One-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine

Article abstract of DOI:10.1002/adsc.201400188

A one-pot oxidative transformation of aldehydes into hydroxamic acids by the use of an aqueous solution of hydroxylamine is reported. The methodology gives high yields and makes use of cheap, abundant and easily available reagents.

Full text of DOI:10.1002/adsc.201400188

UPDATES
DOI: 10.1002/adsc.201400188
One-Pot Synthesis of Hydroxamic Acids from Aldehydes and
Hydroxylamine
Giovanna Dettori,a Silvia Gaspa,a Andrea Porcheddu,a and Lidia De Lucaa,*
a
Dipartimento di Chimica e Farmacia, Universitꢀ degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
Fax : (+39)-079-228-625; phone (+39)-079-229-531; e-mail: ldeluca@uniss.it
Received: February 20, 2014; Revised: March 19, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400188.
Abstract: A one-pot oxidative transformation of al-
dehydes into hydroxamic acids by the use of an
aqueous solution of hydroxylamine is reported. The
methodology gives high yields and makes use of
cheap, abundant and easily available reagents.
prepared from previously activated carboxylic acids
(active ester,[4] mixed anhydrides,[5] and acyl chlo-
ride[6]) and O-protected or N,O-protected hydroxyl-
AHCTUNGTRENNUNG
amine[7] (Scheme 1, pathway 1) and, less frequently,
from unprotected hydroxylamine[8] (Scheme 1, path-
way 2). The coupling of carboxylic acids with protect-
ed hydroxylamines is the preferred method, even
though protected hydroxylamines are highly expen-
sive reagents and an additional step (deprotection) is
necessary to complete the synthesis. In fact the direct
use of unprotected hydroxylamine involves both the
formation of N,O-diacylated by-products (Scheme 1,
Keywords: acyl derivatives; aldehydes; hydroxamic
acids; hydroxylamine
Hydroxamic acids are an important class of com- pathway 2) and difficulties in obtaining the product in
pounds with a broad array of biological activities in- a pure form.
cluding antibacterial, antifungal, anti-inflammatory
These classical syntheses of hydroxamic acids are
and anti-asthmatic properties.[1] They are strong metal highly dependent on the structure of the target mole-
ion chelators and, due to this feature, are contained in cules and product isolation is often extremely diffi-
potent matrix metalloproteinase[2] and histone deace- cult.[9]
tylase inhibitors.[3] Hydroxamic acids are commonly
Scheme 1. Hydroxamic acids from carboxylic acids.
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Giovanna Dettori et al.
Scheme 2. Hydroxamic acids from aldehydes.
Many natural products contain aldehydes that
could be directly transformed into hydroxamic acids
to greatly enhance their pharmacological activity.
An organic chemist needing to transform an alde-
hyde directly into a hydroxamic acid, has only two
methods available. The first method was developed
by Angeli.[10] It consists of the treatment, in aqueous
solution at reflux, of aromatic aldehydes with sodium
nitrohydroxamate, Na2N2O3 (Angeliꢂs salt)[11] to yield
the corresponding sodium salt of hydroxamic acid
(Scheme 2, pathway1). Many aldehydes do not react,
and the methodology is simply not applicable to ali-
phatic aldehydes due to the tedious purification of the
corresponding hydroxamic acids.[12] A second method-
ology to prepare hydroxamic acids from aldehydes
was later proposed by Angeli and Rimini.[13] The pro-
cedure consists of the treatment of an aldehyde with
N-hydroxybenzenesulfonamide in the presence of
a strong base (Scheme 2, pathway 2). Unfortunately
the acidic work-up results in the desired hydroxamic
acid with the benzenesulfinic acid as a by-product.
The latter is not easy to remove from the main prod-
uct. Due to the difficulties associated with the purifi-
cation, the Angeli–Rimini reaction has seldom been
used in organic synthesis.
Scheme 3. Oxidative amidation of aldehydes.
tored by TLC until the disappearance of N-hydroxy-
In relation to the pioneering example of an oxida- succinimide) the reaction mixture was cooled to room
tive amidation of aldehydes via N-hydroxysuccinimide temperature and an aqueous solution of 50% NH2OH
ester formation using a hypervalent iodine reagent (5 equiv.) was added. After 12 h at room temperature
(Scheme 3, pathway 1) reported by Yamamoto and the desired hydroxamic acid 2a was obtained with
co-workers[15] and to our recently reported copper-cat- a 79% yield (Table 1, entry 1). Even if the product
alysed oxidative amidation of aldehydes via N-hy- was obtained with a very good yield, the method did
droxysuccinimide ester formation[16d] (Scheme 3, path- not appear advantageous due to the large excess of al-
way 2), we tested the possibility to transform directly dehyde, oxidising reagent and hydroxylamine em-
an aldehyde into a hydroxamic acid via N-hydroxy- ployed. We repeated the same reaction using stoichio-
succinimide ester formation employing an aqueous metric amounts of aldehyde, TBHP and N-hydroxy-
solution of hydroxylamine (Scheme 3, pathway 3).
succinimide, but very poor results in terms of yield
We started our investigation by treating para-me- (31%) were obtained (Table 1, entry 2). We achieved
thoxybenzaldeyde 1a (2 equiv.) with N-hydroxysuccin- the same reaction with the use of FeCl3·6H2O, obtain-
ACHTUNGTRENNUNGimide (NHS) (1.1 equiv.), CuCAHTUNGTREN(NUNG OAc)2 (15 mol%) as ing the product 2a with a 27% yield (Table 1, entry 3).
a catalyst, an aqueous solution of 70% tert-butyl hy- The reaction was carried out without the use of any
drogen peroxide (TBHP) (2 equiv.) in acetonitrile as catalyst, but the aldehyde did not react even after 8 h
solvent at reflux. After 1 h (the reaction was moni- of reflux. In order to maintain a stoichiometric ratio
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One-Pot Synthesis of Hydroxamic Acids from Aldehydes and Hydroxylamine
Table 1. Screening of reaction conditions.
and 7). When 2-iodoxybenzoic acid (IBX) (Table 1,
entry 8) was used the hydroxamic acid 2a was ob-
tained with a very poor yield. On the contrary (diace-
toxyiodo)benzene PhIACTHNUTRGNE(UGN OAc)2 displayed high efficien-
cy by providing the product with excellent yield 82%
(Table 1, entry 9). This reaction was carried out em-
ploying para-methoxybenzaldeyde 1a (1 equiv.) with
Entry
Oxidant
Catalyst
Yield
N-hydroxysuccinimide (NHS) (1.1 equiv.), PhIACHTUNGTRENNUNG(OAc)2
1
2
3
4
5
6
7
8
9
TBHP
TBHP
TBHP
TBHP
H2O2
H2O2
Oxone
IBX
Cu
Cu
ACHTUNGTRENNUNG
79%[a]
31%[b]
27%[c]
(1.1 equiv.), in acetonitrile at 0 C8 for 1 h. An aque-
ous solution of 50% NH2OH (2 equiv.) was then
added. After 12 h at room temperature, the desired
hydroxamic acid 2a was obtained with a yield of 82%.
It is important to note that the N-hydroxysuccinimide
used could be recovered unmodified. An overview of
the details of the synthesis is provided in Table 1.
After the optimized reaction conditions had been
established, the scope of the methodology was investi-
gated.
FeCl3·6H2O
–
[d]
–
–
–
–
[e]
Cu
–
N
[f]
[g]
–
–
–
24%[h]
82%[i]
PhI
N
[a]
Reaction conditions: para-methoxybenzaldeyde 1a
(2 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
As depicted in Scheme 4, aromatic aldehydes with
a wide range of substituents, both electron-donating,
CuACHTUNGTRENNUNG(OAc)2 (15 mol%), TBHP (aq. sol. 70%) (2 equiv.), in
acetonitrile at reflux for 1 h. NH2OH (aq. sol. 50%)
(5 equiv.) was then added.
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
CuACHTUNGTRENNUNG(OAc)2 (15 mol%), TBHP (aq. sol. 70%) (1.1 equiv.),
in acetonitrile at reflux for 1 h. NH2OH (aq. sol. 50%)
(5 equiv.) was then added.
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
FeCl3 (15 mol%), TBHP (aq. sol. 70%) (1.1 equiv.), in
acetonitrile at reflux for 1 h. NH2OH (aq. sol. 50%)
(5 equiv.) was then added.
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
TBHP (aq. sol. 70%) (1.1 equiv.), in acetonitrile at reflux
for 8 h.
À
such as OMe (Scheme 4, product 2a) and benzylic C
[b]
[c]
[d]
[e]
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
H2O2 (1.1 equiv.), Cu
reflux for 8 h.
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
H2O2 (1.1 equiv.), in acetonitrile at reflux for 8 h.
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
Oxone (1.1 equiv.), in acetonitrile at reflux for 8 h.
ACHTUNGERTN(NUNG OAc)2 (15 mol%), in acetonitrile at
[f]
[g]
[h]
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
IBX (1.1 equiv.), in acetonitrile at room temperature for
1 h. NH2OH (aq. sol. 50%) (2 equiv.) was then added.
Reaction conditions: para-methoxybenzaldeyde 1a
(1 equiv.), N-hydroxysuccinimide (NHS) (1.1 equiv.),
[i]
PhIACHTUNGTRENNUNG(OAc)2 (1.1 equiv.), in acetonitrile at 08C for 1 h.
NH2OH (aq. sol. 50%) (2 equiv.) was then added at
room temperature for 12 h.
of reactants as much as possible, the reaction was car-
ried out employing different oxidising reagents. Using
classical oxidants such as H2O2 and Oxone the alde-
hyde was recovered unreacted (Table 1, entries 5, 6 Scheme 4. Aldehyde diversity.
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Giovanna Dettori et al.
Scheme 6. Hydroxylamine displacement step.
providing ester D. Finally the ester D undergoes a nu-
cleophilic substitution by the hydroxylamine affording
the hydroxamic ester E. In order to prove the mecha-
nism, we examined the hydroxylamine displacement
step (Scheme 6). The para-methoxybenzoate ester 3a
was prepared by treating para-methoxybenzaldehyde
with N-hydroxysucinimide and PhIACTHNUTRGENUN(G OAc)2 in acetoni-
Scheme 5. Proposed mechanism of hydroxamic acid forma-
tion.
trile at room temperature and then isolated.[16d] The
ester 3a was then reacted with NH2OH and after 12 h
the corresponding hydroxamic acid 2a was ob-
H (Scheme 4, products 2c and 2d), and electron-with- tained.[17]
drawing, such as CN, CF3 and NO2 (Scheme 4, prod-
In conclusion, a metal- and base-free synthesis of
ucts 2e, 2f and 2g) provided the desired hydroxamic hydroxamic acids has been developed. The starting
acid with moderate to excellent yields. The reaction reagents are aliphatic and aromatic aldehydes, which
which took place in the aldehydes with a halide sub- are cheap, abundant and easily available substances.
stituent on the aromatic ring provided the corre- The procedure is compatible with the presence of
sponding hydroxamic acid, which could be further water and, as a result, allows the direct use of an
manipulated by conventional cross-coupling reactions aqueous solution of NH2OH. Hydroxamic acids are
(Scheme 4, products 2h and 2i). To prove the synthetic normally very difficult to prepare and this procedure
efficacy of the methodology, thiophene-2-carbalde- offers a way for them to be obtained with great ease,
hyde was subjected to the optimised conditions, pro- in a pure form, and with high yields.
viding the desired heteroarylhydroxamic acid
(Scheme 4, product 2j) with excellent yield. The
methodology was also applied to aliphatic aldehydes, Experimental Section
providing very good results (Scheme 4, products 2k,
2l, 2m, 2n and 2o). Even with sterically hindered sub- General Procedure for the Synthesis of 2a–2r
strates the methodology provided the corresponding
hydroxamic acids with satisfactory yields (Scheme 4,
Aldehyde (4.34 mmol) was added in one portion to a solu-
tion of N-hydroxysuccinimide (550 mg, 4.77 mmol), iodoben-
products 2p and 2q). The reaction was carried out on
trans-cinnamaldeyde obtaining the corresponding un-
saturated hydroxamic acid (Scheme 4, product 2r)
without affecting the double bond. On the basis of
previous studies[15] a possible reaction mechanism is
depicted in Scheme 5.
The aldehyde A reacts with N-hydroxysuccinimide
(NHSI) giving the corresponding hemiaminal B. N-
hydroxysuccinimide (NHS) is oxidized to the corre-
sponding succinimide N-oxy radical (SINO). SINO
abstracts a hydrogen atom from the hemiaminal B
generating the corresponding hemiaminal radical C.
The presence of the N-oxy (SINO) radical and of the
hemiaminal radical C was clearly demonstrated by
ESR measurements of the reaction mixture.[15] The
zene diacetate (1.54 g, 4.77 mmol) in MeCN (6 mL) at 08C
under argon. The reaction mixture was stirred for 1 h at the
same temperature (the reaction was monitored by TLC
until the disappearance of aldehyde), hydroxylamine solu-
tion (50 wt% in H2O) (0.53 mL, 8.68 mmol) was then added.
The reaction mixture was allowed to warm to room temper-
ature and was stirred for 12 h. The solvent was removed
under vacuum, and the residue purified by flash chromatog-
raphy (ethyl acetate:petroleum ether).
Acknowledgements
This work was financially supported by Regione Autonoma
della Sardegna within the project: “High-throughput screen-
hemiaminal radical C is rapidly subjected to oxidation ing (HTS) per l’identficazione di nuove molecule per il tratta-
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One-Pot Synthesis of Hydroxamic Acids from Aldehydes and Hydroxylamine
mento della Sclerosi Laterale Amiotrofica e della Malattia di
Parkinson” and by Fondazione Banco di Sardegna with the
project entitled “Sintesi Assistita dale Microonde di una Li-
breria di Target Molecolri con Potenziale Attivitꢀ Contro il
Virus del Nilo Occidentale” (Prot. U640.2013/AI.564.MGB,
Prat.2013.1194).
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[9] A. Porcheddu, G. Giacomelli, in: The Chemistry of Hy-
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Rappoport, J. F. Liebman), Wiley-VCH, Weinheim,
2009, pp 164–231.
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6 One-Pot Synthesis of Hydroxamic Acids from Aldehydes
and Hydroxylamine
Adv. Synth. Catal. 2014, 356, 1 – 6
Giovanna Dettori, Silvia Gaspa, Andrea Porcheddu,
Lidia De Luca*
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These are not the final page numbers!