Synthesis of 3-aminomethyl-2-aryl-8-bromo-6-chlorochromones

Article abstract of DOI:10.1021/ol062478z

An efficient synthetic route to Cbz-protected 3-aminomethyl-2-aryl-8-bromo- 6-chlorochromones has been developed. 3-AryM-(3-bromo-5-chloro2-hydroxyphenyl)- 2-propen-1-one or 2-aryl-8-bromo-6-chlorochroman-4-one could be reacted under Mannich conditions yi

Full text of DOI:10.1021/ol062478z

ORGANIC
LETTERS
2007
Vol. 9, No. 3
389-391
Synthesis of 3-Aminomethyl-2-aryl-
8-bromo-6-chlorochromones
Erik A. A. Walle´n,†,‡ Kristian Dahle´n,† Morten Grøtli,† and Kristina Luthman*,†
Department of Chemistry, Medicinal Chemistry, Go¨teborg UniVersity,
SE-412 96 Go¨teborg, Sweden, and Department of Pharmaceutical Chemistry,
UniVersity of Kuopio, FI-70211 Kuopio, Finland
luthman@chem.gu.se
Received October 8, 2006
ABSTRACT
An efficient synthetic route to Cbz-protected 3-aminomethyl-2-aryl-8-bromo-6-chlorochromones has been developed. 3-Aryl-1-(3-bromo-5-chloro-
2-hydroxyphenyl)-2-propen-1-one or 2-aryl-8-bromo-6-chlorochroman-4-one could be reacted under Mannich conditions yielding 2-aryl-8-bromo-
6-chloro-3-methylenechroman-4-one, which was further converted to the target compound via an aza-Michael reaction followed by an SeO2
oxidation. This procedure represents a new method to introduce a primary aminomethyl group at the 3-position of a 2-arylchromone scaffold.
The Cbz-protected 3-aminomethyl-2-aryl-8-bromo-6-chlorochromones can, e.g., be used in the synthesis of chromone-based
peptidomimetics.
â-turn
Chromone (chromen-4-one) derivatives are interesting as
structural scaffolds and have been assigned as privileged
structures in drug development.1 Chromones with different
functionalized substituents have been proposed as mimetics
of short peptides, as the conformation of a â-turn of a peptide
(1) corresponds well with the 2,3,6,8-tetrasubstituted chromone
2.2 In addition, many flavonoids are based on the chromone
structure. Several therapeutically interesting biological activi-
ties of the flavonoids have been reported.3
In a project aimed at the synthesis of chromone-based
â-turn peptidomimetics, access to a suitably N-protected
3-aminomethyl-2-aryl-8-bromo-6-chlorochromone 3 was re-
quired.
† Go¨teborg University.
The use of a one-pot Mannich reaction and cyclization
has been reported for the introduction of a tertiary amino-
methyl group in the 3-position on 2-arylchromones;4 how-
‡ University of Kuopio.
(1) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893-930.
(2) Dahle´n, K.; Grøtli, M.; Luthman, K. In Understanding Biology Using
Peptides; Blondelle, S., Ed.; American Peptide Society: San Diego, 2006;
pp 677-678.
(4) (a) Braa, M. F.; Mora´n, M.; Emling, F.; Schlick, E. Drug Des. DiscoV.
1994, 11, 329-334. (b) Rehse, U. Arch. Pharm. 1975, 308, 881-887.
(3) Havsteen, B. H. Pharmacol. Ther. 2002, 96, 67-202.
10.1021/ol062478z CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/05/2007

ever, much less is known on how to introduce primary or
secondary amines. Our attempt to use this reaction to prepare
5 from 4 (Scheme 1) resulted only in trace amounts of
recovered.7 A microwave-assisted procedure was adopted in
which 7a-c were reacted with dimethylamine hydrochloride
and paraformaldehyde in dioxane in a microwave cavity at
165 °C for 10 min.8 Interestingly, instead of obtaining the
desired Mannich products,9 all three starting materials gave
the corresponding 3-methylene-chroman-4-ones 8a-c as the
only products without any unreacted starting material or
impurities present.10 3-Methylenechroman-4-ones have been
obtained before via the Mannich reaction, but only in low
yields, as both the Mannich reaction and the following
â-elimination have been reported to be low-yielding reactions
(10-20% and 3-12%, respectively).5a,b
Scheme 1. Attempted One-Pot Reaction from 4 to 5
Accordingly, this observation inspired further testing of
reaction conditions for the synthesis of 8. Hence, compound
7c11 was reacted with paraformaldehyde in the presence of
a catalytic amount of morpholine in refluxing acetic acid12
or used in a piperidine-catalyzed aldol condensation with
paraformaldehyde in dioxane.13 Both reactions were run in
a microwave cavity.14 The reactions gave 8c as the main
product with several minor impurities. We did not continue
to study these alternative reactions as our newly discovered
method gave a cleaner product.
product 5 independent of amine (ammonia, primary and
seconday amines), solvent, and temperature used.
Instead, we made attempts to synthesize 3 via a Mannich
reaction on a 2-arylchroman-4-one derivative,5 followed by
oxidation to the corresponding chromone.
The Mannich reaction was investigated using a series of
2-aryl-8-bromo-6-chlorochroman-4-ones, 7a (R ) H), 7b (R
) OMe), and 7c (R ) CF3) (Scheme 2). These starting
Compounds 8a-c were found to slowly dimerize on
standing in room temperature, and therefore, they were
immediately used without prior purification.15 Compounds
8a-c were also useful for our synthetic approach, as an aza-
Michael reaction would provide the desired Cbz-protected
3-aminomethylchroman-4-ones 9a-c.
Scheme 2. Synthetic Route from 6 to 10
An aza-Michael reaction on the crude 8a-c using CbzNH2
in the presence of Tf2NH in acetonitrile at room temperature
was performed according to a recently reported procedure.16
Compounds 9a-c were obtained in overall yields of 69, 73,
and 63%, respectively, calculated from 7a-c. The isomer
(cis/trans) ratio was 3:7 according to 1H NMR spectroscopy.
The major isomer was not assigned as the mixture of isomers
was used in the next reaction step in which the asymmetry
was destroyed.
Compounds 9a-c were oxidized with SeO2 in dioxane-
water under microwave irradiation at 170 °C for 60 min to
(6) The chalcone 6c cyclized upon heating in EtOH (recrystallization
conditions) but the other chalcones 6a and 6b had to be heated in a micro-
wave cavity in EtOH with a catalytic amount of HCl present at 150 °C for
20 min. Even then, the chalcones 6a and 6b did not give more than 75 and
55% conversion, respectively, the rest being mainly unreacted starting
material in both cases.
(7) The other 2-aryl-8-bromo-6-chlorochroman-4-ones 7a and 7c were
not tested using this procedure.
(8) Lehmann, F.; Pilotti, Å.; Luthman, K. Mol. DiVers. 2003, 7, 145-
152.
(9) Similar Mannich products have been reported to be unstable and
undergo â-elimination (ref 5b).
materials were prepared via an acid-catalyzed ring closure
of the corresponding chalcones 6a-c in yields of 75, 55,
and 98%, respectively.6 The first attempt to perform the
Mannich reaction on 7b using dimethylamine hydrochloride,
paraformaldehyde, and a catalytic amount of concentrated
HCl in refluxing EtOH failed as only starting material was
1
(10) Purity verified by H NMR spectroscopy.
(11) The other 2-aryl-8-bromo-6-chlorochroman-4-ones 7a and 7b were
not tested using these procedures.
(12) Kim, M. Y.; Lim, G. J.; Lim, J. I.; Kim, D. S.; Kim, I. Y.; Yang,
J. S. Heterocycles 1997, 45, 2041-2043.
(13) Gericke, R.; Harting, J.; Lues, I.; Schittenhelm, C. J. Med. Chem.
1991, 34, 3074-3085.
(14) The reactions were performed at 160 °C for 10 min.
(15) The structurally similar 6-cyano-2,2-dimethyl-3-methylenechroman-
4-one was also reported to be unstable, forming the Diels-Alder dimer in
solution (ref 13).
(5) (a) Cingolani, G. M.; Gualtieri, F.; Pigini, M. Il Farm. 1971, 26,
718-25. (b) Ward, F. E.; Garling, D. L.; Buckler, R. T. J. Med. Chem.
1981, 24, 1073-1077. (c) Quaglia, W.; Pigini, M.; Gianella, M.; Melchiorre,
C. J. Med. Chem. 1990, 33, 2948-2950.
(16) Wabnitz, T. C.; Spencer, J. S. Org, Lett. 2003, 5, 2141-2144.
390
Org. Lett., Vol. 9, No. 3, 2007

the corresponding chromones 10a-c in 72-74% yield. A
shorter reaction time gave a mixture of starting material and
product.
Scheme 3. Pd-Mediated Reactions to Introduce Substitutents
in Positions 8 and 6
Since the ring closure of 6a-c to 7a-c and the following
Mannich reaction are both acid-catalyzed reactions, the
Mannich reaction conditions were tested using 6a-c as
starting material. We found that 6a-c also gave 8a-c as
the only product. The Mannich reaction on 6b gave an
identical result as compared to the reaction on 7b. However,
6a and 6c did not result in full conversion, and some
unreacted starting material (20% and 30%, respectively)
could be identified in the crude product mixture. Other
reaction conditions were not studied for these two reactions.
Nevertheless, the aza-Michael reaction was performed on
all three crude products without removing unreacted starting
material. Compounds 9a-c were obtained in an overall yield
of 62, 64, and 49%, respectively, calculated from 6a-c.
These yields were somewhat lower than when performing
the Mannich reaction on 7a-c. Compound 9c had the largest
drop in yield, from 63 to 49%, but it also showed the highest
amount of unreacted starting material after the Mannich
reaction.
Interestingly, when comparing the overall yields of 10a-c
calculated from 6a-c for both reactions, it is obvious that
10a,b should be prepared with the Mannich reaction directly
on 6a,b, but that 10c should be prepared with a Mannich
reaction on 7c. In this way, all three compounds 10a-c could
be obtained with an overall yield above 45% from 6a-c.
To demonstrate the applicability of the Cbz-protected
3-aminomethyl-2-aryl-8-bromo-6-chlorochromones 10 for the
study of chromone-based peptidomimetics, we used 10b in
which a benzyl group was introduced in the 8-position and
a vinyl group in the 6-position (Scheme 3). The two
successive Stille cross-coupling reactions in 64 and 79%
yields, respectively, were performed according to our previ-
ously reported procedures17 and provided the Cbz-protected
3-aminomethyl-8-benzyl-2-(4-methoxyphenyl)-6-vinylchro-
mone 12, which can be used for the synthesis of a Gly-Tyr-
Phe-Gly mimetic.
In conclusion, a new method to introduce an aminomethyl
group in the 3-position via a Mannich reaction can use either
chalcones 6a-c or chromones 7a-c as starting materials.
A short reaction sequence consisting of three or four steps,
clean reactions and good overall yields make this an excellent
method to introduce a primary aminomethyl group at the
3-position of both 2-arylchromone and chroman-4-one scaf-
folds. The Cbz-protected 3-aminomethyl-8-bromo-6-chloro-
2-(4-methoxyphenyl)chromone 10b was further demonstrated
to be applicable to our study of peptidomimetics by the
synthesis of 12.
Acknowledgment. Financial support was obtained from
The Knut and Alice Wallenberg Foundation, The Swedish
Research Council, and The Academy of Finland.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Dahle´n, K.; Grøtli, M.; Luthman, K. Synlett 2006, 897-900.
(b) Dahle´n, K.; Walle´n, E. A. A.; Grøtli, M.; Luthman, K. J. Org. Chem.
2006, 71, 6863-6871. For the vinylation reaction, see also: Littke, A. F.;
Fu, G. C. Angew. Chem., Int. Ed. 1999, 38, 2411-2413.
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