Solid phase-solid state synthesis of N-alkyl imides from anhydrides

Article abstract of DOI:10.1055/s-1999-2894

Preparation of N-alkyl imides from anhydrides is developed on polymer support in solid state assisted by microwave for the first time.

Full text of DOI:10.1055/s-1999-2894

LETTER
1597
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Solid Phase-Solid State Synthesis of N-alkyl Imides from Anhydrides
S. Chandrasekhar,* M. B. Padmaja, A. Raza
Indian Institute of Chemical Technology, Hyderabad-500 007 (A.P), India
Received 27 July 1999
Abstract: Preparation of N-alkyl imides from anhydrides is devel-
oped on polymer support in solid state assisted by microwave for
the first time.
Key words: solid phase, solid state, microwave, trifluoroacetic acid
Solvent free approach for organic functional group trans-
formations has gained prominence recently.1 This ap-
proach has several added advantages viz., i) The
environmental hazards through use of solvents is mini-
mized, ii) The microwave2 heating which has become a
powerful alternative for thermal reactions demands sol-
vent free conditions in several cases. The substrate bound
Resins in few cases may not tolerate many solvents due to
swelling properties.3 To address all these issues a judi-
cious programme is initiated by us wherein solvent free
reaction conditions have been developed for N-alkyl imi-
de synthesis4 and 1,3-diol preparation.5 Further to this,
some organic functional groups have been reduced on sol-
id phase (Merrifield Resin as support) wherein no solvent
was used as reaction media.6
of polymer supported alanine with phthalic anhydride10
4a (entry 4), maleic anhydride 5a (entry 5). and succinic
anhydride 6a (entry 6)
This study has provided further evidence in confirming
our hypothesis that Solid Phase-Solid State functional
group transformations can be accomplished in the absence
of solvents and assisted by microwave heating. The imide
derivatives thus synthesized constitute the important skel-
eton of antibody-antibody conjugates, enzyme inhibitors
and enzyme probes.11
General procedure for the preparation of N-alkyl
imides: 4-(1,3-2,3-dihydro-1H-2isoidolyl)butanoic
acid 1b:
Our continued interest in developing new protocols in sol-
id supported organic synthesis has prompted us to study
the preparation of N-phthalimides and derivatives from
anhydrides on solid phase (Merrifield Resin) under sol-
vent free conditions. It is important to note that this reac-
tion needs Lewis acid catalyst adsorbed on silica gel and
heating is essential. Herein we report our latest findings.
Interestingly, this paper describes for the first time two in-
soluble supports namely Merrifield’s Resin and Silica gel
usage in one pot which are easily separated physically by
using different mesh filters.7 To assess the scope of this
methodology, γ-aminobutyric acid was esterified with
Merrifield Resin,8 treated with phthalic anhydride and
TaCl5-SiO2 9 (vide infra), and subjected to microwave ir-
radiation after thorough mixing. The solid mixture was
washed with DMF (2x20 mL), MeOH (2x20 mL), H2O
(2x10 mL) diethyl ether (2x20 mL) CH2Cl2 (2x20 mL).
The resultant polymer bound imide is cleaved from resin
by treatment with trifluoroacetic acid to furnish acid de-
rivative of 1b (entry 1) in 65% yield.
The polymer bound γ-amino butyric acid (1.078g, 1mmol)
entry 1 phthalic anhydride (0.185g, 1.25mmol) and acti-
vated Silica gel (1g) were thoroughly mixed and to this
was added TaCl5-SiO2(0.169g, 10mole percent) and ad-
mixed thoroughly and subjected to microwave
irradiation12 (450watts) for 5min and the solid mixture
was allowed to cool to room temperature and the organic
material is cleaved from resultant resin-silica gel mixture
using TFA (3mL) in CH2Cl2 (10mL) (2x10mL) and the
combined filtrates were evaporated to yield acid deriva-
tive of 1b (0.189g, 65%).
Yield: 1H NMR (CDCl3) : 7.8-7.9 (m, 2H), 7.65-7.75 (m,
2H), 3.7-3.9 (t, 2H), 2.35-2.45 (t ,2H), 1.09-2.05 (m, 2H);
MS: (m/z)233 (M+); HRMS: Calculated 233.0688, Found
233.0692.
Acknowledgement
MBP thanks CSIR New Delhi and AR thanks INSA New Delhi for
financial assistance.
General Equation
References and Notes
This result has encouraged us to study some other sub-
strates wherein polymer supported γ-amino butyric acid
ester is treated with maleic anhydride10 2a (entry 2) and
succinic anhydride 3a (entry 3). Good conversion to imi-
des was obtained. Similar results were observed by the use
#
IICT Communication No.4189.
(1) (a) Toda, F. Acc. Chem. Res. 1995, 28, 480. (b) Toda, F; Koji,
K.; Yagi,M. Angew. Chem. Int. Ed. Engl. 1989, 28, 320
Synlett 1999, No. 10, 1597–1599 ISSN 0936-5214 © Thieme Stuttgart · New York

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S. Chandrasekhar et al.
LETTER
(2) Loopy, A.; Petit, A.; Hamelin, J; Boulet, F. T.; Jacqualt, P.;
Mathe, D. Synthesis 1998, 9, 1213
(3) Encyclopedia Of Polymer Science and Engineering, Second
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(4) Chandrasekhar, S.; Takhi, M.; Uma,G. Tetrahedron Lett.
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(6) Chandrasekhar, S.; Raza, A.; Padmaja, M. B. Synlett 1999,
1061.
(7) The mesh filter is not very efficient in separation of silica gel
(finer than 200 mesh) and resin (≈150µ) is used. However, by
use of resin with more than 300µ (commercially available
from polymer laboratories, USA) should enable easy
separation. In the present instance Merrifield resin (150-300µ)
is used.
(8) Steele, J.; Gordon, D. W. Bio Med.Chem.Lett.1995, 5, 47.
(9) Chandrasekhar, S.; Takhi, M.; Reddy, Y. R.; Mohapatra, S.;
Rao, C. R.; Reddy, K. V. Tetrahedron 1997, 53, 14997.
Synlett 1999, No. 10, 1597–1599 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Solid Phase-Solid State Synthesis of N-alkyl Imides from Anhydrides
1599
(10) Refluxed in benzene for 8h followed by standard workup and
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(12) BPL SANYO (600 watts) domestic microwave was used with
an output at 75% for 5 minutes (after each minute, the reaction
mixture is thoroughly agitated).
Article Identifier:
1437-2096,E;1999,0,10,1597,1599,ftx,en;L08399ST.pdf
Synlett 1999, No. 10, 1597–1599 ISSN 0936-5214 © Thieme Stuttgart · New York