Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids from Aldehydes

Article abstract of DOI:10.1002/chem.201600333

An efficient one-pot synthesis of hydroxamic acids from aldehydes and hydroxylamine is described. A fast, visible-light-mediated metal-free hydroacylation of dialkyl azodicarboxylates was used to develop the subsequent addition of hydroxylamine hydrochloride. A range of aliphatic and aromatic aldehydes were employed in this reaction to give hydroxamic acids in high to excellent yields. Application of the current methodology was demonstrated in the synthesis of the anticancer medicine vorinostat.

Full text of DOI:10.1002/chem.201600333

DOI: 10.1002/chem.201600333
Full Paper
&
Organocatalysis
Photoorganocatalytic One-Pot Synthesis of Hydroxamic Acids
from Aldehydes
Giorgos N. Papadopoulos and Christoforos G. Kokotos*[a]
Abstract: An efficient one-pot synthesis of hydroxamic acids
from aldehydes and hydroxylamine is described. A fast, visi-
ble-light-mediated metal-free hydroacylation of dialkyl azodi-
carboxylates was used to develop the subsequent addition
of hydroxylamine hydrochloride. A range of aliphatic and ar-
omatic aldehydes were employed in this reaction to give hy-
droxamic acids in high to excellent yields. Application of the
current methodology was demonstrated in the synthesis of
the anticancer medicine vorinostat.
Introduction
Hydroxamic acids represent a very important class of chemical
compounds owing to the wide spectrum of biological activities
that they possess. They have been identified as potent inhibi-
tors of histone deacetylases and matrix metalloproteases,
which are associated with a number of diseases, such as
cancer, arthritis, and multiple sclerosis.[1] In the quest for active
histone deacetylases inhibitors, a number of compounds that
are based on the hydroxamic acid functionality have success-
fully passed clinical trials and are currently marketed as drugs.
Vorinostat and belinostat have been approved for the treat-
ment of refractory cutaneous T-cell lymphoma (CTCL) and pe-
ripheral T-cell lymphoma (PTCL), respectively, and in 2015, pan-
obinostat was approved for patients with multiple myeloma
(Scheme 1).[1g] Their potency is derived from their strong bind-
ing affinity to metals.[1] Hydroxamic acids have also been found
to possess antibacterial, antifungal, anti-inflammatory, anti-
asthmatic properties, etc.[2] Furthermore, the hydroxamic acid
moiety has been identified in a number of natural products as
the active functionality.[3]
Scheme 1. Approaches for the synthesis of hydroxamic acids.
The first successful attempt for the synthesis of hydroxamic
acids from aldehydes is more than 115 years old and utilizes
the Angeli–Rimini reaction.[4] However, this method is seldom
used because of the difficulty to remove the benzenesulfinic
acid byproduct. By far, the most common approach for the
synthesis of hydroxamic acids constitutes the coupling of acti-
vated carboxylic acid derivatives with O-protected or N,O-pro-
tected hydroxylamines[5] and less frequently with unprotected
hydroxylamines (Scheme 1).[6] Unfortunately, most of these
methods are substrate dependent and present difficulties in
the product isolation. Starting from an aldehyde, there are
a number of organocatalytic approaches that lead to protected
hydroxamic acids by using carbene chemistry;[7] the main
drawback of these protocols is the need for deprotection to
access the free hydroxamic acid. Very recently, De Luca and
coworkers reported a very elegant approach for the synthesis
of hydroxamic acids by the oxidative reaction of an aldehyde
and its transformation to an N-hydroxysuccinimide derivative.[8]
We have recently turned our attention from organocataly-
sis[9] to photoorganocatalysis.[10] In this initial contribution, we
coupled our experience in activated ketone chemistry[11,12] with
photocatalysis[13] to present a novel photoorganocatalytic hy-
droacylation of dialkyl azodicarboxylates.[10] Herein, we want to
present the direct evolution of this photoorganocatalytic mani-
fold as a linchpin for a one-pot protocol for the synthesis of
hydroxamic acids.
[a] G. N. Papadopoulos, Prof. Dr. C. G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry
National and Kapodestrian University of Athens
Panepistimiopolis 15771, Athens (Greece)
E-mail: ckokotos@chem.uoa.gr
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201600333.
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Results and Discussion
In our previously developed photoorganocatalytic hydroacyla-
tion of dialkyl azodicarboxylates, we identified phenylglyoxylic
acid, among a number of activated ketones, as an efficient
photoorganocatalyst.[10] We recently questioned the ability of
the products of the photocatalytic reaction (acyl imides) to act
as linchpins in a variety of transformations. Initially, we envis-
aged a reactivity that was similar to Weinreb amides upon the
addition of organometallic reagents to give ketones; indeed,
this reactivity was recently presented by Caddick and cowork-
ers,[14] in which acyl hydrazides were firstly prepared and isolat-
ed and then utilized for the synthesis of ketones. We then
turned our attention to exploring the reactivity of these acyl
hydrazides as activated acyl equivalents with the intention of
developing a one-pot protocol, which would be more attrac-
tive because it does not require intermediate purifications. Our
goal was the synthesis of hydroxamic acids (Table 1). Initially,
heptanal (1a) was reacted with diisopropyl azodicarboxylate
(DIAD) (2a) in petroleum ether by using phenylglyoxylic acid
(10 mol%) as the photoorganocatalyst (for reaction setup, see
the Supporting Information). The reaction can be easily moni-
tored, as complete decolorization of the reaction vessel indi-
cates reaction completion (2 h). Direct addition of hydroxyl-
Scheme 2. One-pot photoorganocatalytic synthesis of hydroxamic acids.
Table 1. Optimization of the one-pot protocol for the synthesis of hydroxamic acids
By using the optimum reaction conditions for the
one-pot photoorganocatalytic synthesis of hydroxa-
mic acids (Table 1, Entry2), the substrate scope of
this protocol was explored (Scheme 2). Initially, linear
aliphatic aldehydes were employed, and they led to
the corresponding hydroxamic acids 3a–d in high
yields. Branched aliphatic and unsaturated aldehydes
were utilized with similar success (compounds 3e
and 3 f). Aliphatic side chains that contain aromatic
moieties or protected functionalities, like a hydroxyl
group, led to the isolation of the hydroxamic acids
3g–i in excellent yields. a-Substituted aliphatic
chains or cyclic compounds were also tolerated well
to give high yields of the corresponding products
(compounds 3j–p). In most of these cases, five equiv-
alents of hydroxylamine hydrochloride and the corre-
sponding base were employed (see the Supporting
Information). Finally, aromatic and heteroaromatic al-
dehydes were also gave high yields of the products
(compounds 3q and r). Unfortunately, when N- or O-protected
hydroxylamines, such as BnONH2·HCl or MeONHMe·HCl,
were employed, we did not detect the desired hydroxamic
acid in the reaction mixture. Overall, a green, one-pot photoor-
ganocatalytic protocol for the synthesis of hydroxamic acids
from aldehydes has been developed. Moreover, the main prob-
lems that were associated with previous methodologies,
such as protection/deprotection or harsh reaction conditions,
have been overcome and a broad substrate scope has been
shown. The difficulties associated with purification have also
been dealt with to a great extent; accordingly, byproducts
were easily removed from the highly polar hydroxamic acids,
from aldehydes.
Entry
Conditions
Yield [%][a]
1
2
3
4
5[b]
6[b]
7[b]
8[b]
NH2OH·HCl, Et3N (5 equiv)
NH2OH·HCl, Et3N (3 equiv)
NH2OH·HCl, Et3N (2 equiv)
NH2OH·HCl, Et3N (1.5 equiv)
DIPEA instead of Et3N
DBU instead of Et3N
CHCl3 instead of CH2Cl2
EtOAc instead of CH2Cl2
89
88
54
52
55
75
64
61
[a] Yield of isolated product. [b] Same conditions as Entry 2.
amine hydrochloride and triethylamine led to an excellent
yield of hydroxamic acid 3a (entry 1). Dichloromethane was
chosen as the solvent to dilute the reaction mixture because
previously acquired knowledge showed that some intermedi-
ates were insoluble in petroleum ether;[10] however, it was not
used as the solvent of choice for the photoorganocatalytic
step because it required longer reaction times.[10] Decreasing
the amount of hydroxylamine to three equivalents led to a sim-
ilar high yield of the hydroxamic acid 3a (entry 2); unfortu-
nately, further decrease of the amount of hydroxylamine led to
lower yields (entries 3 and 4). Changing the base or the solvent
for the addition step led to similarly good yields (entries 5–8).
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which also present solubility problems in most common sol-
vents.
optimized, which illustrates an alternative procedure for its
synthesis.
Recognizing the potential of this protocol and the solutions
it provides as a high-yielding synthesis of hydroxamic acids,
we then turned our attention to providing a real-life applica-
tion of our protocol, which would prove that this protocol can
really be employed for previously unsolved synthetic problems.
Vorinostat, also known as suberanilohydroxamic acid (SAHA), is
a member of a class of compounds that inhibit histone deace-
tylases (HDAC) and is marketed under the name Zolinca for
the treatment of cancer.[15] The hydroxamic acid functionality
and the pharmacological application of vorinostat led us to ex-
plore its synthesis by using our optimized one-pot photoorga-
nocatalytic methodology (Scheme 3).
Experimental Section
General procedure for the photoorganocatalytic hydroacyla-
tion of dialkyl azodicarboxylates
Phenyl glyoxylic acid (7.5 mg, 0.05 mmol) was placed in a normal
glass tube followed by diisopropyl azodicarboxylate (101 mg,
0.50 mmol) and petroleum ether 40–608C (1 mL). Freshly distilled
or prepared aldehyde (0.75 mmol) was added, and the reaction
mixture was left stirring under light irradiation (2”15 W household
lamps, see photos below) at room temperature for 90 min to 48 h,
depending on the substrate. After the reaction was judged to be
complete (decolorization of the reaction mixture), hydroxylamine
hydrochloride (104 mg, 1.50 mmol), triethylamine (0.21 mL,
1.50 mmol), and dry CH2Cl2 (4 mL) were added consecutively, and
the reaction mixture was stirred at room temperature for 20 h. The
crude product was purified by using flash column chromatography
(CH2Cl2/MeOH 9:1 or petroleum ether/EtOAc 2:8 or EtOAc).
Acknowledgements
The authors gratefully acknowledge the Latsis Foundation for
financial support through the programme “EPISTHMO
NIKES MELETES 2015” (PhotoOrganocatalysis: Develop-
ment of new environmentally-friendly methods for the synthe-
sis of compounds for the pharmaceutical and chemical indus-
try).
Scheme 3. Application of the one-pot photoorganocatalytic protocol in the
synthesis of vorinostat.
Initially, suberic acid (4) was transformed to the correspond-
ing monoamide 5 in low yield. Reduction of the acid to the
corresponding alcohol by using the Kokotos’ procedure[16] fol-
lowed by Dess–Martin oxidation led to aldehyde 7. Finally, this
aldehyde was submitted to our photoorganocatalytic protocol,
which led to a moderate yield of vorinostat (8). The reactions
were not optimized. The moderate yield in the final step can
be attributed to two main factors: the incomplete photocata-
lytic reaction, even after 48 h (72% conversion by NMR analysis
of the crude reaction mixture), and the difficulty in purification
of the final compound owing to the high insolubility of vorino-
stat.
Keywords: green
chemistry
·
hydroxamic
acids
·
photochemistry · organocatalysis · vorinostat
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Published online on April 1, 2016
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