Recycling Catalyst as Reactant: A Sustainable Strategy to Improve Atom Efficiency of Organocatalytic Tandem Reactions

Article abstract of DOI:10.1021/acs.orglett.8b02898

A sustainable strategy by internally recycling an organocatalyst as a reactant in a downstream reaction to improve the atom efficiency of organocatalytic tandem reactions is described. Specifically, a one-pot tandem Cloke-Wilson/Boulton-Katritzky reaction

Full text of DOI:10.1021/acs.orglett.8b02898

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Recycling Catalyst as Reactant: A Sustainable Strategy To Improve
Atom Efficiency of Organocatalytic Tandem Reactions
Wen Wei, Yuhai Tang, Yan Zhou, Ge Deng, Ziyu Liu, Jun Wu, Yang Li, Junjie Zhang, and Silong Xu*
Department of Chemistry, School of Science, and Xi’an Key Laboratory of Sustainable Energy Materials Chemistry, Xi’an Jiaotong
University, Xi’an 710049, P. R. China
S
* Supporting Information
ABSTRACT: A sustainable strategy by internally recycling an
organocatalyst as a reactant in a downstream reaction to
improve the atom efficiency of organocatalytic tandem
reactions is described. Specifically, a one-pot tandem
Cloke−Wilson/Boulton−Katritzky reaction of cyclopropylke-
tones with a hydroxylamine has been developed for the
synthesis of fully substituted isoxazoles, in which the hydroxylamine serves as both an upstream catalyst and a downstream
reactant.
n important goal of synthetic chemistry is to develop
green methods that maximize the atom and step economy
by utilizing the phosphine oxide byproduct to promote an
array of downstream transformations. Loh6o and Alaimo6n
have demonstrated that In0-mediated processes (e.g., Barbier
reaction) could be integrated with reactions using an in situ
generated InIII byproduct as a Lewis acid catalyst. Wu and co-
workers6c,f,i,l have reported the combination of I2-mediated
iodination of ketones with downstream reactions that were
catalyzed by the thus-formed iodine species (e.g., HI, CuI).
Recently, a sustainable Mo-catalyzed reduction/annulation
process of nitrobenzenes with glycols has been demonstrated
by Sanz and co-workers8a,d for the synthesis of nitrogenated
heterocycles, in which the reduction byproducts of glycols, i.e.
aldehydes or ketones, are internally incorporated into the final
product. Despite this progress, new strategies to improve the
atom efficiency of tandem reactions are still of essential
importance.
A
of organic reactions and minimize the adverse environmental
effects.1 Toward this end, tandem reactions,2 in which multiple
reactions are combined into one operation, have been
extensively investigated to enhance the efficiency of the
chemical process. The convergent nature of tandem reactions
also provides an opportunity for achieving the multifaceted use
of the catalysts or reagents to further improve the atom
efficiency of the process. For example, the “auto-tandem
catalysis”3 involving a single catalyst to facilitate two or more
distinct chemical transformations in a single flask has been
applied in a large number of tandem reactions showing great
synthetic utility (Scheme 1a).4 A sustainable strategy of
“internal recycling of waste”5 has also been developed in which
the byproduct of a stoichiometric reaction is recycled as a
catalyst,6 additive,7 or reagent8 for the following steps (Scheme
1b). Particularly, Shibasaki,7f Zhou,6d,g,7a,c and Toy6h,j have
developed sustainable processes based on the Wittig reaction
Organocatalysis9 has been established as a pivotal method-
ology due to its versatility and metal-free green nature. Various
manifolds of organocatalysis such as nucleophilic catalysis,10
enamine catalysis,11 iminium catalysis,12 NHC catalysis,13 and
Brønsted acid catalysis14 have flourished in recent decades. In
spite of their efficiency,15 an arguable disadvantage of
organocatalysis is the frequent requirement of a high catalyst
loading (typically 20 mol %), which compromises the overall
atom efficiency and limits its large-scale application in industry.
Although several methods for addressing this issue have been
attempted, such as recycling16 and immobilization17 of the
catalyst, the fundamental inefficiency remains. As part of our
interest in organocatalysis,18 we herein report a new
sustainable strategy of “recycling the catalyst as the reactant”
that internally reuses the organocatalyst as a reactant in a
downstream reaction (Scheme 1c). The strategy has the
potential to improve the atom efficiency of tandem processes,
Scheme 1. Sustainable Strategies for Tandem Reactions
Received: September 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02898
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
and also circumvents the concern of a large catalyst loading in
organocatalysis since all catalyst material is incorporated into
the final product. Furthermore, the capacity to use relatively
simple and less reactive organocatalysts can be realized, since
stoichiometric quantities of reagent compensate for reduced
catalytic activity.
In light of our recent studies of organocatalytic ring-opening
reactions of cyclopropanes,18a,b we envisaged that simple and
inexpensive hydroxylamine could not only catalyze the Cloke−
Wilson rearrangement19 of cyclopropylketones, but also
promote a subsequent Boulton−Katritzky reaction20 of the
resulting dihydrofurans to finally afford isoxazole products
(Scheme 2). Gratifyingly, these two distinct transformations
Table 1. Optimization on Reaction Conditions
b
equiv of
NH2OH·HCl
temp
(°C)
yield
(%)
entry
base/equiv
solvent
1
2
3
4
5
6
K2CO3/1.2
Na2CO3/1.2
Cs2CO3/1.2
DBU/1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
THF
CH2Cl2
CH3CN
CH3OH
dioxane
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
110
110
110
110
110
110
reflux
reflux
reflux
reflux
60
110
70
90
130
130
130
66
60
45
46
K3PO4/1.2
tBuOK/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/1.2
K2CO3/2.4
K2CO3/2.4
10
trace
trace
trace
trace
<5
trace
trace
trace
38
7
8
9
10
11
12
13
14
15
16
Scheme 2. Initial Investigation
72
91
93
c
17
a
Under N2 and at indicated temperature, to a solution of 1a (0.2
mmol) in the solvent (2.0 mL) were added the base and NH2OH·
b
c
HCl, and the mixture was stirred for 24 h. Isolated yield. K2CO3 and
NH2OH·HCl were added in two portions in 20% and 80%,
respectively, over 24 h interval.
could be successfully converged into one pot. When cyclo-
propylketone 1a was treated with a catalytic amount of
hydroxylamine (20 mol %) at 110 °C in DMSO, the reaction
produced the dihydrofuran 2a′ in 77% yield together with the
desired isoxazole 2a in 12% yield (Scheme 2, entry 1). Under
identical conditions with a stoichiometric amount of hydroxyl-
amine, the reaction produced 2a in 66% yield as the sole
product (Scheme 2, entry 2).21 Thus, the transformation
involves a seamless integration of two reactions utilizing
hydroxylamine as both catalyst and reactant, respectively,
which presents a new sustainable strategy for tandem reactions.
On the basis of these encouraging results, the conditions of
the Cloke−Wilson/Boulton−Katritzky reaction were opti-
mized (Table 1). Among several common bases tested,
K2CO3 still emerged as the best (entries 1−6). Solvent
screening indicated that DMSO was crucial to the reaction, as
THF, CH2Cl2, CH3CN, CH3OH, 1,4-dioxane, and DMF all
provided very poor yields (entries 7−12). A survey of
temperature found substantially lower yields at a reduced
temperature of 90 or 70 °C and an improved yield of 72% at
130 °C (entries 13−15). When the amount of NH2OH·HCl
and K2CO3 was increased, the yield could be enhanced to 91%
(entry 16). Finally, the yield of 2a could be further improved
to 93% when NH2OH·HCl and K2CO3 were introduced in
two time-separated additions (entry 17). Thus, the optimized
condition consists of heating cyclopropylketones at 130 °C in
DMSO with 2.0 equiv of NH2OH·HCl and 2.4 equiv of
K2CO3 added in two portions.
Information). Vinyl substituted cyclopropylketones (R1
=
vinyl) were also effective which produced the corresponding
allylic alcohol products 2i−n in 40−78% yields. Substrates
containing aliphatic ketones (R2 = Me) were well tolerated in
these cases. In addition, alkyl substituted cyclopropylketones
(R1 = Me) were competent providing isoxazoles 2o−q in good
yields (56−78%) under our standard conditions. Furthermore,
nonsubstituted cyclopropylketones (R1 = H) also reacted
smoothly to afford products 2r−t bearing a primary alcohol in
high yields (79−90%). Of note, cyclopropylketone 1u, bearing
two different ketone moieties, delivered a pair of regioisomeric
isoxazoles 2u and 2u′ in a 3:1 ratio and 55% combined yield.
Taken together, the above results suggest a broad scope of the
tandem Cloke−Wilson/Boulton−Katritzky reaction, which
includes aryl-, alkyl-, vinyl-, and nonsubstituted cyclopropylke-
tones featuring either aromatic or aliphatic ketones. To
demonstrate the practicality, a scale-up reaction of 1a (3.0
mmol) was conducted which afforded the product 2a in 0.76 g,
78% yield.
Subsequently, we probed the possibility of using hydrazine
as both a catalyst and reactant to mediate the Cloke−Wilson/
Boulton−Katritzky reaction of cyclopropylketones to generate
the corresponding pyrazoles. However, this attempt was not
successful because hydrazine failed to catalyze the Cloke−
Wilson rearrangement. Alternatively, when DABCO was
employed as the organocatalyst, the desired pyrazoles 3
could be generated in one pot in excellent yields from
representative cyclopropylketones 1 (Scheme 4). This result,
however, corroborates the dual role of hydroxylamine as both
catalyst and reactant in the Cloke−Wilson/Boulton−Katritzky
reaction.
Utilizing these conditions, the scope of the tandem Cloke−
Wilson/Boulton−Katritzky reaction was probed (Scheme 3).
First, a range of cyclopropylketones bearing various aromatic
substitutions (R1, R2 = aryl) proved to work well in the tandem
reaction, giving the desired isoxazoles 2a−h in good to
excellent yields (65−97%). The product structure was
unequivocally established by X-ray crystallography (for 2c,
CCDC: 1861088; 2f, CCDC: 1861089; see Supporting
B
DOI: 10.1021/acs.orglett.8b02898
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope
Scheme 5. Elaboration of Products for the Synthesis of
Tricyclic Heterocycles
Scheme 6. Proposed Mechanism
a
Under N2 and at 130 °C, to a solution of cyclopropylketone 1 (0.2
mmol) in DMSO (2.0 mL) were added NH2OH·HCl (0.04 mmol)
and K2CO3 (0.04 mmol). After the mixture stirred for 24 h, remaining
NH2OH·HCl (0.36 mmol) and K2CO3 (0.44 mmol) were added, and
b
the mixture was stirred for an additional 24 h. Yield from 3.0 mmol
scale.
NH2OH on cyclopropane 1 via a homoconjugate addition
pathway25 produces an enolate intermediate 6. The anion then
undergoes a favorable 5-exo-tet cyclization to give the
dihydrofuran 2′ and release the NH2OH catalyst. The
subsequent Boulton−Katritzky reaction initiates when
NH2OH acts as a reactant to condense with the dihydrofuran
2′ to afford oxime 7, which is deprotonated by a catalytic
amount of base (e.g., K2CO3) to give intermediate 8.
Cyclization then occurs to generate 9, which undergoes
fragmentation and protonation to afford the aromatic hetero-
cycle 2. The isolation of intermediate 2a′, as shown in Scheme
2, entry 1, suggests the rate of the Cloke−Wilson rearrange-
ment should be significantly faster than the downstream
Boulton−Katritzky reaction.
In summary, we have described a new sustainable strategy of
“recycling catalyst as reactant” which holds great promise for
improving the atom efficiency of organocatalytic tandem
reactions. Specifically, a hydroxylamine-mediated Cloke−
Wilson/Boulton−Katritzky reaction of cyclopropylketones
has been developed for the efficient assembly of fully
substituted isoxazoles, wherein the hydroxylamine serves as
both the catalyst for the Cloke−Wilson rearrangement and a
reactant for the downstream Bouton−Katritzky reaction. By
recovering the catalyst as a reactant, the strategy may
a
Scheme 4. One-Pot Synthesis of Pyrazoles 3
a
Conditions: DABCO (0.5 equiv), DMSO, 120 °C, 24 h, then
NH2NH2·H2O (2.0 equiv), K2CO3 (2.4 equiv), 24 h.
Isoxazoles22 and pyrazoles23 are privileged heterocycles
embedded in a large number of biologically active molecules
and pharmaceuticals. The above Cloke−Wilson/Boulton−
Katritzky reactions thus provide an efficient and convenient
route to these hetereocycles. The homobenzylic alcohol unit of
the products offers a good opportunity for further elaboration.
To demonstrate the potential, Friedel−Crafts alkylations of the
products in the presence of TFA24 were achieved to access
tricyclic skeletons 4 and 5 in good yields (Scheme 5). The
structure of 4a was confirmed by X-ray crystallography
(CCDC: 1861090).
A plausible mechanism for the Cloke−Wilson/Boulton−
Katritzky tandem reaction is proposed in Scheme 6. For the
initial Cloke−Wilson rearrangement,18b nucleophilic attack of
C
DOI: 10.1021/acs.orglett.8b02898
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02898.
Experimental procedures, analytical data, NMR spectra,
and crystallographic information (PDF)
Accession Codes
CCDC 1861088−1861090 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
(5) For a book chapter: Zhou, J.; Zeng, X. P. Waste-Mediated
Reactions. In Multicatalyst System in Asymmetric Catalysis; Zhou, J.,
Ed.; John Wiley & Sons: 2014; pp 633−670.
Corresponding Author
*E-mail: silongxu@mail.xjtu.edu.cn.
ORCID
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Yang Li: 0000-0002-9311-3412
Silong Xu: 0000-0003-3279-9331
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21871218,
21602167), the Natural Science Basic Research Plan in
Shaanxi Province of China (No. 2015JQ2050), the China
Postdoctoral Science Foundation (Nos. 2014M550484,
2015T81013, 2015M580830), Shaanxi Province Postdoctoral
Science Foundation, and Key Laboratory Construction
Program of Xi’an Municipal Bureau of Science and Technology
(201805056ZD7CG40).
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DOI: 10.1021/acs.orglett.8b02898
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