Synthesis of 3-alkoxy- and 3-alkylamino-2-alkyl-3-arylisoindolinones

Article abstract of DOI:10.1055/s-1999-3116

Solvent-controlled regioselectivity in the reactions of 3- chloroisoindolinones with primary amines allows the rational synthesis of isoindolinones by a route suitable for parallel combinatorial chemistry.

Full text of DOI:10.1055/s-1999-3116

LETTER
997
Synthesis of 3-Alkoxy- and 3-Alkylamino-2-alkyl-3-arylisoindolinones
Martin S. Kitching,a William Clegg,b Mark R. J. Elsegood,b Roger J. Griffin,a Bernard T. Goldinga*
a Department of Chemistry, Bedson Building, The University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, UK
b Chemical Crystallography Unit, Department of Chemistry, Bedson Building, The University of Newcastle upon Tyne, Newcastle upon
Tyne NE1 7RU, UK
Fax +44(191)2226929; E-mail: b.t.golding@ncl.ac.uk
Received 16 February 1999
The reaction of 6a with redistilled propylamine in tetrahy-
Abstract: Solvent-controlled regioselectivity in the reactions of
drofuran gave two products. Separation of these by col-
3-chloroisoindolinones with primary amines allows the rational
1
umn chromatography, and subsequent analysis by H
synthesis of isoindolinones by a route suitable for parallel combina-
NMR spectroscopy, indicated that they were the isomeric
3-alkylaminoisoindolinones 3a (30%) and 3b (10%)
(Scheme 2).5,9
torial chemistry.
Key words: isoindolinones, regioselectivity, solvent effect, combi-
natorial synthesis
The molecular diversity offered by isoindolinones 1 is at-
tractive in the context of the synthesis of combinatorial li-
braries for evaluation against targets implicated in the
molecular pathology of cancer.
Figure 1
The literature on the synthesis of such isoindolinones is
confusing because the common route from 2-benzoylben-
zoic acids provides numerous opportunities for the gener-
ation of isomeric structures.1 We have found that 3-
alkoxy- and 3-alkylamino-2-alkyl-3-arylisoindolinones
(2a-e and 3a-c, respectively) can be rationally synthesized
from 2-benzoylbenzoic acid by a sequence in which each
intermediate and the end-products have been structurally
defined.
Scheme 1
Reaction of 2-benzoylbenzoic acid with 1 equiv. of thio-
nyl chloride in tetrahydrofuran, containing a catalytic
quantity of dimethylformamide, gave 3-chloro-3-phenyl-
isobenzofuranone (4)2 as an unstable oil (~ 100%),3 which
was obtained by removal of the reaction solvent in vacuo.
Immediate reaction of 4 with 2.2 equiv. of either benzyl-
amine or propylamine in tetrahydrofuran gave 3-hydroxy-
3-phenylisoindolinones4,5 5a/b in good yield (71 and
93% respectively). Functionalisation of 5a or 5b was
achieved via conversion into 3-chloroisoindolinones 6a/b
(~ 100%),2 compounds which have previously been de-
scribed as highly reactive and not isolable.6 We obtained
crystals of 2-benzyl-3-chloro-3-phenylisoindolinone (6a)
by refrigerating the initially formed oil under petroleum
ether.7 3-Alkoxyisoindolinones 2a-e (31-97%) were ob-
tained by quenching 6a/b with dry alcohols (Scheme 1).5,8
Scheme 2
Synlett 1999, S1, 997–999 ISSN 0936-5214 © Thieme Stuttgart · New York

998
M. S. Kitching et al.
LETTER
These isomeric products were also obtained with 1,4-di- The literature suggested that reaction of 6a with methy-
oxane as reaction solvent. The literature suggested that lamine would proceed via attack on the 1-position of 6a
only one of the products would be an isoindolinone.10 In leading to the formation of 3-benzylamino-2-methyl-3-
our case iminoamide 7a, resulting from the attack of the phenylisoindolinone (3d) as the sole product.14 When tet-
amine on the 1-position of 6a, has evidently undergone rahydrofuran was used as the reaction solvent we obtained
cyclization to give 3b in addition to 3a, which arises from two products, 2-benzyl-3-methylamino-3-phenylisoin-
amine attack at the 3-position.
dolinone (3c) (33%) and a non-isoindolinone product,
probably 7b (20%) (Scheme 2). In acetonitrile we ob-
tained only 3c (66%). Assignment of the isoindolinone
structures was again based on 1H NMR spectroscopy.
1H NMR spectroscopy allowed conclusive identification
of the isomeric isoindolinones. The diastereotopic ben-
zylic methylene protons of 5 exhibit a large chemical shift
difference.11 The chemical shifts of the protons in the N- We believe that the reactions of 6 described for relatively
1
methylene groups of compounds 3 provide a useful H polar solvents (i.e. acetonitrile and dichloromethane) in-
NMR chemical marker. We compared the spectra of com- volve the isoindolinone carbocation 8,15 which reacts se-
1
pounds 3 with the H NMR spectrum of 5a, to identify lectively at C-3. In the less polar, but nucleophilic
which compound has a benzyl substituent attached to the tetrahydrofuran or dioxane, the carbocation may be in
5-ring nitrogen and which has a pendant benzylamino equilibrium with the adduct 9, by analogy with trityl cat-
moiety. The identifications were supported by adding a ions.16 The presence of this species may influence the re-
1
drop of deuterium oxide to the H NMR sample and re- gioselectivity of amine attack.
cording another spectrum. This allowed determination of
which protons were coupled to the exchangeable amino
proton, and hence which moiety was pendant, and which
was attached to the 5-ring nitrogen. These structural as-
signments were subsequently shown to be correct by crys-
tal structure analysis.12,13
The use of acetonitrile as the solvent in the reaction of
6a with propylamine was found to lead to only one
product, 2-benzyl-3-phenyl-3-propylaminoisoindolinone
3a (61%). An identical result was obtained when the
reaction solvent was changed to dichloromethane.
Acknowledgement
We are grateful to the EPSRC and the Cancer Research Campaign
for support of M.S.K. and we thank the EPSRC for funding the dif-
fractometer. Many thanks are due to Dr. L. Horsburgh for crystal
structure analysis.
References and Notes
This solvent effect was verified by synthesizing 3-hy-
(1) Kubota, Y.; Tatsuno, T. Chem. Pharm. Bull. 1971, 19, 1226.
droxy-3-phenyl-2-propylisoindolinone (5b) (71%), con-
Bhatt, M. V.; El Ashry, S. H.; Somayaji, V. Indian J. Chem.
verting it into the chloride 6b (~ 100%) in the usual
manner, and then reacting 6b with benzylamine in either
1980, 19B, 473. Sloan, K. B.; Koch, S. A. M. J. Org. Chem.
1983, 48, 3777. Nishio, T.; Yamamoto, H. J. Heterocycl.
tetrahydrofuran or acetonitrile. Similar results were ob-
tained as in the reaction of 6a with propylamine, i.e. two
isomeric isoindolinones 3a (7%) and 3b (35%) were
formed in tetrahydrofuran, whereas only one isoindolino-
ne 3b (36%) was formed in acetonitrile.
Chem. 1995, 32, 883.
(2) 3-Chloroisobenzofuranone 4 and 3-chloroisoindolinone 6.
2-Benzoylbenzoic Acid (500 mg, 2.21 mmol) or 3-
hydroxyisoindolinone 5 (1.59 mmol) was dissolved in dry
THF (20 mL). Thionyl chloride (2.21 mmol or 1.59 mmol
respectively) and DMF (1 drop) were added. The mixture was
stirred overnight. The reaction was monitored by heating a
sample of the reaction mixture with dry methanol before TLC
analysis. Removal of the solvent in vacuo gave a pale yellow
oil 4 (~ 100%) or 6 (~ 100%) which was used without further
purification.
(3) Sloan, K. B.; Koch, S. A. M. J. Org. Chem. 1983, 48, 635.
(4) To a stirred solution of 3-chloroisobenzofuranone 4 (2.21
mmol) in dry THF (20 mL) was added the primary amine
(4.86 mmol). In all cases a precipitate appeared almost
immediately. After completion (overnight unless otherwise
stated) the reaction was filtered and the solvent was removed
in vacuo. The residue was taken up into ethyl acetate (30 mL)
and washed with water (3 x 30 mL). After drying (Na2SO4) the
ethyl acetate was removed in vacuo leaving a solid residue,
Synlett 1999, S1, 997–999 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Alkoxy- and 3-Alkylamino-2-alkyl-3-arylisoindolinones
999
which was dissolved in a minimum of boiling ethyl acetate
and recrystallised by the dropwise addition of petrol to give 3-
hydroxyisoindolinone 5 (71-93%).17, 18
After removal of the eluent each compound was obtained as an
oil which crystallised when overlayed with petrol and
refrigerated. 3a (334 mg, 0.94 mmol, 30%): white solid; mp.
102-103°C [Rf 0.77 (3:2 petrol:ethyl acetate)] and 3b (112 mg,
0.31 mmol, 10%): white solid; mp. 139-141°C (lit. 137-
138°C)10 [Rf 0.68 (3:2 petrol:ethyl acetate)].
(5) All yields in this paper, with the exception of 4 and 6a/b, are
for isolated, analytically pure racemates.
(6) Armarego, W. L. F.; Sharma, S. C. J. Chem. Soc. (C). 1970,
1600.
(10) Valter, R. É. Chem. Heterocycl. Cmpd., Engl. Transl. 1973, 9,
701.
(11) Lewin, A. H.; Lipowitz, J.; Cohen, T. Tetrahedron Lett. 1965,
1241.
(7) Crystal of 6a was colourless, monoclinic, P21/c, a =
11.9175(10), b = 10.0768(9), c = 14.2218(12) Å, β =
102.826(3)°, C21H16ClNO, M = 333.80, T = 160 K, Bruker
SMART CCD diffractometer, MoKα radiation. R = 0.0352,
3922 reflections, 218 parameters. CCDC reference 114164.
(8) 3-Chloroisoindolinone 6 was dissolved in the dry alcohol (10
mL, large excess) and the resulting solution stirred at room
temperature for 30 min. Removal of the solvent in vacuo gave
a translucent oil which was dissolved in ethyl acetate (30 mL)
and washed with water (3 x 30 mL). The organic layer was
dried (Na2SO4) and the solvent removed in vacuo. The
residual oil crystallised when overlayed with petrol and
refrigerated, to give 3-alkoxy-3-arylisoindolinone 2 (31-
97%). All analytical data obtained (1H NMR, 13C NMR, IR,
MS, CHN) supported the assigned structures.
(9) 2-Benzyl-3-phenyl-3-propylaminoisoindolinone (3a) and 3-
benzylamino-3-phenyl-2-propylisoindolinone (3b). 2-
Benzyl-3-chloro-3-phenylisoindolinone (6a) (1.05 g, 3.17
mmol) was dissolved in dry THF (20 mL) and redistilled
propylamine (3 mL) was added. A white precipitate formed
immediately and the mixture was stirred at room temperature
for 2 weeks. After removal of the solvent in vacuo the solids
were taken into ethyl acetate (30 mL) and washed with water
(3 x 30 mL). The organic layer was dried (Na2SO4), absorbed
onto silica gel, and the isomeric products were separated by
column chromatography with (20% EtOAC/petrol) as eluent.
(12) Crystal of 3a was colourless, triclinic, P1, a = 7.1991(9), b =
8.6242(10), c = 16.1894(19) Å, α = 87.743(3), β = 83.227(3)
γ = 75.242(3)°, C24H24N2O, M = 356.45, T = 160 K, R =
0.0419, 4408 reflections, 248 parameters. CCDC reference
114165.
(13) Crystal of 3b was colourless, monoclinic, P21/n, a =
10.3147(2), b = 14.1360(14), c = 13.3327(13) Å, β =
93.897(3)°, C24H24N2O, M = 356.45, T = 190 K, R = 0.0434,
4560 reflections, 249 parameters. CCDC reference 114166.
(14) Valter, R, É.; Karlivan, G. A. Chem. Heterocycl. Cmpd., Engl.
Transl. 1976, 12, 999.
(15) Bartfeld, H-D.; Flitsch, W. Chem. Ber. 1973, 106, 1423.
(16) Bleasdale, C.; Ellwood, S. B.; Golding, B. T. J. Chem. Soc.,
Perkin Trans. 1 1990, 803.
(17) Winn, M.; Zaugg, H. E. J. Org. Chem. 1968, 33, 3779.
(18) Nishio, T.; Okuda, N.; Mori, Y.; Kashima, C. Synthesis 1989,
396.
Article Identifier:
1437-2096,E;1999,0,S1,0997,0999,ftx,en;W07899ST.pdf
Synlett 1999, S1, 997–999 ISSN 0936-5214 © Thieme Stuttgart · New York