Synthesis of 3,6-diaminophthalimides for ureidophthalimide-based foldamers

Article abstract of DOI:10.1021/ol0524757

Herein, we report an improved methodology for the synthesis of a variety of 3,6-diaminophthalimides in high yields. This enables decoration of the periphery of foldamers with a wide range of functionalities.

Full text of DOI:10.1021/ol0524757

ORGANIC
LETTERS
2006
Vol. 8, No. 3
383-385
Synthesis of 3,6-Diaminophthalimides
for Ureidophthalimide-Based Foldamers
Renatus W. Sinkeldam, Michel H. C. J. van Houtem, Guy Koeckelberghs,
Jef A. J. M. Vekemans, and E. W. Meijer*
Laboratory of Macromolecular and Organic Chemistry, EindhoVen UniVersity of
Technology, P.O. Box 513, 5600 MB EindhoVen, The Netherlands
E.W.Meijer@tue.nl
Received October 12, 2005
ABSTRACT
Herein, we report an improved methodology for the synthesis of a variety of 3,6-diaminophthalimides in high yields. This enables decoration
of the periphery of foldamers with a wide range of functionalities.
Natural as well as synthetic helical architectures have
attracted great interest recently. Of all helical architectures,
the foldamer most resembles natural systems.1 Appropriate
functionalization of the covalent backbone of an oligomer
or polymer allows for dynamic intramolecular interactions.
Within the area of foldamer research, many classes have been
described ranging from the hydrogen-bond-based peptides
and peptidometics to systems in which π-π interactions
determine the secondary architecture.2-4 Recently, we have
reported on the synthesis of a ureidophthalimide-based
foldamer which has been synthesized by the reaction of a
3,6-diaminophthalimide (1a) with its corresponding diiso-
cyanate (Scheme 1).5 The polyurea has proven to fold in
THF and heptane but not in CHCl3. To expand the scope of
the current system, decoration of the core with a variety of
functionalities has been envisaged. Incorporation of chro-
mophores and functionalities that simultaneously ensure
solubility in water form an important part of the scope.
However, synthesis of phthalimides with the 1,2,3,6-
substitution pattern, as in 1, is not trivial. A general method
is not available. Despite the availability of several approaches
to 3,6-disubstituted phthalic acid derivatives, such as a
Diels-Alder adduct of 1,4-disubstituted 1,3-butadiene with
alkynes6 and of 2,5-dimethylfuran with N-methylmaleimide,7
(1) (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893. (b) Block, M. A. B.; Kaiser, C.; Khan, A.;
Hecht, S. Top. Curr. Chem. 2005, 89. (c) Gellman, S. H. Acc. Chem. Res.
1998, 31, 173.
(2) (a) Huc, I. Eur. J. Org. Chem. 2004, 17. (b) Estroff, L. A.; Incarvito,
C. D.; Hamilton, A. D. J. Am. Chem. Soc. 2004, 126, 2. (c) Sandford, A.
R.; Yamato, K.; Yang, X.; Yuan, L.; Gong, B. Eur. J. Biochem. 2004, 1416.
(d) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc. 1997, 119,
10587.
(3) Berl, V.; Kirsche, M. J.; Huc, I.; Lehn, J. M.; Schmutz, M. Chem.-
Eur. J. 2000, 6, 1938.
(5) van Gorp, J. J.; Vekemans, J. A. J. M.; Meijer, E. W. Chem. Commun.
2004, 60.
(4) Berl, V.; Huc, I.; Khoury, R. G.; Lehn, J. M. Chem.-Eur. J. 2001,
7, 2798.
(6) (a) Schmidt, R. R.; Wagner, A. Synthesis 1981, 273. (b) Schmidt, R.
R.; Wagner, A. Synthesis 1982, 958.
10.1021/ol0524757 CCC: $33.50
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Published on Web 01/10/2006

Scheme 1
Table 1. Two-Step Conversion of 3,6-Bis(acetylamino)phthalic
Anhydride 5 to 3,6-Diaminophthalimides 1a-g
these approaches do not lead to the required substituents.
Moreover, the imidation of 3,6-dinitrophthalic anhydride 3
leading to 2 (Scheme 1) only works with specific amines.
In this paper, we present a general methodology for the
synthesis of 3,6-diaminophthalimide building blocks employ-
ing 3,6-bis(acetylamino)phthalic anhydride (5) as a starting
material. The latter is obtained via the palladium-mediated
catalytic reduction of 3,6-dinitrophthalic acid (4),8 followed
by exposure of the unstable diaminophthalic acid to acetic
anhydride9 (Scheme 2). Subsequent reaction of 5 with
Scheme 2
a Isolated yield for the 3,6-bis(acetylamino)phthalimides. b Isolated yield
for the 3,6-diaminophthalimides. c Based on NMR.
The final step toward the desired monomeric building
blocks for the foldamer is the removal of the N-acetyl
functionalities. Exposure of 3,6-bis(acetylamino)phthalimides
(6a-g) to a 1.6 M solution of HCl in aqueous dioxane at
reflux furnishes the corresponding 3,6-diaminophthalimides
in 70-95% yield, without noticeable imide hydrolysis.
We have found that the outcome of imide formation is
strongly governed by the substituents on both the anhydride
and the N-source and have revealed that 3,6-bis(acetylami-
no)phthalic anhydride (5) is more suitable than 3,6-dinitro-
phthalic anhydride (3). Primary aromatic amines can be
reacted with 3,6-dinitrophthalic anhydride (3) affording the
corresponding functionalized phthalimide (2) in a yield
typically between 40 and 60%.5 However, this strategy
cannot be applied for the introduction of primary aliphatic
amines. This may be rationalized by the mechanism of the
primary amines in dioxane at reflux affords a variety of 3,6-
bis(acetylamino)phthalimides (6a-h) in good to almost
quantitative yields (Table 1). All phthalimides have been
purified by column chromatography or crystallization.
(7) Fraile, J. M.; Garcia, J. I.; Gomez, M. A.; de la Hoz, A.; Mayoral, J.
A.; Moreno, A.; Prieto, P.; Salvatella, L.; Vazquez, E. Eur. J. Org. Chem.
2001, 2891.
(8) (a) Will, W. Chem. Ber. 1895, 28, 367. (b) Momose, T.; Torigoe,
M. J. Pharm. Soc. Jpn. 1951, 71, 977.
(9) Shah, J.; Conner, B. P.; Swartz, G. M., Jr.; Hunsucker, K. A.; Rougas,
J.; Amato, D. R.; Pribluda, V.; Teston, A. Patent WO 03014315, 2003.
384
Org. Lett., Vol. 8, No. 3, 2006

reaction (Scheme 3). Moreover, during incorporation attempts
of aliphathic amines, substitution of one of the nitro
functionalities was observed.
and the basicity of the aliphatic amines, compared to the
aromatic ones. Consequently, conversion of the electron-
withdrawing nitro function into the electron-donating acet-
amide strongly improves the ring-closure reaction. In addi-
tion, the intramolecular hydrogen-bonding ability of the
acetamido group may influence the ring opening of the
anhydride as well as the ring closure to the imide.11
Scheme 3
As seen in Table 1, the broad scope of the methodology
toward imides 6 and 1 is obvious. Not only were weakly
nucleophilic aromatic amines 7a-f successfully incorporated
but also were strongly nucleophilic aliphatic amines 7g-h.
Even the more sterically demanding amine 7h was integrated
in good yield. In addition, in the case of synthon 6h,
derivatization prior to removal of the acetyl groups is
envisaged. The scope covers the introduction of hydrophobic
7a and 7d-h, as well as hydrophilic 7b-c, functionalities.
The current strategy via 3,6-bis(acetylamino)phthalic anhy-
dride (5) has proven to be superior to our previously reported
approach (Scheme 1) starting from 3,6-dinitrophthalic an-
hydride (3). To summarize, with this library of novel 3,6-
diaminophthalimides in hand, the synthesis and study of a
wide range of appealing foldamers are viable.
The formation of the phthalimide most likely proceeds via
two steps, starting with a ring-opening reaction involving
the nucleophilic attack of the amine on the carbonyl carbon
of the phthalic anhydride. The second step is the ring closure
to the phthalimide system with concomitant release of water.
The remaining carboxylic acid functionality of the amic acid
intermediate readily protonates the amine giving an organic
Acknowledgment. For financial support, we thank NWO.
We kindly acknowledge Xianwen Lou and Henk Eding for
their measurements concerning the MALDI-TOF MS and
elemental analysis, respectively. Guy Koeckelberghs is a
postdoctoral fellow of FWO-Vlaanderen (Fund for Scientific
Research-Vlaanderen).
1
salt, as is observed in H NMR. Although not observed in
our research, the formation of an isoimide by dehydration
of the amic acid followed by rearrangement to the imide
has also been reported.10 In the case of aromatic amines, the
organic salt is in equilibrium with the free acid.
However, when aliphatic amines are employed, the
intermediate is trapped as the organic salt. This is due to the
combination of the electron-withdrawing nature of the nitro
groups, which enhances the acidity of the carboxylic acid,
Supporting Information Available: Experimental pro-
cedures of all synthesized compounds including their char-
acterization (1H NMR, 13C NMR, FT-IR, UV-vis, MALDI-
TOF MS, and elemental analysis). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0524757
(10) Verbicky, J. W., Jr.; Williams, L. J. Org. Chem. 1981, 46, 175 and
references sited therein.
(11) The relevance of intramolecular hydrogen bonding by the acetamido
group was kindly suggested by a reviewer.
Org. Lett., Vol. 8, No. 3, 2006
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