Organopromoted Selectivity-Switchable Synthesis of Polyketones

Article abstract of DOI:10.1021/acs.orglett.7b02731

In this work, an organopromoted metal-free pharmaceutical-oriented selectivity-switchable benzylic oxidation was developed, affording mono-, di-, and trioxygenation products, respectively, using oxygen as the oxidant under mild conditions. This process facilitates dioxygenation of 2,6-benzylic positions of heterocycles, which could be inhibited by heterocycle chelation to the metal cocatalysts. Enantiopure chiral ketones could also be prepared. The noninvolvement of transition metals and toxins avoids metal or hazardous residues, consequently ensuring a final-stage gram-scale synthesis of Lenperone.

Full text of DOI:10.1021/acs.orglett.7b02731

Letter
pubs.acs.org/OrgLett
Organopromoted Selectivity-Switchable Synthesis of Polyketones
Jie Liu,† Kang-Fei Hu,† Jian-Ping Qu,*,‡ and Yan-Biao Kang*,†
†Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
‡Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing 211816, China
S
* Supporting Information
ABSTRACT: In this work, an organopromoted metal-free pharma-
ceutical-oriented selectivity-switchable benzylic oxidation was
developed, affording mono-, di-, and trioxygenation products,
respectively, using oxygen as the oxidant under mild conditions.
This process facilitates dioxygenation of 2,6-benzylic positions of
heterocycles, which could be inhibited by heterocycle chelation to
the metal cocatalysts. Enantiopure chiral ketones could also be
prepared. The noninvolvement of transition metals and toxins avoids
metal or hazardous residues, consequently ensuring a final-stage
gram-scale synthesis of Lenperone.
n recent decades, methods for synthesis of aromatic
ketones1−10 have been well established, since aromatic
Table 1. Dioxygenation of 2, 3, and 6 with Reported Methods
I
ketones are useful feedstocks in organic synthesis, representing
convenient intermediates for manufacturing pharmaceuticals
(Figure 1). Conventional methods, such as the Friedel−Crafts
Figure 1. Representative pharmaceuticals containing polyketones.
reaction, could afford monoketones successfully via an electro-
philic aromatic substitution. However, the ketone products are
less reactive than their precursors due to the electron-
withdrawing effect of their carbonyl group, giving rise to the
nonoccurrence of multiple acylations which are necessary for the
generation of polycarbonyl arenes. Despite being seemingly
simple, the synthesis of di- or polyketone remains a
challenge.5b,7b,h,i,8d−f,9c
Considering alkylarenes are inexpensive and abundant
industrial materials, the synthesis of aromatic ketones by
oxygenation of a benzylic C−H bond under environment-
friendly conditions has attracted much attention.2−8 However, it
is difficult to obtain dioxygenation products as a result of the
electron-withdrawing effect of the carbonyl groups on the ketone
intermediates which are less reactive than their original
molecules. For example, the oxygenation with IBX could only
convert diethylbenzene to monoketone 4, but failed to give
dioxygenation product 5 (Table 1).2 Similarly, Co- or Cu-
catalyzed aerobic benzylic oxygenation,3,4 which has been
successfully applied in the synthesis of monoketones, could not
afford the dioxygenation product 5 either (Table 1). Despite
there being few examples of selective dioxygenation, a ratio of
only around 2:1 has been achieved.7b,l,8d In addition, the control
of mono-/di-/polyselectivity is even more challenging when
Received: September 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02731
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Organic Letters
Letter
there are more than two benzyl sites in the substrates. Moreover,
in the aforementioned approaches, toxic organics as well as high-
valent transition metals have been widely used as oxidants,
causing the problem of the removal of residual metal/toxics in
the products which limits their applications in pharmaceutical
synthesis. Therefore, the development of a transition-metal-free
and selectivity-switchable oxygenation is essential for a
pharmaceutically oriented synthesis.
To investigate the conditions for controlling the selectivity
between mono- and dioxygenation, diethylbenzene 3 was
subjected to various reaction conditions in the presence of
NHPI and TBN under O2. Only monoketone 4 was obtained
with 0.5 equiv of NHPI and 1 equiv of TBN (Table 2, entry 3),
Table 2. Selectivity Control
Lenperone 1 (Figure 1) is a typical antipsychotic of the
butyrophenone chemical class. Using a strategy of final stage
oxygenation, the previously reported Fe−PyCO2H−tBuOOH
system afforded only 24 mg of Lenperone 1 in 26% isolated yield
after 5 days of oxidation (Table 1A, entry 1).3h We also screened
the reported catalytic Co/NHPI system (entries 2−5), but no
dioxygenation reaction occurs. Thus, the dioxygenation of
compound 2 to Lenperone via a final stage oxidation remains
as an unsolved issue in organic synthesis.
Encouraged by the unsuccessful trial in the above-mentioned
issue, the synthesis of ketones via the selectivity-switchable
benzylic oxygenation was then explored with common
methods2−4 in the oxidation of 3 to monoketone 4 or diketone
5 as a model reaction and the results are summarized in Table 1B.
Methods using IBX or cobalt catalysts afforded mono-oxygen-
ation product 4 as the only product in moderate yields, but the
copper system totally failed (left column). Unfortunately,
dioxygenation product 5 did not occur in any previous
conditions (right column).
Pyridine-containing alkyl heteroarenes are difficult to react
utilizing the benzylic C−H oxidation and special protecting
strategy that has been employed in previous work.4c We then
tested dioxygenation of pyridine-containing substrate 6 in which
the ethyl substituent is directly adjacent to a coordinating N-
atom (Table 1C). In transition-metal catalysis, the pyridine core
can inhibit the oxygenation by chelation to the metal cocatalyst.3j
Neither Ishii’s or Stahl’s procedure can be used as an alternative
for such substrates (entries 1−4).
Thus, all aforementioned reported methods failed to realize
either the dioxygenation of dialkyl arene 5 or pyridine-containing
heteroarene 7. Therefore, a new method must be established for
dioxygenation of such dialkyl arenes and heteroarenes. Recently,
we reported that an N-hydroxyphthalimide (NHPI)/tBuONO
(TBN) system could generate benzyl radicals and provide an
efficient approach to mono-/diselectivity control in aromatic
nitrile synthesis.11a Herein we report our latest results in the
development of a NHPI/tBuONO12 promoted selectivity-
switchable benzylic oxidation in the presence of O2 to achieve
mono-, di-, and polyoxygenation products, using a strategy of an
organopromoted interrupted radical trapping process (Figure 2).
b
b
entry
x
y
atmosphere
4 (%)
5 (%)
1
2
3
4
5
6
7
30
50
50
50
100
50
50
3
O2
57
62
84
60
0
0
3
O2
12
trace
5
1
O2
0.5
2
O2
O2
73
0
1
argon
air
23
1
42
0
a
Conditions: 1a (0.5 mmol), O2 (1 atm)tBuONO, NHPI, dry MeCN
(1 mL), 80 °C, 24 h. By H NMR with internal standards.
b
1
whereas the product was switched to dioxygenation product 5
when 1 equiv of NHPI and 2 equiv of TBN were employed
(entry 5). Thus, the selectivity of mono-/dioxygenation was
synergistically controlled by the amount and ratio of TBN/
NHPI. The reaction under argon or air lowered the yield of 4
(entries 6 and 7), indicating that O2 is a necessary oxidant in this
reaction. The reaction conditions demonstrated in entries 3 and
5 were then chosen as the standard conditions for mono- and
dioxygenation, respectively. These results again demonstrate the
advantage of our approach over metal catalysis in the oxidation of
heterocycles bearing a chelating groups. Despite the fact that
substoichiometric or stoichiometric NHPI has to be employed,
our metal-free method shows advantages in selective dioxygena-
tion of alkylarenes and potential utility in substituted ketone
synthesis. Although the regeneration of PINO with TBN/O2 or
O2 alone is possible in principle, the efficiency is not high.
Stoichiometric TBN enables the sufficient generation of a high
concentration of the PINO radical which is needed for the
generation of radicals from less reactive electron-deficient
substrates or intermediates.
Subsequently, the scope of the substrate has been investigated
under optimized conditions to evaluate the control of selectivity
between mono- and dioxygenation (Table 3). A wide range of
mono- and dioxygenation products have been selectively
prepared from corresponding dialkylarenes. For example,
under standard Condition A, a variety of monoketones have
been obtained in generally good yields (left column). Pyridine-
containing substrates were selectively converted to monoketone
8 and diketone 7 in 63% and 54% yields, respectively. Either
para- or meso-diethylbenzene afforded corresponding mono-
ketone 4 or 9 in an 82% or 80% isolated yield. The gram-scale
synthesis shows synthetic capability in preparation (9 and 10). In
all cases, the selectivity was good and only trace dioxygenation
products were observed. The regioselectivity is consistent with
the stability of the radical pathway, in which the diaryl benzyl
position is prior to the ethyl side (11). On the other hand, under
standard Condition B, various dioxygenation products were
achieved, in which no monoketones were observed (right
column).
Figure 2. Working model of oxygen interruption.
The rapid interruption of oxygen over NO in trapping benzylic
radical intermediates enables the oxygenation over amination.
This transition-metal-free and toxic-free synthetic method
provides a practical and convenient access to pharmaceuticals
containing substituted aromatic ketones from environmental and
economic viewpoints.
Enantioenriched alkylarenes could be oxidized to afford mono-
and dioxygenation products while retaining ee-values (Scheme
B
DOI: 10.1021/acs.orglett.7b02731
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Organic Letters
Letter
a
Table 3. Selectivity-Switchable Synthesis of Polyketones
Scheme 2. Mono-, Di-, and Polyoxygenation
conversion of 28. In each case, high selectivity was achieved,
indicating the ability of precise control of the selectivity.
Finally, in the pharmaceutically oriented synthesis, Condition
B could afford 1.1 g of Lenperone 1 in 62% of yield (Scheme 3)
Scheme 3. Gram-Scale Final-Stage C−H Oxidation to
Lenperone
without the involvement of any metal (see above-mentioned
Table 1), indicating the potential application of the current
method in pharmaceutical manufacturing. The standard
condition affords only Lenperone 1 with neither monoketones
nor the byproducts from the oxidation of N-atom or N-α-
positions.
More examples of electron-deficient substrates are shown in
Scheme 4. The electron-withdrawing groups such as NO2-, CF3-,
Ac, nitrile, and ester are all feasible.
a
Condition A: dialkyl arene (0.5 mmol), O2 (1 atm), NHPI (0.25
mmol), tBuONO (0.5 mmol), CH3CN (1.0 mL), 80 °C, isolated yield.
Condition B: same as standard Condition A, except that 0.5 mmol of
t
NHPI and 1.0 mmol of BuONO were used.
1). For example, mono-oxygenation product 24 and dioxygena-
tion product 25 were both achieved in 99.9% ee from their
Scheme 4. Electron-Deficient Ketones under Condition B
Scheme 1. Synthesis of Enantiopure Ketones
TEMPO efficiently inhibits the oxygenation of ethylbenzene
to acetophenone (eq 1), suggesting that this oxygenation
proceeds via a radical process. Phthalimide-N-oxyl (PINO)
generated from NHPI could abstract the benzylic hydrogen atom
of ethylbenzene to form alkyl radicals.3
A reaction mechanism is proposed in Scheme 5. The PINO
radical is generated by the reaction of NHPI and TBN. PINO
abstracts a hydrogen to form the benzyl radical A, which is rapidly
trapped by oxygen to form intermediate B. Monoketone C is
formed from rearrangement of B.3 The stoichiometric TBN
generates sufficient concentration of PINO, enabling further
formation of radical intermediates of electron-deficient acetyl C.
Thus diketone D is afforded after the second oxygenation.
In conclusion, we have developed a pharmaceutically oriented
synthetically practical and scalable method for the selectivity-
switchable approach to mono-, di-, and polyoxygenation via a
highly efficient aerobic benzylic oxidation of alkylarenes. This
enantiopure precursor 23. Chiral monoketone 27 was obtained
in 98% ee using standard Condition A.
To further examine the capability of controlling selectivity, this
method was tested in the oxygenation of 1,3,5-triethylbenzene
28 by simply tuning the ratios of tBuONO/NHPI (Scheme 2).
All three oxygenation products 29, 30, and 31 could be
selectively obtained with moderate to good yields in 36 h. The
synthesis of triketone 31 was performed at 90 °C to obtain full
C
DOI: 10.1021/acs.orglett.7b02731
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02731.
■
S
Experimental details and spectroscopic data for all
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ybkang@ustc.edu.cn.
*E-mail: ias_jpqu@njtech.edu.cn.
ORCID
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Notes
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2007, 63, 2439. (b) Dohi, T.; Takenaga, N.; Goto, A.; Fujioka, H.; Kita,
Y. J. Org. Chem. 2008, 73, 7365. (c) Nammalwar, B.; Fortenberry, C.;
Bunce, R. A.; Lageshetty, S. K.; Ausman, K. D. Tetrahedron Lett. 2013,
The authors declare no competing financial interest.
́
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4418.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21672196, 21404096, 21602001, U1463202) and Anhui
Provincial Natural Science Foundation (1608085MB24) for
financial support.
̌ ́
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