Atom-Economic Silver-Catalyzed Difunctionalization of the Isocyano Group with Cyclic Oximes: Towards Pyrimidinediones

Article abstract of DOI:10.1002/anie.201801363

An unprecedented silver-catalyzed difunctionalization of the isocyano group with cyclic oximes is described. This method allows efficient and atom-economic assembly of a vast array of structurally novel and interesting pyrimidinediones, and tolerates a range of functionalities. The resulting products can be easily converted into some useful compounds. Furthermore, the method can also be applied for the late-stage modification of a few biologically active molecules.

Full text of DOI:10.1002/anie.201801363

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Accepted Article
Title: Atom-Economic Silver-Catalyzed Difunctionalization of Isocyano
Group with Cyclic Oximes Toward Pyrimidinediones
Authors: Ye Wei, Hong-Wen Liang, Zhen Yang, Kun Jiang, and Ying
Ye
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801363
Angew. Chem. 10.1002/ange.201801363
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10.1002/anie.201801363
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Atom-Economic Silver-Catalyzed Difunctionalization of Isocyano
Group with Cyclic Oximes Toward Pyrimidinediones
Hong-Wen Liang, Zhen Yang, Kun Jiang, Ying Ye, and Ye Wei*
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday
Abstract: An unprecedented silver-catalyzed difunctionalization of
isocyano group with cyclic oximes is described. This method allows
efficient and atom-economic assembly of a vast array of structurally
novel and interesting pyrimidinediones and tolerates a range of
functionalities. The resulting products can be easily converted into
some useful compounds. Furthermore, our method can also be
applied for the late-stage modification of a few biologically active
Scheme 1. Functionalization of Isocyano Group.
molecules.
result in low functional group tolerance and atom/step economy.
Herein, we develop an unprecedented silver-catalyzed protocol
Owing to the unique reactivity, isocyanides have been
explored as versatile building blocks for organic synthesis.[1]
for the expedient synthesis of pyrimidinediones, which utilizes
cyclic oximes and isocyanides as the starting materials. In the
Such substrates can participate in a range of reactions, such as
multicomponent reactions[2] (e.g. Ugi and Passerini reactions),
reactions, multiple new chemical bonds are generated in one
insertion reactions,[3] and cycloaddition reactions.[4] In terms of
step involving the difunctionalization of the isocyano group. More
the isocyano group functionalization,[5] most of these reactions
significant, the reaction features excellent atom economy,
operationally simple procedure, good functional group tolerance,
merely involve the functionalization of the isocyanide terminal
carbon atom, and the isocyanide nitrogen atom remains intact
and amenability to late-stage synthetic applications.
(Scheme 1a). Considering the potential reactivity of nitrogen and
carbon functionalities toward new chemical bond formation, we
can envision that exploration of both the nitrogen and carbon
atoms of the isocyano group as reactive sites to simultaneously
construct new chemical bonds in one step (difunctionalization of
isocyano group) would provide opportunities for the creation of
structurally new and important molecules. In this context, a few
groups have recently reported their pioneering work toward
cycloaddition
reactions
between
isocyanides
and
propargylamines,[6] between isocyanides and enamides,[7] and
between two isocyanides (Scheme 1b).[8] These reactions
simultaneously generated new C−C, C−N, and/or N−N bonds at
the isocyano group. Despite these advances, the reported
reactions are still restricted to a narrow substrate scope, thus
limiting the molecule diversity. Clearly, such a difunctionalization
strategy will only be widely used in organic synthesis when
diverse compounds can be generated with high efficiency. Thus,
exploiting new reactivity profile of the isocyano group and
Scheme 2. Proposed reaction process of a cyclic oxime with an isocyanide.
Our research interests[13] in transition metal-catalyzed oxime
N−O bond transformations[14] inspired us to investigate the
insertion reactions of isocyanide into the cyclic oxime N−O bond
to construct N-heterocycles. The proposed reaction process is
shown in Scheme 2. An isocyanide inserts into the N−O bond of
a cyclic oxime with the assistance of a transition metal to furnish
developing
new
synthetic
strategies
involving
the
difunctionalization of the isocyano group are highly significant
and desirable.
an imidate, which subsequently undergoes
a Mumm-type
rearrangement[15] to generate a N-heterocycle. To this end,
considerable experimentations were surveyed,[16] and finally we
found that the reactions between isocyanides and isoxazol-5-
ones[17] catalyzed by a silver salt afforded pyrimidinediones. Note
that the isoxazol-5-ones can be readily prepared by several
methods (Scheme 3), including (1) condensation of β-ketoesters
The pyrimidinedione scaffold is ubiquitous in a large number
of molecules, such as pharmaceuticals, agrochemicals, and
functional materials.[9] For instance, thymine and uracil are
indispensable for DNA and RNA, respectively.[10] 5-Fluorouracil
and tipiracil are drugs used for the treatment of cancer.[11]
Consequently, many synthetic methods have been developed to
construct the pyrimidinediones:[12] for example, the reactions of
substituted ureas with diketene, and the reactions of 1,3-
oxazine-2,4-diones with amines. However, many of these
reactions require the use of strong base/acid or high
temperature or involve multiple synthetic steps, which would
with
hydroxylamine
hydrochloride,
(2)
Knoevenagel
condensation of isoxazol-5(4H)-ones with carbonyl compounds,
followed by nucleophilic addition, (3) nucleophilic substitution of
the isoxazol-5(4H)-ones with alkyl halide.
[*]
H.-W. Liang, Z. Yang, K. Jiang, Y. Ye, Prof. Dr. Y. Wei
College of Pharmacy, Third Military Medical University,
Chongqing, 400038 (China)
E-mail: weiye712@hotmail.com
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Substrate scope of cyclic oximes.[a]
Scheme 3. Synthetic methods for the isoxazol-5-ones.
Scheme 4. Gram-scale reaction.
An illustrative example is the gram-scale reaction of 3-phenyl-
5-isoxazolone with ethyl isocyanoacetate (Scheme 4). The
reaction of 3-phenyl-5-isoxazolone 1a with ethyl isocyanoacetate
2a proceeded smoothly with Ag2O as a catalyst and pyridine as
an additive, giving rise to pyrimidinedione 3aa in 87% yield. The
structure of 3aa was unambiguously confirmed by single-crystal
X-ray diffraction.[18] In this reaction, two C−N bonds and one
C=O bond were newly formed at the isocyano group, and all
atoms of the two reactants were incorporated into the final
product, thus exhibiting excellent atom economy.
To evaluate the feasibility of the current isocyano group
difunctionalization protocol toward the pyrimidinedione synthesis,
a wide spectrum of cyclic oximes were surveyed (Table 1). It is
found that both the electronic nature and position of the
substituents on the aryl ring have negligible effect on the
reaction efficiency. For instance, substrate 1 containing electron-
donating (OMe, NMe2, and Me) or electron-withdrawing groups
(CF3, NO2, OCHF2, Cl, Br, and I) at different positions (para or
meta) of the aryl ring reacted with 2a efficiently to generate the
corresponding products 3ba−3ka in 62−92% yields. Furthermore,
the sterically hindered ortho-methyl group substituted substrate
did not affect the reaction, because the desired product was
generated in 91% yield (3la). In addition, cyclic oxime with a
naphthyl functionality also exhibited excellent reactivity (3ma).
Note that our method was also amenable to several heterocycle-
derived cyclic oximes, which include the ones derived from
thiophene (3na), pyrrole (3oa), furan (3pa), and benzodioxole
(3qa). Besides the pyrimidinediones bearing (hetero)arenes at
the C6 position, the products containing methyl, cyclopropyl,
olefinic, ether, or ester groups were also obtained in 73−97%
yields (3ra−3wa). More importantly, this method not only
provided C6-substituted pyrimidinediones, but also afforded C5-
and C6-disubstituted products 3xa−3afa in moderate to
excellent yields. The functionalities at the C5 position include
phenyl (3xa), furylmethyl (3ya), methyl (3za), n-butyl (3aaa), and
ketone groups (3aca and 3ada). Of note is that a polyenic
moiety stemmed from farnesol, an important natural product and
biologically active compound,[19] was successfully introduced into
the desired product (3aba).
[a] Reaction conditions: 1 (0.2 mmol), 2a (1.5 equiv), Ag2O (5 mol%), pyridine
(1 equiv), 1,4-dioxane (2 mL), 80 °C, 6 h, under Ar.
Table 2. Substrate scope of isocyanides.[a]
[a] Reaction conditions: 1a (0.2 mmol), 2 (1.5 equiv), Ag2O (5 mol%), pyridine
(1 equiv), 1,4-dioxane (2 mL), 80 °C, 6 h, under Ar.
We next turned our attention to evaluate the substrate scope
with respect to the isocyanides (Table 2).
A variety of
isocyanides with acidic C−H bonds, including methyl
α
isocyanoacetate, p-tolylsulfonylmethyl isocyanide, diethyl
isocyanomethylphosphonate, 1-cyclohexyl-2-isocyanoethanone,
and benzotriazol-1-ylmethyl isocyanide, reacted smoothly with
1a to deliver a diverse set of pyrimidinediones 3ab−3af in good
to excellent yields. Similar efficiencies were observed for 2-
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morpholinoethyl isocyanide and benzyl isocyanide, and the
corresponding products were formed in 87 and 60% yields (3ag
and 3ah). Besides, our approach was also suitable for the
isocyanide without a hydrogen at the α position. For instance, 1-
isocyanonaphthalene displayed moderate reactivity in the
synthesis of product 3ai. Unfortunately, tert-butyl isocyanide
showed very low reactivity (<10%) and cyclohexyl isocyanide did
not react with 1a at all.
for the synthesis of the pyrimidinedione 5 employs 6-chlorouracil
4 as a starting material, and such a method involves six
synthetic steps, such as N-protection, Pd-catalyzed Suzuki
reaction, and ammonium hexanitrate cerium-mediated N-
deprotection steps. Moreover, the total yield of 5 is significantly
lower than 20% yield after six steps. Compared with the known
method, our protocol exhibited obvious advantages in terms of
reaction efficiency and step economy. Specifically, the catalytic
product 3ha was easily transformed into the compound 5 in 86%
total yield after ester hydrolysis and amide formation steps.
Scheme 7. Synthetic transformations of pyrimidinediones. Reaction conditions:
(a) 3aa (0.2 mmol), diphenylacetylene (1.5 equiv), [RuCl2(p-cymene)]2 (7.5
mol%), Na2CO3 (2 equiv), Cu(OAc)2 (2 equiv), PhCl, 120 °C , 10 h. (b) 3ta (0.2
mmol), 3-chloroperbenzoic acid (1.1 equiv), DCM, rt, 4 h. (c) 3ta (0.2 mmol),
Br2 (2.2 equiv), DCM, rt, 12 h. (d) 3ra (0.2 mmol), Br2 (1.1 equiv), DCM, 65 °C ,
2 h.
Scheme 5. Late-stage modification of some biologically active compounds.
To demonstrate the function of this newly developed method
for the late-stage functionalization[20] of biologically active
compounds, several cyclic oximes installed with different key
moieties in biologically active compounds were tested under the
standard reaction conditions. As depicted in Scheme 5, the
pregnenolone-derived substrate 1ag was subjected to this
protocol, furnishing the desired product 3aga in 81% yield.
Furthermore, cetirizine, a drug used to treat allergies,[21] was first
converted into the corresponding cyclic oxime 1ah, which then
reacted with 2a to afford 3aha in 73% yield. Similarly, starting
from tolectin that is applicable in the treatment of rheumatoid
arthritis,[22] a pyrimidinedione 3aia was obtained in 89% yield.
The synthetic value of our method was further demonstrated
by
the
synthetic
transformations
of
the
obtained
pyrimidinediones (Scheme 7). For example, compound 3aa
reacted with diphenylacetylene via Ru-catalyzed C−H cyclization
process to provide a polycyclic N-heterocycle 7 in good yield.
Besides, compound 3ta can efficiently undergo epoxidation and
multiple bromination to form epoxide 8 and polybrominated
compound 9 in 69 and 97% yields, respectively. Similarly, mono-
brominated product 10 was achieved for the pyrimidinedione 3ra,
of which a 65% yield being obtained.
Scheme 6. Synthesis of a biologically active molecule.
Of note is that our method can be utilized to prepare a
pyrimidinedione 5, a precursor of compound 6 that displays
autotaxin inhibitory activity (Scheme 6).[23] An existing approach
Scheme 8. Mechanistic investigations.
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To shed light on the reaction mechanism of this
transformation, several experiments were carried out (Scheme
8). Firstly, O18-labelled substrate 1a-O18 was subjected to the
reaction to react with 2a to investigate the oxygen atom source
(Scheme 8a). The mass spectrometry result revealed that the
O18 atom was incorporated into the final product 3aa-O18. As
such, all of the atoms in the two starting materials were
implanted into the target product. Secondly, an isoxazol-5(2H)-
one derivative 1aj was prepared, which reacted with 2a under
the standard reaction conditions to afford the corresponding
product 3aia in 67% yield (Scheme 8b). This observation implied
that the isoxazol-5(2H)-one might be an intermediate in the Ag-
catalyzed pyrimidinedione synthesis. Lastly, the model reaction
of 1a with 2a took place under the standard reaction conditions
Acknowledgements
Financial support from the NSFC (No. 21772231, 21302220),
the Natural Science Foundation of Chongqing (No.
cstc2016jcyjA0008), and the Third Military Medical University is
greatly appreciated.
Keywords: oximes • isocyanides • N-heterocycles • silver •
homogeneous catalysis
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Scheme 9. Proposed mechanism.
Although the exact mechanism of this reaction remains
elusive, on the basis of the above observations and the previous
work, a plausible mechanism is illustrated to account for the
unprecedented Ag-catalyzed pyrimidinedione synthesis from
cyclic oximes and isocyanides. As depicted in Scheme 9, the
cyclic oxime 1 may tautomerize to the isoxazol-5(2H)-one 1’[24]
that then reacts with Ag(I) salt by using pyridine as a base to
generate a silver complex A. Subsequent isocyanide insertion
affords an intermediate B, followed by ring opening to give rise
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Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hong-Wen Liang, Zhen Yang, Kun
Jiang, Ying Ye, and Ye Wei*
Page No. – Page No.
Atom-Economic
Silver-Catalyzed
Difunctionalization of Isocyano Group
with
Cyclic
Oximes
Toward
Pyrimidinediones
An unprecedented silver-catalyzed difunctionalization of isocyano group with
cyclic oximes has been achieved. This method allows efficient and atom-
economic assembly of a vast array of structurally novel and interesting
pyrimidinediones and tolerates a range of functionalities. The resulting products
can be easily converted into some useful compounds. Furthermore, our method
can also be applied for the late-stage modification of a few biologically active
molecules.
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