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LETTER 343
Microwave-Assisted Parallel Synthesis of a 2-Aryl-lH-Isoindole-l,3-DioneLibraryBernardo M. Barchín, Ana M. Cuadro, Julio Alvarez-Builla*
Departamento de Química Orgánica, Universidad de Alcalá. Ora. Madrid-Barcelona Km 33,600, c.P. 28871, Alcalá de Henares, Madrid,SpainFax +34(91 )8854686; E-mail: [email protected]\'ed 25 Oclober 2001
Abstraet: An efficient parallel synthesis of a representative 28member library of phthalimides is described. Parallel chromatography afforded the library members in suitable purity and with highyields.
Key words: library, microwave, phthalimide, 2-aryl-IH-isoindole1,3-dione, TNF-u
Imide derivatives are compounds of considerable interestdue to their biological properties, I and their interest asgeneral intermediates in synthesis2 and in polymer chemistry.3 Today, available routes for the synthesis of imidederivatives involve either Lewis-acid mediated condensa
tion of an amine with maleic or phthalic anhydride2a.-l orN-alkylation of the corresponding imide with halides,5 oralcohols under Mitsunobu conditions.2a.-la There is, however, still need of simple, efficient and general methodsfor the synthesis of functional ised imides. Recently, a substantial improvement of classical methods has been obtained using microwaves6 and solvent-free procedureswith7 and without8 catalyst, have been published.
In an effort to develop an efficient one-pot chemical transformation, we had developed a method for a rapidparallel9 synthesis of smalllibraries, using a domestic microwave oyen, and we report the application of the technique to the synthesis of a phthalimide library, as atechnique capable of providing a large numbers of interesting intermediates.
The procedure has been developed along several steps:
i) Structure of the Oven. Highest Irradiation Area Determination. In a domestic oyen. not all areas in the dish are
irradiated with the same intensity. It is thus, necessary tofix, for reproducibility, where the samples should beplaced. The determination of the highest irradiation area(HIA) -which is similar for nearly all commercial domestic ovens- was easily performed by heating a disk of moistfilter paper (26 cm diameter) placed over the oyen dish,for 15 min (550 W output). As a result, a burned area between 16 cm and 22 cm from the central point of the cirde, was obtained. Consequently, a disk made of teflon (5mm thick) was designed (Figure 1, measures in mm), ablelo hold 28 vials (20 mm diameter) in the area indicated.
Synlett 2002, No. 2, 01022002. Article Identifier:I·B7-2096,E;2002,0,02,0343.0345,ftx,en;G3150 1ST.pdf.© Georg Thieme Verlag Stuttgart . New YorkISSN 0936-5214
Other similar devices for a smaller number of bigger sampies are currently being tested.
ii) Optima! Reaction Conditions. The reaction between panisidine and phthalic anhydride was chosen as a modelprocess, and tests were carried using open vials in the teflon disk -evenly spaced on it- at different oyen outputsand reaction times. With the experiments, it was concluded that one sample, irradiated 1 min at 550 W in the HIA,produced the highest yields. Also, it was concluded thatthe sample, once the product was formed, could be additionally heated up to 15 min at the same energy. withoutappreciable decomposition.
The optimal reaction conditions (l min 550 W) were applied to four anilines: (a, R3 = Ome; b, R1 = R5 = Et; c, RI
= Me, R2 = Cl; d, R3 = F) each test being repeated fourtimes, and giving the following mean yields: a) 95 ±0.28%; b) 78 ± 2.98%, c) 80 ± 2.70%; d) 80 ± 2.85%.
In a typical general procedure, 4 mL vials, containing amixture of the corresponding phthalic anhydride (0.68mmol) and the aniline (0.68 mmol), without solvent, wereirradiated in a domestic microwave oyen 10 at 550 W for12-15 mino Reaction mixtures were diluted in 1-3 mL of
CH2CI2-MeOH (90: 10) and filtered through a 2 cm pad ofneutral alumina, using a VacMaster SPE sample processing station.11 The vials with the organic extracts wereevaporatedl2 to leave the crude products which were purified by recrystalilsation when needed.
iii) Time Versus Number of Samp!es: Starting from p-anisidine and phthalic anhydride, sets of 4, 8 or 12 sampleswere irradiated with different reaction times (Table 1).
Figure 1
344 B. M. Barchín et al. LETTER
From these results, the time required to obtain yieldsaround 95% or higher were determined, and the time versus number of samples was plotted13 and fitted to a curveas indicated in Figure 2. The model serves, as a reference,to calculate the time in minutes (t) needed to expand theconditions developed for one sample, to a set of a givennumber of vials (n) (Equation).
Table 2 Synthesis of 2-Aryl-(5-methyl)-IH-isoindole- 1,3-(2H)-diones"
Table 1 Time Versus Number of Samples
Time/sample MeanYield (%)
3c (93)
3d(91)16
3e (71)17
3f (78)14
3g (87)IS
3h (93)IS
3i (95)14
3j (90)14
3k (93)19
31 (95)15
Comp.
(% yield)
3a (90)14
3b (97)15
Et
i-Pr
i-Pr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
R~
H
OMe H
el
H
H
H
H
H
F
H
H
H i-Pr H
H
H
H
H
Et
H
i-Pr H
R'
Me H
OMe H
H H
H
H
F
H H
H el
H
e
ee
e
e
e
e
e
ee
e
e
7
3
4
2
5
6
11
Entry Anh. X
8
9
10
12
96±0.36
96±1.43
96±4.63
95±0.28
•
0.75
0.625
0.5
Yield >95%
5
6
3
Time (min)
8
7
4
íñ 4.S!;:,.!: 3.sal 2E¡::
12
N° samples
Ni Samples (n)
o
O 5 10 15
13
14
15
e
eN
Br H
Me el
H
Br
H
Br
H
H
H
e02Me 3m (34)
H 3n (93)
30 (43)211
Figure 216 2 e H H H H H
" AIl new compounds gave satisfactory spectroscopic and analyticaldata.
In conclusion, the present microwave-assisted procedureallowed a rapid parallel synthesis of a representative 28membered library of phthalimides, providing an efficient
i-Pr H
4b (89)
4c (87)
4d (88)
4e (87)
4f (97)22
4g (79)
4h (63)
4i (98)
4j (97)')
4k (88)
41(85)
4m (89)
i-Pr
i-Pr
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
i-Pr H
H
OMe H
H
el
H
H
F
H H
H
H
H
Me H
Me el
Et H
H
F H
OMe H
H el
H H
H H
H
H H
e
e
e
e
e
e
e
e
e
ee
e
18 2
20 2
22 2
28 2
24 2
26 2
23 2
17 2
21 2
19 2
27 2
25 2
Equation
t = 2.004Ln(n) + 0.7687r2= 0.9715; S = 0.32*r2 = correlation coefficient; s= standard error
iv) Paralle! Synthesis of N-Phenylphthalimides: Theabove mentioned model was applied to the synthesis of alibrary of 28 phthalimides (Scheme), giving a t = 7.5 minoOne additional minute was added to favour the less reac
tive anilines. Consequently, 28 vials containing a mixtureof the phthalic anhydride (0.68 mmol) and the COlTesponding aniline (0.68 mmol) were placed in the microwave oyen and ilTadiated for 8.5 min at 550W.
Purification through neutral alumina as described, usingCH2CI2-MeOH (90: 10) as eluent, afforded the librarywith high yields. No unreacted material was detected inany of the reactions (Table 2).
This study describes a successful approach to solvent-freeparallel synthesis, using a domestic microwave oyen. Incontrast to the techniques of solid-phase synthesis, microwave technology does not require linking-cleaving chemistry and can produce compounds immediately availablefor biological screening.
Synlell 2002, No. 2, 343-345 ISSN 0936-5214 © Thieme Stuttgart· New York
LETTER
Scheme
R~OO
1, R = H2, R = Me
Microwave-Assisted Parallel Synthesis of a 2-Aryl-IH-Isoindole-l,3-Dione Library
Neat, 550w, 8.5 min••
3a-n (R = H, x= e, 34-97%)30 (R=H, X = N, 43%)4a-01 (R =Me, x= e, 63-97%)
345
methodology, with good yields, fast reaction times, andgeneral applicability to substrates bearing a wide varietyof substituents.
Acnowledgement
AlIthors acknowledge slIpport of this work by the Comisión Interministerial de Ciencia y Tecnología (CICYT) throllgh the project2FDI997-1248.
References
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Synlett 2002, No. 2, 343-345 ISSN 0936-5214 © Thieme Stuttgart· New York
