Angeli-Rimini's reaction on solid support: A new approach to hydroxamic acids

Article abstract of DOI:10.1021/jo061018g

Angeli-Rimini's reaction has been performed for the first time on solid phase. A convenient one-step procedure for the synthesis of hydroxamic acids starting from aldehydes and solid-supported N-hydroxybenzenesulfonamide is reported. The hydroxamates are isolated in good to high yields and purities by simple evaporation of the volatile solvents, after treatment of the crude reaction mixture with sequestering agents.

Full text of DOI:10.1021/jo061018g

The growing number of published synthetic methods further
points to the biological significance of hydroxamic acids.6
During these last years, solid-phase organic synthesis (SPOS)
has become an important tool for production of combinatorial
libraries and represents an important tool for the rapid identi-
fication of new lead compounds.7 Recently, several routes for
the preparation of hydroxamic acids on solid phase have been
published. These generally involve either the preparation of a
special linker to which hydroxylamine is attached through a
special N- or O-linkage or the formation of masked hydroxamic
acids on solid support.8 Hydroxamic acids might also be
obtained by direct cleavage of resin-bound esters with hydroxyl-
amine.9 The development of alternative methods to synthesize
this class of compounds is therefore desirable.
Angeli-Rimini’s Reaction on Solid Support:
A New Approach to Hydroxamic Acids
Andrea Porcheddu* and Giampaolo Giacomelli
Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via
Vienna 2, I-07100 Sassari, Italy
anpo@uniss.it
ReceiVed May 17, 2006
The research of unconventional reaction pathways has
frequently encouraged the transfer of solution-phase methodolo-
gies to the solid phase.10 In this context, here we wish to report
a novel technique that exploits a solid-phase version of the
Angeli-Rimini’s reaction as an alternative means to achieve
hydroxamic acids.
Angeli-Rimini’s reaction has been performed for the first
time on solid phase. A convenient one-step procedure for
the synthesis of hydroxamic acids starting from aldehydes
and solid-supported N-hydroxybenzenesulfonamide is re-
ported. The hydroxamates are isolated in good to high yields
and purities by simple evaporation of the volatile solvents,
after treatment of the crude reaction mixture with sequester-
ing agents.
At the end of the last century, in 1896, Angeli and Rimini11
discovered that N-hydroxybenzenesulfonamide 1 formed hy-
droxamic acids 4 in fair to good yields if treated with aldehydes
(5) (a) Durette, Ph. L.; Baker, F.; Baker, P. L.; Boger, J.; Bondy, S. S.;
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Hydroxamic acids are strong metal ion chelators,1 they
possess a wide spectrum of biological activities, such as
antibacterial, antifungal, anti-inflammatory, anti-asthmatic prop-
erties, etc.,2 and are identified as potent inhibitors of matrix
metalloproteinases, a family of zinc-dependent enzymes associ-
ated with diseases, such as cancer, arthritis, and multiple
sclerosis.3 Moreover, several hydroxamic acids show therapeutic
potential as ribonucleoside diphosphate reductase (RDPR)
inhibitors,4 a key enzyme involved in the rate-determining step
of DNA biosynthesis, while the hydroxamic acid function is
present in several natural products and widespread siderophores.5
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960829, 1996. (b) Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M.
Tetrahedron Lett. 1996, 37, 8045. (c) Floyd, C. D.; Whittaker, M. PCT Int.
Appl. WO 9626918 A1 960906, 1996. (d) Chen, J. J.; Spatola, A. F.
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20, 8045. (j) Khan, S. I.; Grinstaff, M. W. Tetrahedron Lett. 1998, 39,
8031. (k) Dankwardt, S. M. Synlett 1998, 761. (l) Ede, N. J.; James, I. W.;
Krywult, B. M.; Griffiths, R. M.; Eagle, S. N.; Gubbins, B.; Leitch, J. A.;
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Dankwardt, S. M.; Billedeau, R. J.; Lawley, L. K.; Abbot, S. C.; Martin,
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* To whom correspondence should be addressed. Fax: +39-079-212069.
E-mail: anpo@uniss.it.
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10.1021/jo061018g CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/01/2006
J. Org. Chem. 2006, 71, 7057-7059
7057

TABLE 1. Synthesis and Purification of Hydroxamic Acids
SCHEME 1. Angeli-Rimini’s Reaction
SCHEME 2. Polymer-Bound
N-Hydroxybenzenesulfonamide 6 Synthesis
2 in the presence of a strong base in MeOH (Scheme 1).12
Unfortunately, the acidic workup afforded the desired hydrox-
amic 4 together with the benzensulfinic acid 3 as a byproduct.
Because this impurity is not easily removed from the desired
product, the Angeli-Rimini’s reaction has been seldom used
in organic synthesis.
Intrigued by this old procedure, we envisaged that a solid-
supported N-hydroxybenzenesulfonamide reagent would solve
this problem and make easier the preparation and the final
purification of the hydroxamic acids. This new supported reagent
6 was so prepared by shaking at room temperature a pyridine
solution of HCl‚NH2OH with polystyrene sulfonyl chloride13
(Ps-TsCl) 5 in CH2Cl2 for 12 h, as outlined in Scheme 2.
Colorimetric and spectroscopic techniques often offer simple,
practical tools to qualitatively and/or quantitatively monitor
solid-phase reactions.14 Thus, the formation of N-hydroxyben-
zenesulfonamide on the resin was monitored using a simple
bead-staining test15 to check if the reaction was complete
(Scheme 3). When the final color of the beads is white or off-
white, the reaction is ended.
This rather sensitive assay enables the detection of even small
amounts of free chlorosulfonyl groups on the resin, and thereby
a negative test indicates that the hydroxylamine is quantitatively
anchored on the solid support. The presence on the resin of
hydroxamic acid groups can be easily detected using an iron-
(III) test, too, that gives an intensely colored complex (rust-
brown) with this functional group.15 As observed from the
colorimetric analyses, a quantitative loading was achieved using
a 5-fold excess of hydroxylamine hydrochloride. The outcomes
of the colorimetric tests were further confirmed by elemental
analyses.
(11) (a) Angeli, A. Gazz. Chim. Ital. 1896, 26, 17. (b) Rimini, E. Gazz.
Chim. Ital. 1901, 31, 84. (c) Angeli, A.; Angelico, E. Gazz. Chim. Ital.
1904, 34, 50. (d) Yale, H. L. Chem. ReV. 1943, 33, 228. (e) Vlasov, B. M.;
Zaharova, O. V. J. Org. Him. 1974, 10, 66. (f) Lwowsky, W. Angew. Chem.,
Int. Ed. Engl. 1967, 6, 897.
(12) A possible reaction mechanism was described in the literature, even
if not definite in all details: Hassnerr, A.; Wiederkehr, E.; Kascheres, A.
J. J. Org. Chem. 1970, 35, 1962.
(13) (a) The polystyrene sulfonyl chloride employed was obtained from
Argonaut Technologies Inc. (Biotage AB, loading 2.70 mmol/g). (b) For a
reviews on the use of Ps-TsCl, see: Huang, W.; He, B. Chin. J. React.
Polym. (Engl.) 1992, 1, 61. (c) For additional product information, see the
specifications (pdf file) available free of charge via the Internet at http://
www.biotage.com/Download.aspx?id)1785.
(14) Different colorimetric methods to monitor functional groups on resin
are collected in: Gaggini, F.; Porcheddu, A.; Reginato, G.; Rodriquez, M.;
Taddei, M. J. Comb. Chem. 2004, 6, 805.
(15) A few beads of the resin from the mixture reaction were treated
with ethylenediamine to convert unreacted sulfonyl chloride functions into
sulfonamide-linked primary amines. The free amine groups on polymer were
monitored using the bromophenol blue test (or Kaiser test). In the presence
of free amine (it means unreacted sulfonyl chloride moiety), resin beads
immediately take on blue appearances. Alternatively, beads in which the
starting chlorosulfonyl groups have reacted completely retain their original
color.
a Only the trans isomer was isolated.
7058 J. Org. Chem., Vol. 71, No. 18, 2006

SCHEME 3. Bromophenol Blue Test
The formation of N-hydroxybenzenesulfonamide on the resins
was also characterized by FTIR, monitoring the infrared
absorption band at 1365 cm-1 (-S-O stretch of -SO2Cl),
which shifts to 1320 cm-1 (-SO2-NH-) as well as by the
As seen from the data referring to the compounds 4i and 4j
(Table 1), this synthetic approach indicates even an interesting
solution for the preparation of monohydroxamic acids, in a
single step, from substrates containing carboxylic acid functions,
too, without implementing protection/deprotection strategies.
Within the limits of the Angeli-Rimini’s procedure, due mainly
to the basic conditions,21 this method is easy to use for many
synthetic purposes as it neither produces byproducts nor requires
tedious purifications of the product obtained. In conclusion, we
report a convenient preparation of a polymer-supported N-
hydroxybenzenesulfonamide that was successfully used to
convert aldehydes into hydroxamic acids, adapting a seldom-
used procedure in order to facilitate access to the hydroxamic
acid functionality. The procedure is selective and tolerates the
presence of other functional groups on the substrates. Work is
underway to explore if the resin-bound N-hydroxybenzene-
sulfonamide 6 could also be used as an interesting source for
producing HNO in biochemistry studies.22
appearance of a typical OH absorption at 3430 cm-1
.
To check the eventual limits of the applicability of Ps-Ts-
NHOH 6 in the Angeli-Rimini reaction, a series of structurally
different aldehydes 2a-p were reacted in parallel with this solid-
phase-bound reagent. Owing to the poor swelling ability of
polystyrene/1% divinylbenzene resin in conventional MeOH,
all the reactions were performed in THF.
The resin 6, suspended in THF, was treated with a solution
of NaOMe in MeOH and then reacted with several aliphatic
and aromatic aldehydes. After the reaction was complete, the
resin was filtered off and dry MeOH was added to the starting
solvent.16 The solution containing the crude reaction mixture
was then treated with acid ion-exchange resin Dowex 7 that
quenches excess MeONa by reducing the pH to ∼517 (Table
4). The unreacted aldehyde was then sequestered by polystyrene
sulfonyl hydrazide 8 (Ps-Ts-NHNH2), leaving behind a
solution containing the desired product, free of starting com-
ponents (HPLC or TLC analysis). Finally, the mixture was
filtered through a small plug of silica gel to remove traces of
water and salts, and the resulting solution was concentrated to
give the desired N-hydroxyamide. To optimize the yield, the
reaction was initially conducted with 1 equiv of Ps-Ts-NHOH
6 relative to the aldehydes 2a-p. In this case, the conversion
from aldehyde to hydroxamic acid was incomplete, and
significant amounts of aldehydes were recovered (20-30%).
Two equivalents of 6 was, however, sufficient to achieve a high
conversion of aldehydes 2a-p into the N-hydroxyamides 4a-p
(Table 1).
The progress of the reaction was monitored by HPLC, and
this procedure affords the desired hydroxamic acids 4a-p in
good yields and excellent purity. All the runs were conducted
at least in duplicate or in multiple batches to ensure the
reproducibility of the methodology. The results are summarized
in Table 1.
Aromatic or conjugated aldehydes (2a-l) react in excellent
yields, whereas the reaction with aliphatic aldehydes (compare
2m-p with 2a-l) requires longer times and leads to N-
hydroxyamides 4m-p in lower, although satisfactory, yield.18
As it is known,19 ketones do not react under these condi-
tions,20 and therefore, when both aldehyde and ketone groups
are present on the same substrate (2g), only the aldehyde moiety
is selectively transformed into the corresponding N-hydroxy-
amide function. Noteworthy also is that the Ps-Ts-NHOH 6
reacts with aldehyde 2h, affording the desired hydroxamic acid
4h, not affecting the methyl ester.
Experimental Section
Polymer-Bound N-Hydroxybenzenesulfonamide (6) Synthesis.
Polystyrene sulfonyl chloride 5 (222 mg, 0.6 mmol) suspended in
anhydrous THF (5 mL) was treated with a pyridine solution (5 mL)
of hydroxylamine hydrochloride (208.5 mg, 3.00 mmol) at room
temperature for 12 h. The reaction progress was monitored by the
colorimetric “bromophenol blue test” (negative) and “iron(III) test”
(positive). The polymer was filtered, washed several times with
THF, and then a mixture of THF and H2O (1:1), H2O, and
anhydrous THF, and, finally, dried under high vacuum to give off-
white resin beads. IR (KBr): 3430 (br), 1446, 1320 (s), 1162 (s).
Sample Procedure. The resin 6 previously obtained (0.6 mmol)
was swelled in 5 mL of THF, treated with a 5.4 N solution of
NaOMe (1.2 mmol) in MeOH (0.22 mL), shaken at room
temperature for 10 min and then reacted with p-chlorobenzaldehyde
2e (42.2 mg, 0.3 mmol). After 6 h, the resin was filtered off and
alternatively rinsed with THF (4 × 1 mL) and MeOH (3 × 1 mL).
The combined extract (THF:MeOH 3:1) was transferred to another
tube, and Dowex 50WX2-400 ion-exchange resin 7 (150 mg) was
portionwise added to adjust the pH to ∼5. The ion-exchange resin
was collected by filtration, the solution treated with Ps-Ts-NHNH2
8 (200 mg, 0.6 mmol), and the suspension shaken at room
temperature for additional 4 h. The resin was filtered out and washed
with THF (2×), MeOH (2×), DCM (2×), and MeOH (2×). The
filtrate was concentrated in vacuo, diluted with DCM (2 mL), and
filtered through a small plug (1.00 cm) of silica gel with hexane/
AcOEt (1:1). Finally, the solution, after evaporation of the solvent,
gave the desired N-hydroxyamide 4e (50.4 mg, 98% respect to 2e)
as the sole product. The product gives a red color with FeCl3, too.
Acknowledgment. The work was financially supported by
the University of Sassari (Fondi MIUR ex 40% 2005).
Supporting Information Available: Experimental procedures
and characterization. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) Using 1 mL of MeOH for each 3 mL of THF.
(17) The pH was adjusted as required by adding the acid ion-exchange
resin Dowex 7 and confirmed by a pH meter.
JO061018G
(18) The reaction did not reach completion even after 2 days.
(19) Panizzi, L.; diMaio, G.; Tardella, P. A.; D’Abbiers, L. Ric. Sci.,
Parte 8, Sez. A 1961, 31, 312.
(20) Under this reaction condition, acetophenone or hexan-2-one did not
react even after 1 week at room temperature or 12 h at refluxing temperature.
(21) In particular, the use of MeONa in the reaction could not allow the
use of optically active amino acids that are known to racemize easily under
these conditions.
(22) Wilson, E. K. Chem. Eng. News 2004, 82, 39.
J. Org. Chem, Vol. 71, No. 18, 2006 7059