A free radical alkylation of quinones with olefins

Article abstract of DOI:10.1039/c9cc01704f

We demonstrated herein an Fe(iii)-mediated radical alkylation of quinones. A wide range of bioactive molecules with quinone motifs can be rapidly synthesized by using readily available and inexpensive NaBH₄/NaBD₄ with alkenes at room temperature under open flask conditions.

Full text of DOI:10.1039/c9cc01704f

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DOI: 10.1039/C9CC01704F
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A Free Radical Alkylation of Quinones with Olefins
Shuai Liua,b, Tong Shena, Zaigang Luoa and Zhong-Quan Liu*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We demonstrated herein an Fe(III)-mediated radical alkylation of quinones represents an attractive protocol to
alkylation of quinones. A wide range of bioactive molecules overcome these disadvantages in part (Scheme 1). For
with quinone motifs can be rapidly synthesized by using example,
AgNO3/K2S2O8
and
(NH4)2S2O8-promoted
readily available and inexpensive NaBH4/NaBD4 with alkenes decarboxylative alkylation of N-heterocycles and quinones
at room temperature under open flask conditions.
with carboxylic acids was achieved by Minisci, Jacobsen and
Lee (Scheme 1a).10
Quinone frameworks belong to a highly important class of
building blocks which are widely distributed in natural
products and pharmaceuticals.1 Due to the unique structure of
quinones, they have many desirable properties for applications
in chemistry, materials, medicine and biology.2 For instance,
many quinones have excellent antimicrobial,3a anti-tumor,3b
anti-cancer3c and anti-diabetes3d properties. In addition, they
also play a crucial role in cell respiration and cell metabolism,4
and have great attraction to the dye industry.5 However,
efficient and economical strategies for direct functionalization
of quinones are rare.
Heck coupling is a well-known and efficient method for
construction of C-C but it is not suitable for quinones. As
quinones are good ligands and oxidants, interacting with
transition metal such as Pd presents a huge challenge to this
type of coupling.6 Several optional strategies have been
proposed through the efforts of chemists, one of which is
Lewis acid-promoted nucleophilic addition of electron-rich
arenes to quinones.7 The other is transition-metal-catalyzed
addition of boric acid or borate to quinones8 and Pd-catalyzed
cross-coupling of halogenated quinones.9 But these
approaches usually require a re-oxidation step to convert
hydroquinone to quinone. Besides, halogenated quinones are
usually not commercially available. Alternatively, free radical
Previous work
:
a)
Minisci, Jacobsen and Lee's work:
O
O
AgNO3/K2S2O8
or (NH4)2S2O8
+
R1
R1
R
CO2H
40-65oC
R
O
O
O
b)
Ilangovan's work:
O
AgNO3
K2S2O8
+
R1
R1
R
R
OH
rt
O
O
O
c)
Lee's work:
O
O
O
Cu(OTf)2
TBHP
80oC, 6-7h
+
R1
R1
n
O
n
d)
Molander's work:
O
O
O
R
TFA
Na2S2O8
EtO2C
CO2Et
Me
+
R1
R1
rt, 48h
R
Me
N
H
O
a.
College of Chemical Engineering, Anhui University of Science and Technology,
Huainan, Anhui 232001, P. R. China
State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of
This work:
O
O
O
b
4
R1
H
NaB
H/D
R2
Fe(NO3)3•9H2O
rt, 0.5 h
R2
Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
E-mail: liuzhq@lzu.edu.cn
+
+
and/or
D
NaB
R1
4
O
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Approaches to C-H alkylation of quinones.
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Under similar conditions, Ilangovan11 showed that investigated, and they were also compatible with thVisiewreAartcictlieoOnnl(in6e-
cyclopropanols were oxidized to open the ring to obtain alkyl 12). Gratifyingly, the benzoquinones beDaOrinI:g10.1e0it3h9e/Cr 9CeCle0c1t7r0o4nF-
radicals, which were then added to quinones to generate donating or withdrawing groups all resulted in good yields. Notably,
alkylated quinones (Scheme 1b). In 2016, Lee’s group12 the product 9 was also obtained from the apoptosis inducer
reported a copper-catalyzed quinones alkylation with cyclic Coenzyme Q0 in 60% yield. To our surprise, 2,5-dichlorocyclohexa-2,
alkanes in the presence of tert-butyl hydroperoxide (Scheme 5-diene-1,4-dione gave a dialkylated quinone (12) while mono-
1c). Later Molander13 found that 1,4-quinones could be alkylated quinones were isolated as the major product in most
alkylated with 1,4-dihydropyridines under oxidative conditions cases.
without metal or photocatalysts (Scheme 1d). Nevertheless,
these radial strategies also have limitations such as limited
Table 2 Examination of the quinones substrates.a
substrate scope, less efficiency and harsh reaction conditions.
O
O
Hence, more efficient and novel synthesis strategies are still
highly desirable. Herein, we developed an Fe(III)/NaBH4-
mediated direct C-H functionalization of quinones by utilizing
olefin as the alkyl radical source (Scheme 1).
Fe(NO3)39H2O
R
H
NaB
4
R
+
+
Si
EtOH/CH3CN(1/1)
rt, 30min
Si
O
O
O
H
O
O
O
O
O
In recent several years, a series of highly efficient C-C
bond formation systems using alkene as the alkyl radical
precursor have been explored by Boger, and others.14 Inspired
by these previous works and ours,15 we began to hypothesize
that a radical alkylation of quinones with olefins as the radical
precursors would be possible. Initially, we focused on the
optimization of reaction conditions with naphthalene-1,4-
dione and allyltrimethylsilane as the model compounds (Table
1; see also the Supporting Information). When the reaction
was carried out without Fe(III) salt (entry 1), no target product
was observed. With the increase of the load of iron salts, the
yields improved (entries 2-4). We found the yield also
depended on the amount of NaBH4 and olefins (entries 5-8).
Cl
OH
Si
Si
Si
Si
O
O
H
H
H
H
b
4
, 62%
2
, 45%
from Vitamina k3
3,
1
70%
, 63%
from Lawsone
O
OH
O
O
O
Si
3
2
H
Si
Si
Si
O
O
O
O
H
H
H
5
, 68% (2/3 = 1/1)
from Juglone
6
7
8
, 67%
, 51%
, 64%
O
O
O
O
Si
O
O
O
Cl
Cl
H
Cl
Si
O
Si
Si
Cl
Si
O
O
O
H
H
H
O
H
Table 1 Modification of the typical reaction conditions. a
9, 60%b
10
, 58%
11
, 60%
12
, 58%
from Coenzyme Q0
O
a Reaction conditions: quinones (1 equiv, 0.2 mmol), allyltrimethylsilane (4 equiv,
0.8 mmol), NaBH4 (4 equiv, 0.8 mmol), Fe(NO3)3·9H2O (5 equiv, 1 mmol),
CH3CN/EtOH (1/1, 4 mL), rt, 0.5 h. Isolated yields. b NaBH4 (6 equiv, 1.2 mmol, add
in two portions), unless otherwise noted, for details, see the SI.
O
Fe(NO3)3•9H2O(z equiv)
H
NaB
+
4
Si
+
EtOH/CH3CN(1/1)
rt, 0.5h
Si
O
O
H
y equiv
x equiv
1equiv
In an attempt to have a further understanding of the versatility
of this reaction, a series of olefins were examined. As demonstrated
in Table 3, a variety of alkenes were screened to be effective
substrates. An array of cyclic alkenes afforded the desired alkylation
products in moderate yields (13-16). Then, a broad range of linear
olefins were examined (17-24). It is worth mentioning that various
functional groups such as hydroxyl, carboxylic acid, epoxy, silyl, aryl,
ester, amide, etc. could be tolerated in the process. Natural product
rose oxide (racemate) enabled a quaternary carbon center to be
formed in 30% yield (24). The relative low yield might be due to the
steric effect. Notably, this reaction could be amplified to grams and
maintained its efficiency (19).
entry
x
Y
Z
yield
(%)b
(equiv.)
(equiv.)
(equiv.)
1
2
3
4
5
6
7
8
5
5
5
5
4
2
5
5
4
4
4
4
4
4
5
3
0
2
4
5
5
5
5
5
0
20
53
65
63
37
68
45
a Reaction conditions: naphthalene-1,4-dione (1 equiv, 0.2 mmol), CH3CN/EtOH
(1/1, 4mL), rt, 0.5 h. b Isolated yields.
Table 3 Examination of the olefinsa
Since we have established the optimal reaction conditions, the
general applicability of the reaction needed to be investigated. As
portrayed in Table 2, the reaction was performed with a wide range
of quinones. Firstly, a variety of substituted naphthoquinones were
found to provide the corresponding products in moderate to good
yields (1-5). Interestingly, Vitamin K3 (2), Lawsone reagent (4) and
Juglone (5) can react efficiently and smoothly. To our delight, very
sensitive phenolic hydroxyl groups can also be tolerated in this
system (5). Next, a series of substituted benzoquinones were
O
O
O
H
R
typical
conditions
R
Q
H
NaB
+
+
4
Q
=
O
2 | J. Name., 2012, 00, 1-3
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O
O
O
O
View Article Online
H
H
Q
H
Q
Q
DOI: 10.1039/C9CC01704F
O
Q
OH
OH
Si
H
O
O
14,
50%
15,
52%
13,
Q
16
50%
, 48%
D
D
D
31,
70%
29
, 61%
30
, 59%
O
Br
H
H
OH
a
H
O
Reaction conditions: naphthalene-1,4-dione (1 equiv, 0.2 mmol), alkenes (4
H
Q
Q
Q
equiv, 0.8 mmol), NaBD4 (4 equiv, 0.8 mmol), Fe(NO3)3·9H2O (5 equiv, 1 mmol),
CH3CN/EtOH (1/1, 4 mL), rt, 0.5 h. Isolated yields.
Br
19
, 70%
17
18
20
, 64%
, 63%
, 68%
56% (1.1 g)
Finally, a radical clock experiment was carried out to verify the
reaction mechanism further. Scheme 2 supports that this reaction
underwent a radical process. First of all, a formal H radical would be
formed via single-electron oxidation of the hydride by Fe(III) salt.
Subsequently, radical A was generated by addition of H-atom to the
1,6-diene followed by a radical 6-endo-trig cyclization. The usual 5-
exo-trig cyclization was not observed, which might be due to the
stability of the radical intermediate. Then addition of A to quinone
would afford radical intermediate B. Ultimately, single-electron
oxidation again followed by deprotonation leads to the
corresponding product 32.
O
O
O
N
H
OH
H
H
Q
O
Q
Q
O
O
Q
H
21
, 62%
23
, 54%
22
, 66%
24
, 30%
a
Reaction conditions: naphthalene-1,4-dione (1 equiv, 0.2 mmol), alkenes (4
equiv, 0.8 mmol), NaBH4 (4 equiv, 0.8 mmol), Fe(NO3)3·9H2O (5 equiv, 1 mmol),
CH3CN/EtOH (1/1, 4 mL), rt, 0.5 h. Isolated yields.
This strategy can also be applied to the synthesis of drug molecules,
such as the antimalarial drug, parvaquone, which can be
synthesized in one step with high efficiency and good yield (Eq 1).
O
O
O
O
O
typical
conditions
O
O
typical
conditions
OH
OH
+
H
+
NaB
4
H
H
NaB
+
(eq 1)
+
4
O
O
O
EtO2C
O
CO2Et
O
O
Fe(III)
H
32
H
, 60%
- e-
- H+
25
, 64%
H
H
O
H
6-endo-trig
EtO2C
CO2Et
In recent years, the strategy of deuterium substitution has
been widely used in drug research16. Substitution of hydrogen in
drug molecules with deuterium may screen metabolic sites and
reduce the production of toxic metabolite17. Additionally, it can
prolong the half-life of drugs in the body17. Hence, we hope to
introduce deuterium atoms into organic molecules through this
CO2Et
EtO2C
B
A
Scheme 2 Mechanistic studies.
In conclusion, we developed a simple and practical Fe(III)-
strategy. Fortunately, deuterium atoms can be smoothly installed mediated C-H conversion of quinones with unactivated
into quinones by using NaBD4 as the deuterium source (Table 4). alkenes. This protocol provides a mild, rapid, and step-
We found that various olefins are compatible with this system (26- economic access to a broad range of functionalized quinones,
31). In all cases, the D-atom was introduced into the molecules at which could be converted into various bioactive molecules and
the least hindered position since the more stable C-centered radical drugs via late stage transformation. Furthermore, deuterium
intermediate could be formed. These results not only allow a atom can also be conveniently installed into organic molecules
convenient access to deuterized compounds, but also confirm that through this method. Hence broad application of this strategy
the H- and/or D-atoms do come from NaBH4 and/or NaBD4.
in drug synthesis would be expected.
We thank the National Natural Science Foundation of
China (No. 21672089) for financial support.
Table 4 Introduction of deuterium atom into molecules.a
O
O
R
Fe(NO3)39H2O
D
R
NaB
+
+
4
Notes and references
EtOH/CH3CN(1/1)
rt, 30min
O
O
D
1
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O
O
O
O
O
D
Br
O
D
D
28
, 62%
26
27
, 60%
, 50%
2
3
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DOI: 10.1039/C9CC01704F
Graphical Abstract
A Free Radical Alkylation of Quinones with Olefins
Shuai Liua,b, Tong Shena, Zaigang Luoa and Zhong-Quan Liu*b
a. College of Chemical Engineering, Anhui University of Science and Technology, Huainan, Anhui 232001, P. R. China
b State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China
E-mail: liuzhq@lzu.edu.cn
O
O
R1
H
NaB
4
Fe(NO3)3•9H2O
rt, 0.5h
H/D
R2
R2
+
+
and/or
R1
D
NaB
4
O
O
scaled-up to grams mild conditions D-atom installation site-specific
We demonstrated herein an Fe(III)-mediated radical alkylation of quinones. A wide range of bioactive
molecules with quinone motifs can be rapidly synthesized by using readily available and inexpensive
NaBH4/NaBD4 with alkenes at room temperature under open flask conditions.