A new linker for anchoring/masking primary amines on solid support

Article abstract of DOI:10.1021/ol047710k

(Chemical Equation Presented) A polymer-supported diketone was synthesized and used to fully protect/mask primary amines by the formation of a pyrrole ring. Various reactions can be performed on this system which then can be cleaved with full restoration of the amine functionality. The resin can also be recycled at least once without loss of purity of the final compound.

Full text of DOI:10.1021/ol047710k

ORGANIC
LETTERS
2005
Vol. 7, No. 4
565-568
A New Linker for Anchoring/Masking
Primary Amines on Solid Support
Antonietta Paladino, Claudia Mugnaini, Maurizio Botta,* and Federico Corelli*
Dipartimento Farmaco Chimico Tecnologico, UniVersita` degli Studi di Siena,
Via A. Moro, 53100 Siena, Italy
corelli@unisi.it
Received November 8, 2004
ABSTRACT
A polymer-supported diketone was synthesized and used to fully protect/mask primary amines by the formation of a pyrrole ring. Various
reactions can be performed on this system which then can be cleaved with full restoration of the amine functionality. The resin can also be
recycled at least once without loss of purity of the final compound.
Because of its basicity and hydrogen-bonding properties, the
guanidine moiety is an important functional group in many
biologically active compounds of natural or synthetic origin.1
Accordingly, methodologies for the parallel synthesis of
guanidine derivatives have attracted much attention from both
academia and industry.2 In the course of our ongoing efforts
directed toward the preparation of analogues of agmatine of
type a3 (Scheme 1) starting from the appropriate diamine b,
The following characteristics were key to the necessary
amino-protecting group: (a) nonionizable; (b) nonnucleo-
philic; (c) stable in the presence of strong bases; (d) stable
to strong reducing agents.
We focused our attention on 2,5-dimethylpyrrole which
was first described by Bruekelman4 as a versatile primary
amine protecting group, compatible with a range of trans-
formations commonly employed in synthetic organic chem-
istry. 2,5-Dimethylpyrrole is readily installed by treatment
of an amine with 2,5-hexanedione in the presence of an acidic
catalyst and can be cleaved by treatment with hydroxylamine
hydrochloride.5
Scheme 1. Retrosynthetic Analysis of Target Compounds a
(2) (a) Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron 2002, 58,
1739-1743. (b) Ho, K.-C.; Sun, C.-M. Bioorg. Med. Chem. Lett. 1999, 9,
1517-1520. (c) Padmanabhan, S.; Lavin, R. C.; Thakker, P. M., Guo, J.;
Zhang, L.; Moore, D.; Perlman, M. E.; Kirk, C.; Daly, D.; Burke-Howie,
K. J.; Wolcott, T.; Chari, S.; Berlove, D.; Fischer, J. B.; Holt, W. F.; Durant,
G. J.; McBurney, R. N. Bioorg. Med. Chem. Lett. 2001, 11, 3151-3155.
(3) (a) Botta, B.; Carmignani, M.; Volpe, A. R.; Botta, M.; Corelli, F.;
Delle Monache, G. Curr. Med. Chem. 2003, 10, 1845-1862. (b) Carmig-
nani, M.; Volpe, A. R.; Botta, B.; Espinal, R.; De Bonnevaux, S. C.; De
Luca, C.; Botta, M.; Corelli, F.; Tafi, A.; Sacco, R.; Delle Monache, G. J.
Med. Chem. 2001, 44, 2950-2958. (c) Cona, A.; Manetti, F.; Leone, R.;
Corelli, F.; Tavladoraki, P.; Ponticelli, F.; Botta, M. Biochemistry 2004,
43, 3426-3435.
we became aware of the importance of having a protecting
group (PG) which could totally mask one amino moiety (c),
thus allowing further elaboration of the molecule (d).
(1) (a) Mansuy, D.; Boucher, J. L. Free Rad. Biol. Med. 2004, 37, 1105-
1121. (b) Heys, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. ReV. 2000, 29,
57-67. (c) Kelley, M. T.; Burckstummer, T.; Wenzel-Seifert, K.; Dove,
S.; Buschaufer, A.; Seifert, R. Mol. Pharm. 2001, 60, 1210-1225. (d)
Laeckmann, D.; Rogister, F.; Dejardin, J.-V.; Prosperi-Meys, C.; Geczy,
J.; Delarge, J.; Masereel, B. Bioorg. Med. Chem. 2002, 10, 1793-1804.
(e) Yamamoto, T.; Hori, M.; Watanabe, I.; Harada, K.; Ikeda, S.; Ohtaka,
H. Chem. Pharm. Bull. 2000, 48, 843-849.
(4) Bruekelman, S. P.; Leach, S. E.; Meakins, G. D.; Tirel, M. D. J.
Chem. Soc., Perkin Trans. 1 1984, 2801-2807.
(5) (a) Kashima, C.; Maruyama, T.; Fujioka, Y.; Harada, K. J. Chem.
Soc., Perkin Trans. 1 1989, 1041-1046. (b) Macor, J. E.; Chenard, B. L.;
Post, R. J. J. Org. Chem. 1994, 59, 7496-7498. (c) Bowers, S. G.; Coe, D.
M.; Boons, G.-J. J. Org. Chem. 1998, 63, 4570-4571. (d) Xu, G.; Singh,
M. P.; Gopal, D.; Sayre L. M. Chem. Res. Toxicol. 2001, 14, 264-274.
10.1021/ol047710k CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/28/2005

During the course of our investigations, we became
interested in developing an efficient solid phase approach
that could help us to avoid the tedious and troublesome
purification procedures which usually accompany the chem-
istry of polyamines. However, because of the heterogeneous
nature of organic reactions occurring at the interface of
polymeric support and solution, working on solid-phase often
requires a long reaction time or results in incomplete
conversion of starting materials. It has been demonstrated6
that microwave dielectric heating can be used to speed up
organic reactions carried out on solid polymeric supports.
The combination of solid support as a medium for chemical
synthesis with microwave heating offers several advantages
over conventional techniques. Rapid and elevated heating
of reaction mixtures can induce the completion of chemical
transformations in minutes while several hours or days may
be required for the same chemistry under conventional
conditions; moreover, microwave-accelerated chemistry often
delivers products of higher purity when compared to
conventional heating techniques, since it permits decreasing
the time of exposure of chemicals to high temperatures and
hence lessens their thermal degradation.
Scheme 2. Anchoring of the Linker to the Solid Support
detection of primary amino groups. The chloromethyl
polymer 2, treated with CH3COOK, gave 3 which, by
transesterification with benzyl alcohol in the presence of Bu4-
NBr, afforded the alcohol 4 which represents the key
intermediate for the activation of the polymer in the form of
trichloracetimidate (TCA). The presence of the OH group
on the resin was visualized with a colorimetric test.9 The
whole sequence, starting from the commercially available
polymer 1 to the alcohol 4 could be performed in only 30
min by the use of MW irradiation.
Taking advantage of the aforementioned techniques, we
explored the possibility of using 2,5-dimethylpyrrole to
completely protect/mask amino groups on the solid phase
using an approach that could be easily adapted for parallel
synthesis and extended to the preparation of a small library
of guanidines.
To the best of our knowledge, there have been no reports
about the use of 2,5-dimethylpyrrole as an amine protecting
group in solid-phase synthesis, despite its well-documented
use in solution.
The TCA derivative 5 (appearance of a strong CdN
stretching band at 1664 cm-1 in the IR spectrum) was
obtained by reacting a suspension of resin 4 in CH2Cl2 with
trichloroacetonitrile in the presence of DBU.7 The complete
conversion of the polymer-bound benzyloxy group to benzyl
trichloroacetimidate was shown by treating 5 with AcCl/
Et3N: no AcO absorption band was observed in the IR
spectrum of the product. Polymer 5 was finally used for
O-benzylation of the alcohol 6, prepared according to the
literature,10 in the presence of BF3‚OEt2: the reaction was
monitored by IR spectroscopy, observing the disappearance
of the band of the CdN stretching and the appearance of
the carbonyl band of the diketone 7 at 1713 cm-1.
To prove its ability to react with amines, 7 was first treated
with p-anisidine in the presence of catalytic amount of
pyridine hydrochloride in refluxing dioxane11 (Scheme 3).
The formation of the polymer-bound pyrrole derivative 8
proved to be complete after two cycles of reaction as shown
by IR analysis.
TentaGel S-NH2 (TG), a standard type of resin used for
peptide synthesis, solid-phase organic synthesis, and com-
binatorial chemistry, was chosen as the solid support since
it swells well even in aqueous solvent; moreover, as the
reaction occurs at the end of poly(ethylene glycol) (PEG)
spacer and there is no cross-linking between them, the access
of reagents to the reaction site is easier than with polystyrene
resin (PS), and hence, the reaction rate on TG is usually
higher than on PS.
We decided to anchor the linker to the solid support by
the formation of a benzyl ether,7 a functionality which is
usually compatible with the conditions required by a variety
of synthetically useful transformations, particularly basic
conditions. Resin 1 (Scheme 2) was acylated with 4-chloro-
methylbenzoic acid in the presence of EDC/HOBt, and the
complete transformation of 1 into 2 was confirmed by a
negative colorimetric Kaiser test,8 which is specific for the
(6) (a) Al-Obeidi, F.; Austin, R. E.; Okonya, J. F.; Bond, D. R. S. Mini-
ReV. Med. Chem. 2003, 3, 449-460. (b) Dai, W.-M.; Guo, D.-S.; Huang,
X.-H. Org Lett. 2003, 5, 2919-2922. (c) Blackwell, H. E. Org. Biomol.
Chem. 2003, 1, 1251-1255. (d) Lidstrom, P.; Westman, J.; Lewis, A. Comb.
Chem. High Throughput Screen. 2002, 5, 441-458. (e) Kappe, C. O. Curr.
Opin. Chem. Biol. 2002, 6, 314-320. (f) Lew, A.; Krutznik, P. O.; Hart,
M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95-105. (g) Kappe, C.
O. Am. Lab. 2001, 33, 13-19.
This result was further confirmed by opening of the pyrrole
ring using hydroxylamine hydrochloride and Et3N in a
(9) Attardi, M. E.; Falchi, A.; Taddei, M. Tetrahedron Lett. 2000, 41,
7395-7399.
(10) Ballini, R.; Bosica, G.; Petrelli, L.; Petrini, M. Synthesis 1999, 7,
1236-1240.
(7) Hanessian, S.; Xie, F. Tetrahedron Lett. 1998, 39, 733-736.
(8) Kaiser E.; Colescott R. L.; Bossinger C. D.; Cook P. I. Anal. Biochem.
1970, 34, 595-598.
(11) Lisowski, V.; Enguehard, C.; Lancelot, J. C.; Caignard, D. H.;
Lambel, S.; Leonce, S.; Pierre, A.; Atassi, G.; Renard, P. S. Bioorg. Med.
Chem. Lett. 2001, 11, 2205-2208.
566
Org. Lett., Vol. 7, No. 4, 2005

tory 80% yield by deprotection of 11c (25% pyperidine/
DMF) and subsequent acylation. This result prompted us to
investigate more deeply the cyclization reaction of polymer
7 with 4-nitroaniline. It was easy to demonstrate, by simple
cleavage of 11b under standard conditions to give 4-nitro-
aniline (35% yield), that the low yield in the benzamide
formation was essentially due to the scarce nucleophilicity
of 4-nitroaniline, leading to incomplete formation of 11b.
Next, we investigated the possibility of preparing com-
pounds having a guanidine core by using the approach we
had set up on solid phase. Polymer 11d (Scheme 5) was
Scheme 3. Protection and Deprotection of p-Anisidine by the
Use of Polymer-Bound Linker 7
Scheme 5. Synthesis of Di-Boc-Protected Guanidines 14a-c
refluxing H2O/iPrOH mixture. After washing of the resin 9
and alkalinization of the filtrate, p-anisidine was obtained
in pure form and quantitative yield, demonstrating that along
the whole solid-phase sequence the loading of each inter-
mediate had been quantitative. Alternatively, the formation
of the pyrrole ring was successfully achieved under micro-
wave irradiation12 using a few drops of DMF as solvent and
an excess of amine. With this approach, the solid-supported
2,5-dimethylpyrrole was obtained in only 5 min, thus
confirming the importance of microwaves in speeding the
reaction rate on solid phase.
To further probe the scope of the reaction and to evaluate
the possibility of its general use for the synthesis of our target
compounds, 7 was then reacted with a series of structurally
different amines 10 (Scheme 4), and the corresponding
products 11a-d were further chemically elaborated.
reacted under Mitsunobu conditions (PPh3, DEAD, THF)
with di-Boc-protected S-methylisothiourea, and the formation
of 12 was confirmed by a colorimetric test. The polymer-
bound S-methylisothiourea 12 was then divided into three
portions which were reacted in parallel, in a Bu¨chi Syncore
Reactor synthesizer, with benzylamine, 3,4-dichlorobenzyl-
amine, and 4-methoxybenzylamine respectively (CH3CN, 45
°C, overnight), to give the corresponding solid-supported
guanidines 13a-c. Cleavage under standard conditions led
to the Boc-protected guanidines 14a-c in 55%, 60%, and
65% yield, respectively. The satisfactory results thus obtained
confirmed the usefulness of our linker for the preparation,
on solid phase, of the afored mentioned compounds and our
initial idea of adapting this methodology to the synthesis of
a small library of compounds by means of parallel synthesis.
Even better results were obtained starting from polymer
11c (Scheme 6) which was first deprotected14 to give the
amine 15 and then reacted with cyclohexyl isothiocyanate
or phenyl isothiocyanate in CH2Cl2. The corresponding
thioureas 16a and 16b were first alkylated with Mukaiyama’s
reagent (the reaction was repeated three times in order to
avoid the recovering of unreacted thiourea)15 and then treated
with (()-1-(1-naphthyl)ethylamine and 4-methoxybenzyl-
amine to afford the solid supported guanidines 17a and 17b.
Opening of the pyrrole ring under the usual conditions gave
compounds 18a and 18b in an excellent 90% yield.
Scheme 4. Protection of Structurally Different Amines by the
Use of Linker 7
In fact, alkylation of 11a according to Mitsunobu condi-
tions (MeOH, PPh3, DEAD) gave the corresponding methyl
ether, which, after cleavage of the pyrrole ring (NH2OH‚
HCl/Et3N), afforded 4-methoxyaniline in 70% yield.
The nitro group of11b was first reduced in the presence
of Cu(acac)2 and NaBH4 in EtOH/DMF,13 and the NH2
moiety thus obtained was acylated with benzoic acid in the
presence of DIC and catalytic amounts of DMAP. After
cleavage, N-(4-aminophenyl)benzamide was obtained in 30%
yield. The same compound was obtained in a more satisfac-
The opening of 2,5-dimethylpyrrole with NH2OH‚HCl and
Et3N is known to proceed through the formation of a
(14) Li, M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2001, 42,
2273-2275.
(15) Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O. A.;
Anslyn, E. V. Tetrahedron 1998, 54, 15063-15086.
(12) Danks, T. N. Tetrahedron Lett. 1999, 40, 3957-3960.
(13) Hanaya, K.; Muramatsu, T., Kudo, H.; Chow, Y. L. J. Chem. Soc.,
Perkin Trans. 1 1979, 10, 2409-2410.
Org. Lett., Vol. 7, No. 4, 2005
567

compatible with the solid phase, we focused our attention
on tert-butyl hydroperoxide (TBHP)18 as the oxidizing agent
because of the possibility to work in mild reaction conditions
without the formation of precipitates that are difficult to
remove from the solid support. Thus, TBHP was added to a
suspension of 9 in acetone, and the reaction mixture was
refluxed for 24 h. The formation of 7 was confirmed by IR
analysis. Cyclization of 7 with 4-methoxyaniline to provide
8 and subsequent ring opening of 8 gave 4-methoxyaniline
in 90% yield. A further cycle of oxidation, cyclization, and
ring opening resulted in a loss of purity of the recovered
amine (50%, determined by GC), thus indicating the possi-
bility to use the same resin not more then twice.
Scheme 6. Synthesis of Guanidines 18a,b
In summary, it has been demonstrated that polymer-bound
diketone 7 reacts smoothly with primary amines giving a
pyrrole system, which in turn can be easily opened to release
in solution the original amine in a pure form and high yield.
For this reason, 2,5-dimethylpyrrole can be considered a good
protecting group for protecting/masking terminal amines on
the solid phase, a crucial point in the synthesis of guanidine
compounds of type a. Resin 7 can also be recycled at least
once without loss of purity of the final compound. The
possibility to extend this methodology to the synthesis of
small libraries of compounds by means of parallel synthesis
has been also ascertained.
dioxime.16 The formation of oximes represents a largely used
approach for the protection of ketones and aldehydes and
several methods are known for the conversion of dioximes
into the corresponding carbonyl compounds. We thought,
therefore, to use polymer 9 (Scheme 7), obtained as a side
Scheme 7. Regeneration and Recycling of Polymer 7
Acknowledgment. This work was supported by grants
form the Italian MIUR, PRIN projects (2002038577 and
2003054595), and the University of Siena. M.B. thanks the
Merck Research Laboratories (2004 Academic Development
Program Chemistry Award).
product from the pyrrole opening reaction, to regenerate the
diketonic resin 7. Since most of the methods known for the
conversion of oximes to carbonyl compounds17 are not
Supporting Information Available: Experimental pro-
cedures and characterization for compounds 2-5, 7, 8, 11,
13, and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Findlay, S P. Chem. Ber. 1956, 89, 4-645.
(17) (a) Larzlo, P.; Polla, E. Synthesis 1985, 439-440. (b) Olah, G. A.;
Liao, Q.; Lee, C. S.; Suryaprakash, G. K. Synlett 1993, 427-428. (c) Joseph,
R.; Sudalai, A.; Ravindranathan, T. Tetrahedron Lett. 1994, 35, 5493-
5494.
OL047710K
(18) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Sudalai, A.
Tetrahedron Lett. 1997, 38, 653-656.
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