophthalimide Derivatives inCH2Cl2

Molecule kr� 10�9 [s�1] knr� 10�9 [s�1]

4a 0.0212 0.05184b 0.0515 0.01724c 0.0542 0.0060

13a 0.0122 0.059613b 0.0523 0.020313c 0.0562 0.0069

was highly influential on the reaction yield. Furthermore, the spectroscopic studiesindicated that the synthesized 5-amino phthalimide derivatives are fluorescentmolecules. Due to their fluorescence properties, these molecules can be used inseveral areas such as the laser industry, organic light-emitting diodes (OLED), solarcells, protein labeling, sensors applications, etc.

Experimental Part

General. All reagents used were commercially available unless otherwise specified and all solventswere distilled before use. M.p.: Gallenkamp melting-point device. UV/VIS Absorption and fluorescencespectra: Perkin Elmer Lambda 35 UV/VIS spectrophotometer and a Shimadzu RF-5301PC spectro-fluorophotometer, resp. Fluorescence and absorption measurements of all aminophthalimide derivativeswere performed at r.t. in CH2Cl2. For the steady-state fluorescence measurements, all the samples wereexcited at 350 nm, and fluorescence intensities were recorded between 360 and 700 nm. Thefluorescence-lifetime measurements were carried out with a LaserStrobeTM mode TM-3 spectrofluor-ophotometer from PTI. The excitation source was a combination of a pulsed nitrogen laser/tunable dyelaser. The samples were excited at 337 nm. The decay curves were collected over 200 channels using anonlinear time scale, with the time increment increasing according to arithmetic progression. Thefluorescence decays were analyzed with the lifetime distribution analysis software supplied by theinstrument manufacturer. The quality of fits was assessed by c2 values and weighed residuals [17].Fluorescence quantum yield (Ff) for 5-aminophthalimide derivatives were calculated by using theParker�Rees equation [18]. Quinine sulfate in a 0.5m H2SO4 soln. was used as the reference. 1H- and13C-NMR spectra: Varian 400 and Bruker 400 instruments; in CDCl3. Elementel analysis: Leco CHNS-932 instrument.

Compound 11 was synthesized as described in [11a]. By the same method, we obtained ketone 12.The Singlet-Oxygen Ene Reaction of 3a,4,7,7a-Tetrahydro-2-methyl-1H-isoindole-1,3(2H)-dione (6)

[11a]. To a stirred soln. of 6 (907 mg, 5.5 mmol) in CH2Cl2 (150 ml) was added tetraphenylporphyrin(TPP; 20 mg). The resulting mixture was irradiated with a tungsten halogen projection lamp (500 W),with O2 being passed through the soln., and the mixture was stirred at r.t. After the evaporation of thesolvent (308, 20 mmHg), the major product, trans-8, was separated by fractional crystallization fromCH2Cl2/hexane. The 1H-NMR signals of unpurified isomer cis-8 were were assigned by comparison of the1H-NMR spectrum of isomers of trans-8 and their mixture.

3a,4,5,7a-Tetrahydro-5-hydroperoxy-2-methyl-1H-isoindole-1,3(2H)-dione (trans-8). Yield: 920 mg(85%). Colorless solid. M.p. 117 – 1188. IR (KBr): 3373, 2946, 1774, 1692, 1439, 1381, 1289. 1H-NMR(400 MHz, CDCl3): 8.68 (s, OOH); 6.12 – 6.06 (m, 2 H); 4.48 – 4.45 (m, 1 H); 3.49 – 3.47 (m, 1 H); 3.29 –3.23 (m, 1 H); 2.97 (s, 3 H); 2.21 – 2.18 (m, 2 H). 13C-NMR (100 MHz, CDCl3): 179.2; 176.6; 129.1; 126.0;75.4; 41.3; 36.3; 25.5; 25.2. Anal. calc. for C9H11NO4 (197.19): C 54.82, H 5.62, N 7.10; found: C 55.01, H5.16, N 7.14.

Reduction of 8 with Me2S. To the magnetically stirred slurry of Me2S (176 mg, 2.84 mmol) in CH2Cl2

(25 ml) was added a soln. of 8 (279 mg, 1.42 mmol) in CH2Cl2 (25 ml) at r.t. After the addition wascomplete (10 min), the mixture was stirred for 6 h, CH2Cl2 was evaporated, the residue was extractedwith CH2Cl2 (3� 30 ml), and the extract was dried (Na2SO4). The soln. was evaporated to give 3a,4,5,7a-tetrahydro-5-hydroxy-2-methyl-1H-isoindole-1,3(2H)-dione (10 ; crystallized from CH2Cl2/hexane;210 mg, 82%). Colorless crystals. M.p. 95 – 968. IR (KBr): 3450, 2932, 1774, 1693, 1439, 1385, 1288,1221, 1166. 1H-NMR (400 MHz, CDCl3): 6.02 (dtd, J ¼ 10.1, 2.2, 0.7, 1 H); 5.85 (ddd, J ¼ 10.1, 4.0, 1.8,1 H); 4.13 (s, OH); 3.44 (tt, J ¼ 6.2, 2.1, 1 H); 3.20 (dt, J ¼ 13.5, 5.5, 1 H); 2.94 (s, 3 H); 2.48 (s, 1 H); 2.39(dtd, J ¼ 13.2, 4.7, 0.7, 1 H); 1.73 (ddd, J ¼ 13.2, 8.8, 5.8, 1 H). 13C-NMR (100 MHz, CDCl3): 179.1; 176.9;135.2; 122.8; 62.6; 41.1; 37.1; 30.1; 25.1. Anal. calc. for C9H11NO3 (181.19): C 59.66, H 6.12, N 7.73; found:C 59.67, H 5.83, N 7.72.

Synthesis of 3a,7a-Dihydro-2-methyl-1H-isoindole-1,3,5(2H,4H)-trione (12). To a mixture ofpyridinium chlorochromate (PCC; 560 mg, 2.6 mmol, 2 equiv.) and powdered molecular sieves (3 �,one-half of the weight of PCC) in dry CH2Cl2 was added 10 (235 mg, 1.3 mmol, 1 equiv.) at 08. The


mixture was stirred for 4 h at r.t. CH2Cl2 was evaporated, and Et2O was added to the residue. The slurrywas stirred and filtered through a pad of Celite. The residue was washed with Et2O (3 – 4� 10 ml) andfiltered. The filtrate was concentrated to give virtually pure 12 (104 mg, 45%). Colorless solid. M.p. 225 –2278. IR (KBr): 3417, 3223, 2963, 2924, 1784, 1707, 1439, 1385, 1300, 1279. 1H-NMR (400 MHz, CDCl3):6.70 (dd, J¼ 10.2, 1.1, 1 H); 6.20 (d, J¼ 10.2, 1 H); 3.77 (s, 1 H); 3.43 (d, J¼ 8.1, 1 H); 3.18 (dd, J¼ 17.9,1.5, 1 H); 3.04 (s, 3 H); 2.84 (dd, J¼ 17.9, 8.4, 1 H). 13C-NMR (100 MHz, CDCl3): 193.4; 177.3; 174.2;142.4; 132.2; 71.8; 45.4; 31.6; 25.7.

General Procedure for the Preparation of 4a – 4c and 13a – 13c. To a magnetically stirred slurry of 11or 12 (0.67 mmol) in CH2Cl2 (20 ml) was added a soln. of amine (pyrrolidine, EtNH2, Me2NH;0.67 mmol) in CH2Cl2 (10 ml) over 3 h at r.t. Then, the solvents were evaporated under reduced pressure,and the residue was purified by column chromatography (CC; SiO2 (20 g); AcOEt/hexane 10 : 90) toafford pure compounds as yellow solids.

2-Methyl-5-(pyrrolidin-1-yl)-1H-isoindole-1,3(2H)-dione (4a) . Crystallized from CH2Cl2/hexane.Yield: 62%. Yellow crystals. M.p. 180 – 1818. IR (KBr): 2962, 2844, 1754, 1693, 1618, 1513, 1448, 1427,1379, 1345, 1260. 1H-NMR (400 MHz, CDCl3): 7.58 (d, J ¼ 8.4, 1 H); 6.90 (d, J ¼ 2.2, 1 H); 6.60 (dd, J ¼8.4, 2.2, 1 H); 3.38 (m, 4 H); 3.10 (s, 3 H); 2.05 (m, 4 H). 13C-NMR (100 MHz, CDCl3): 169.7; 169.3;152.0; 135.2; 125.0; 117.3; 114.7; 106.0; 48.2; 25.7; 23.9. Anal. calc. for C13H14N2O2 (230.11); calc. C 67.81,H 6.13, N 12.17; found: C 67.46, H 6.34, N 11.05.

5-(Dimethylamino)-2-methyl-1H-isoindole-1,3(2H)-dione (4b) [9]. Crystallized from CH2Cl2/hex-ane. Yield: 68%. Yellow crystals. M.p. 186 – 1878. IR (KBr): 2924, 1750, 1702, 1619, 1519, 1427, 1381, 1283,1227. 1H-NMR (400 MHz, CDCl3): 7.63 (d, J ¼ 8.4, 1 H); 7.06 (d, J ¼ 2.2, 1 H); 6.76 (dd, J ¼ 8.4, 2.2,1 H); 3.12 (s, 3 H); 3.11 (s, 3 H); 3.10 (s, 3 H). 13C-NMR (100 MHz, CDCl3): 169.6; 169.2; 154.5; 135.1;124.9; 118.0; 114.6; 105.9; 40.7; 24.0. Anal. calc. for C11H12N2O2 (204.09); C 64.69, H 5.92, N 13.72; found:C 64.51, H 5.72, N 13.38.

5-(Ethylamino)-2-methyl-1H-isoindole-1,3(2H)-dione (4c). Crystallized from CH2Cl2/hexane. Yield60%. Yellow crystals. M.p. 149 – 1508. IR (KBr): 3386, 2963, 1755, 1703, 1622, 1542, 1453, 1428, 1382,1261. 1H-NMR (400 MHz, CDCl3): 7.57 (d, J ¼ 8.4, 1 H); 6.94 (d, J¼ 1.8, 1 H); 6.68 (dd, J¼ 8.4, 2.2, 1 H);4.4 (br. s, NH); 3.27 – 3.24 (m, 2 H); 3.1 (s, 3 H); 1.29 (t, J¼ 7.1, 3 H). 13C-NMR (100 MHz, CDCl3): 169.3;169.1; 153.4; 135.4; 125.1; 119.3; 115.8; 106.1; 38.4; 24.0; 14.7. Anal. calc. for C11H12N2O2 (204.09): C 64.69,H 5.92, N 13.72; found: C 65.04, H 5.96, N 13.17.

2-Ethyl-5-(pyrrolidin-1-yl)-1H-isoindole-1,3(2H)-dione (13a) . Crystallized from CH2Cl2/hexane.Yield: 60%. Dark-yellow crystals. M.p. 187 – 1888. IR (KBr): 3100, 1692, 1615, 1509, 1396, 1095.1H-NMR (400 MHz, CDCl3): 7.60 (d, J¼ 8.4, 1 H); 6.93 (d, J¼ 2.2, 1 H); 6.62 (dd, J¼ 8.4, 2.2, 1 H); 3.67(q, J¼ 7.1, 2 H); 3.39 (t, J¼ 6.6, 4 H); 2.08 – 2.05 (m, 4 H); 1.24 (t, J¼ 7.0, 3 H). 13C-NMR (100 MHz,CDCl3): 169.4; 169.1; 152.0; 135.2; 125.0; 117.4; 114.7; 106.0; 48.3; 32.78; 25.7; 14.4. Anal. calc. forC14H16N2O2 (244.12): C 68.83, H 6.60, N 11.47; found: C 69.19, H 6.37, N 11.47.

5-(Dimethylamino)-2-ethyl-1H-isoindole-1,3(2H)-dione (13b). Crystallized from CH2Cl2/hexane.Yield: 66%. Yellow crystals. M.p. 112 � 1138. IR (KBr): 2928, 1758, 1703, 1616, 1519, 1440, 1395, 1372,1350, 1283, 1226. 1H-NMR (400 MHz, CDCl3): 7.60 (d, J¼ 8.4, 1 H); 7.03 (d, J¼ 2.2, 1 H); 6.74 (dd, J¼8.4, 2.2, 1 H); 3.66 (q, J¼ 7.1, 2 H); 3.08 (s, 6 H); 1.22 (t, J¼ 7.1, 3 H). 13C-NMR (100 MHz, CDCl3): 169.3;169.0; 154.5; 135.1; 124.8; 118.0; 114.7; 105.9; 40.7; 32.8; 14.3. Anal. calc. for C12H14N2O2 (218.11): C 66.04,H 6.47, N 12.84; found: C 65.62, H 6.21, N 12.70.

2-Ethyl-5-(ethylamino)-1H-isoindole-1,3(2H)-dione (13c). Crystallized from CH2Cl2/hexane. Yield:44%. Yellow crystals. M.p. 106 – 1078. IR (KBr): 3380, 2972, 1754, 1703, 1619, 1541, 1451, 1396, 1376,1349, 1284. 1H-NMR (400 MHz, CDCl3): 7.57 (d, J¼ 8.4, 1 H); 6.94 (d, J¼ 2.2, 1 H); 6.68 (dd, J¼ 8.4, 2.2,1 H); 4.38 (br. s, NH); 3.67 (q, J¼ 7.1, 2 H); 3.26 (dq, J¼ 7.3, 1.8, 2 H); 1.30 (t, J¼ 7.3, 3 H); 1.23 (t, J¼ 7.1,3 H). 13C-NMR (100 MHz, CDCl3): 169.1; 168.9; 153.4; 135.4; 125.1; 119.3; 115.8; 106.0; 38.4; 32.8; 14.7;14.3. Anal. calc. for C12H14N2O2 (218.11); C 66.04, H 6.47, N 12.84; found: C 66.29, H 6.26, N 12.52.

The authors are grateful to Atat�rk University for financial support (Grant No. 2010/283), and to Dr.Hasan SeÅen, Dr. Umit Demir, and Bilal Altundas for helpful discussions.


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Received November 5, 2013


A New and Convenient Synthesis of Amino-phthalimide (1 H -Isoindole-1,3(2 H )-dione) Derivatives and...

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