Radical Benzylation of Quinones via C-H Abstraction

Article abstract of DOI:10.1021/acs.joc.9b01004

Herein we report the development of radical benzylation reactions of quinones using Selectfluor and catalytic Ag(I) initiators. The reaction is believed to proceed via a C-H abstraction mechanism after Ag(I)-mediated reduction of Selectfluor. This reaction occurs under mild conditions and is effective for a variety of quinones and radical precursors bearing primary benzylic carbons. The use of preformed Ag(4-OMePy)₂NO₃ as a catalyst proved effective in improving the reaction efficiency by reducing unwanted degradation pathways available to Selectfluor.

Full text of DOI:10.1021/acs.joc.9b01004

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Note
Radical Benzylation of Quinones via C–H Abstraction
Jordan D Galloway, Duy N. Mai, and Ryan D. Baxter
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 26 Aug 2019
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The Journal of Organic Chemistry
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Radical Benzylation of Quinones via C–H Abstraction
Jordan D. Galloway, Duy N. Mai, and Ryan D. Baxter*
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Department of Chemistry, Chemical Biology, University of California, 5200 North Lake Road, Merced, California 95343,
United States
ABSTRACT: Herein we report the development of radical benzylation reactions of quinones using Selectfluor and catalytic
Ag(I) initiators. The reaction is believed to proceed via a C–H abstraction mechanism after Ag(I)-mediated reduction of
Selectfluor. This reaction occurs under mild conditions and is effective for a variety of quinones and radical precursors bearing
primary benzylic carbons. The use of pre-formed Ag(4–OMePy)2NO3 as a catalyst proved effective in improving reaction
efficiency by reducing unwanted degradation pathways available to Selectfluor.
Functionalized quinones are well-established as
oxidants for organic and organometallic transformations,
but are also important structural motifs in biologically
active molecules.1a Even very simple quinone structures
have shown potent biological activity and have been
utilized by pharmaceutical and agrochemical
industries.1b-d Specifically, benzylated quinones have
radical precursor, and elevated temperatures to
circumvent unfavorable radical pathways.
Previously, our group had shown that quinones and
aromatic heterocycles could be directly alkylated or
arylated via carboxylic or boronic acid radical precursors
using Selectfluor and catalytic AgNO3 (Figure 2A).5
Others have demonstrated that diazabicyclo radical cation
SF-I, formed after single-electron reduction or direct
photolysis of Selectfluor, is a suitable hydrogen atom
transfer (HAT) agent to generate carbon centered radicals
leading to C–F and C–C bond formation (Figure 2B).6 We
sought to combine mechanistic features of these two
protocols to develop a quinone benzylation reaction that
operates via C–H abstraction from SF-I after single-
electron transfer between a Ag(I) source and Selectfluor
(Figure 2C).
demonstrated
enzyme
inhibition1e,
antitumor1f,
anticancer1g, and antifeedant1h properties (Figure 1). A
benzylated adduct of menadione is responsible for the
high potency and antimalarial properties of Plasmidione
towards blood-stage parasites.1j-k
O
O
MeO
CH2F
OH
O
O
O
Enzyme Inhibitor
Antifeedant
A) Silver-Catalyzed Minisci Reactions Using Selectfluor as a Mild Oxidant
O
O
O
O
O
O
O
O
Me
CF3
Me
N
Ag(I) catalyst, Selectfluor
H
R
R–CO2H; alkyl
N
OH
R–B(OH)2 or R–BF3; aryl or alkyl
O
O
Plasmodione
Antimalarial
Antitumor
Anticancer
B) Hydrogen Atom Abstraction of sp3 C-H Bonds via Selectfluor
Figure 1. Biologically active quinones bearing benzylic
substitution.
Cl
N
Reductant
C(sp3)-H
Cl
N
C(sp3)
N
or
N
Several methods are known for the synthesis of
functionalized quinones including palladium-catalyzed
coupling
F
Direct Photolysis
Selectfluor
SF-I
reactions2,
alkylation/oxidation
of
C) C-H Benzylation of Quinones Using Selectfluor and Methyl Arenes (This Work)
hydroquinones and phenols3, and direct radical
functionalization.4 In the context of radical
functionalizations, several methods have been reported
that utilize Minisci-type conditions for radical
functionalization of quinones, typically involving pre-
functionalized radical precursors and strong oxidants.5
Oxidative radical processes leading to quinone
substitution from unfunctionalized reagents often require
air and moisture free conditions, large excess of the
O
O
O
O
Me
Ar
Ag(I) catalyst
Selectfluor
H
+
Ar
Figure 2. Selectfluor as an oxidant and/or HAT precursor.
Preliminary studies using p-xylene as a radical
precursor in a biphasic solvent system (see Supporting
Information solvent effect on reaction) showed that
benzoquinone could be directly alkylated in moderate
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O
H
O
O
O
Me
yield using a AgNO3 / Selectfluor reagent system (Table
1, entry 1) with minor oxidized and fluorinated side-
products observed. In our previous studies on radical
fluorination via C–H abstraction, we found that pyridine
additives lowered the onset oxidation potential of Ag(I)
to facilitate single-electron transfer to Selectfluor.7
Within the context of quinone functionalization we have
also extended ligand additives and their effects on the
shift in onset oxidation potential of silver. Guided by
those results, we examined the effect of pyridine additives
to develop a catalyst that would be more effective towards
this benzylation reaction. We began with 4-
methoxypyridine hypothesizing that electron rich
pyridines would have the greatest effect in lowering the
onset oxidation potential of silver, thus allowing for
greater concentrations of the desired product.
Interestingly, although one equivalent of 4-
methoxypyridine had a deleterious effect on the reaction
(Table 1, entry 2); catalytic amounts led to a slight
increase in conversion (Table 1, entry 3). Examining
order of the addition (Table 1, entry 4) of reagents used
led us to observe an increase yield when Selectfluor is
added last. Because the synthesis of Ag(I)[pyridine]2
salts is straightforward8, we examined their efficacy as
catalysts for the benzylation reaction. A series of
conditions were screened, and we discovered that 20 mol
% of Ag(4-OMePy)2NO3 was optimum to produce 1 in
good yield (73%, Table 1, entry 5). Catalysts with
different pyridines led to diminished conversion (Table 1,
entries 6 and 7), suggesting the electron-rich nature of 4-
methoxypyridine was important for electron transfer. We
examined Ag–complexes with bidentate ligands (Table 1,
entries 8 and 9) with high reactivity observed when
phenanthroline was the ligand, but no product formation
when 2,2′-bipyridine was used. Interestingly, although a
control reaction without Ag(I) yielded no product (Table
1, entry 10), one equivalent of 4-methoxypyridine was
capable of promoting radical alkylation without a metal
initiator (Table 1, entry 11), suggesting that electron
transfer between the pyridine and Selectfluor was
occurring.8 Reaction with the standard oxidant for
Minisci reactions, (NH4)2S2O8, led to a mixture of
benzylated products (Table 1, entry 12).
2 equiv. Selectfluor
Conditions
Me
1
2
3
4
5
6
7
8
+
+
DCE / H2O (1:1), 50 °C
24 h
O
Me
Me
A1
1
1 equiv.
10 equiv.
Entry
Deviation from standard conditions
20 mol % AgNO3
Yield of 1a
49%
Yield of A1a
11%
1
20 mol % AgNO3, 1 equiv. 4-methoxypyridine
20 mol % AgNO3, 40 mol % 4-methoxypyridine
20 mol % AgNO3, 40 mol % 4-methoxypyridine
2
32%
3%
3
4b
60%
11%
69%
10%
5
6
7
20 mol % Ag(OMePy)2NO3
20 mol % Ag(Py)2NO3
73% (71%)
62%
15%
20%
14%
9
20 mol % Ag(4-t-BuPy)2NO3
20 mol % Ag(Phen)2NO3
20 mol % Ag(ByPy)2NO3
47%
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8
9
68%
0%
13%
30%
10
11
12
No Silver
no reaction
17%
no reaction
5%
No Silver, 1 equiv. 4-methoxypyridine
(NH4)2S2O8 instead of Selectfluor
38% + 14% Bis
10%
Table 1. Optimization of quinone functionalization.
Reaction conditions: 1,4-benzoquinone (0.2 mmol), p-
xylene (2.0 mmol), Selectfluor (0.4 mmol), Ag(4-
OMePy)2NO3 (0.04 mmol), 2 mL of DCE/H2O (1:1). a 1H-
NMR yields to 1,3,5-trimethoxybenzene, values in
b
parentheses indicate isolated yield. Selectfluor was added
last to the reaction.
With the optimized conditions established, we
examined the scope of the benzylation reaction with a
variety of quinones and methyl arene reaction partners
(Figure 3). Para substituted toluenes with electron
donating groups (2–3) benzylated benzoquinone in
moderate to good yield.
Electron-withdrawing
methylarene (4) was less effective resulting in poor yields
with the isolation of unreacted benzoquinone accounting
for mass balance. Ortho-substituted arenes with methyl
substitution (5) furnished product in moderate yield.
Meta-methylated (6) and tetramethylated (7) arenes were
also effective partners in generating desired products. A
variety of quinones were screened to determine the scope
of electrophiles suitable for this reaction. Benzylated 1,4-
benzoquinone (8) was synthesized in moderate yield. It is
interesting to note that using solvent quantities of the
radical precursor results in largely similar reaction
conversions. An increase in yield is also observed when
the equivalents of Selectfluor are raised from 2 to 5
equivalents. Both methylated (9–10) and halogenated
(11–12) benzoquinones were effective coupling partners
and resulted in moderate yields of benzylated products
with no bis-benzylated products observed. Finally,
functionalized naphthaquinone (13) and associated
analogs such as juglone (14) and menadione (15) can also
be accessed. Efforts to extend this method towards other
C–H radical precursors and heterocyclic substrates
resulted in poor yields (see Supporting Information for
details).
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The Journal of Organic Chemistry
mmol) in DCE/H2O (4 mL, 1:1) at 50 ºC for up to 24 h.
O
O
O
Me
1
2
3
4
Using a glass microsyringe, 200 μL aliquots were taken from
the aqueous phase at specified time points. Conversions
were determined by 19F-NMR using trifluorotoluene as an
external standard.
2 equiv. Selectfluor
20 mol % Ag(4-OMePy)2NO3
R
Ar
R
O
Ar
+
DCE / H2O (1:1), 50 °C, up to 24 h
O
10 equiv.
O
O
O
5
6
7
8
We were interested, however, in comparing the use of
AgNO3 and catalytic 4-methoxypyridine to Ag(4-
OMePy)2NO3 to establish the benefit of the pre-formed
catalyst. A catalytic amount of AgNO3 consumed
approximately 80% of Selectfluor within 24 hours,
confirming that a nitrogen additive is not required for the
Ag(I)/(II) redox cycle under these conditions (Figure 4A).
A Ag(I)/(II) redox cycle is proposed because following
the oxidation of Ag(I) by Selectfluor to generate Ag(II);
aqueous solutions of Ag(II) are unstable and readily
oxidize water to oxygen at room temperature regenerating
Ag(I).10 A catalytic amount of 4-methoxypyridine
consumes Selectfluor in an apparent 1:1 stoichiometry
with an initial rate that is on par with the AgNO3-
mediated reaction (Figure 4B). Under these conditions
only trace amounts of product are formed, confirming that
free 4-methoxypyridine has a deleterious effect on the
desired transformation even in catalytic quantities.
Finally, reaction with pre-formed Ag(4-OMePy)2NO3
produces the highest overall reaction rate for
consumption of Selectfluor, while providing the desired
product in the highest overall conversion (Figure 4C).
These data suggest that the pre-formed catalyst
circumvents unfavorable interactions between 4-
methoxypyridine and Selectfluor, presumably because
strong association to Ag(I) precludes the occurrence of
free pyridine in solution.
Me
OMe
OAc
CN
O
O
O
O
O
1 (71%)
2 (36%)
3 (56%)
Me
4 (20%)
O
O
O
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Me
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Me
O
Me
O
O
O
O
Me
O
8 (46%, 51%a, 79%b)
5 (57%)
6 (29%)
Me
7 (38%)
O
O
Me
Me
Cl
Cl
Cl
Me
Cl
O
O
O
O
9 (49%)
10 (45%)
11 (45%)
12 (52%)
From phlorone
O
O
O
O
O
Me
*
O
OH
13 (42%)
14 (23%)
(1.1:1)
from juglone
15 (21%)
from menadione
Figure 3. Scope of quinone benzylation. Yields refer to
a
chromatographically pure compounds. Toluene was used
instead of DCE as organic solvent. b5 equivalents of
Selectfluor used instead of 2 equivalents.
To better understand the effect of 4-methoxypyridine as
a ligand for Ag(I), we tracked the concentration of
Selectfluor by 19F-NMR over the course of a typical
experiment. Due to the biphasic nature of the reaction, in
situ reaction monitoring posed a challenge. Instead, small
aliquots were removed from the aqueous phase of the
reaction to determine Selectfluor concentration against an
external standard over the course of 24 hours (see
Supporting Information for details). Entry 2 from Table 1
suggested that excess 4-methoxypyridine had a negative
effect on reaction conversion, and previous work in our
group had established that electron-rich pyridines can
directly consume Selectfluor in an unproductive manner,
an observation that is now extended to this biphasic
solvent system.9a
A
Cl
Cl
N
N
Ag(4-OMePy)2NO3
“Ag(I)”
[Ag(4-OMePy)2NO3]+
“Ag(II)”
F
+
+
N
N
F
SF-I
O
O
B
Cl
N
R
O
O
O
N
Me
Ar
Ag(II)
Ag(I)
R
SF-I
R
Ar
-H+
Cl
N
N
O
-
Ar
Ar
H
Figure 5. Proposed mechanism for quinone benzylation.
A plausible mechanism for the benzylation of quinone
is shown in Figure 5. Single-electron transfer between
Ag(4-OMePy)2NO3 and Selectfluor generates SF-I and
the Ag(II) complex with concomitant generation of
fluoride anion (Figure 5A). Hydrogen atom abstraction of
a methylarene via SF-I leads to a nucleophilic benzyl
radical that is trapped by an electrophilic quinone
substrate. The resulting radical intermediate is then
oxidized, either by Selectfluor or Ag(II), and
deprotonated to produce the expected C–H benzylated
product (Figure 5B).
Figure 4. 19F-NMR monitoring of the consumption of
Selectfluor (1.0 mmol) with either (A) 0.1 mmol of AgNO3,
(B) 0.2 mmol of 4-methoxypyridine, or (C) 0.1 mmol of
Ag(4-OMePy)2NO3. Reaction conditions: Selectfluor (1.0
In summary, we have developed a robust catalyst
system for generating benzylic radicals via C–H
abstraction, and combining these radicals with various
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electrophilic quinones.11 A pre-formed Ag(I)/pyridine
catalyst was found to be optimum for reducing Selectfluor
via single-electron transfer to generate diazabicyclo
radical cation SF-I as hydrogen atom transfer agent. The
quinone benzylation reaction is simple to perform and
operates under mild reaction conditions without pre-
functionalized substrates. Efforts are ongoing to identify
new catalyst systems to make the reaction more
compatible with alternative radical precursors or
electrophilic partners such as aromatic heterocycles.
bis(pyridine)silver(I) nitrate complex (Ag(Py)2NO3). The
1
2
3
4
5
6
7
8
general procedure was employed using AgNO3 (169 mg, 1.0
mmol) and pyridine (170 L, 2.1 mmol). The reaction afforded
Ag(Py)2NO3 (259.0 mg, 79% yield) as a white solid (m.p.
80−84 °C). 1H NMR (400 MHz, CD3CN): 8.62 – 8.54 (m, 2H),
7.89 (tt, J = 7.7, 1.7 Hz, 1H), 7.48 (ddd, J = 7.7, 4.7, 1.4 Hz,
2H). 13C{1H} NMR (100 MHz, CD3CN): 151.8, 138.9, 125.7.
HRMS (ESI-TOF) m/z: [M – NO3]+ Calcd for C10H10AgN2
264.9889; Found 264.9878.
bis(4-(tert-butyl)pyridine)silver(I) nitrate complex (Ag(4-
tBuPy)2NO3). The general procedure was employed using
AgNO3 (169 mg, 1.0 mmol) and 4-tert-Butylpyridine (308 L,
2.1 mmol). The reaction afforded Ag(4-tBuPy)2NO3 (380.6 mg,
86% yield) as a white solid (m.p. 138−139 °C). 1H NMR (400
MHz, CD3CN): 8.49 (dd, J = 4.9, 1.6 Hz, 2H), 7.50 (dd, J = 4.9,
1.7 Hz, 2H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CD3CN):
163.3, 151.7, 122.8, 35.6, 30.4. HRMS (ESI-TOF) m/z: [M –
NO3]+ Calcd for C18H26AgN2 377.1141; Found 377.1126.
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General Considerations
Reagents and solvents were purchased at the highest
commercial quality and used without purification. Yields refer
to chromatographically and spectroscopically (1H NMR, 13C
NMR, 19F NMR) homogenous material, unless otherwise noted.
Reactions were monitored by GCMS (Agilent Technologies
5975 Series MSD GC MS) and thin-layer chromatography
using 0.25 mm E. Merck silica gel plates (60F-254) using UV
light. HRMS data were collected on a
bis(4-methoxypyridine)silver(I)
nitrate
complex
(Ag(OMePy)2NO3). To a round bottom containing a stir bar
was added AgNO3 (510 mg, 3.0 mmol) and 4-methoxypyridine
(640 L, 6.3 mmol) which were mixed in MeCN (20 mL) and
stirred at room temperature overnight protected from light. The
reaction mixture was filtered through Celite, and the solvent
removed from the filtrate under vacuum. The resulting residue
was washed with diethyl ether to afford Ag(OMePy)2NO3
(1,094.5 mg, 94% yield) as a white solid(m.p. 141−143 °C). 1H
NMR (500 MHz, CD3CN): 8.40 (dd, J = 5.1, 1.5 Hz, 2H), 7.02
(dd, J = 5.1, 1.5 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (125
MHz, CD3CN): 167.7, 153.3, 111.8, 56.5. HRMS (ESI-TOF)
m/z: [M – NO3]+ Calcd for C12H14AgN2O2 325.0101; Found
325.0106.
Thermo Fisher Scientific Exactive Plus Oribitrap Mass
Spectrometer. Melting points were recorded from
a
Electrothermal IA9100. NMR spectra were recorded on a
Bruker-INOVA 400 MHz or 500 MHz spectrometer and
calibrated using residual undeuterated solvent as an internal
reference (CDCl3 – 1H NMR 7.26 ppm, 13C NMR 77.16 ppm).
The following abbreviations were used to explain multiplicities
(s – singlet, d – doublet, t – triplet, q – quartet, m – multiplet).
General Reaction Procedures
General Procedure
bis(phenathroline)silver(I)
nitrate
complex
(Ag(phen)2NO3). The general procedure was employed using
AgNO3 (169 mg, 1.0 mmol) and phenanthroline (378 mg, 2.1
mmol). The reaction afforded Ag(phen)2NO3 (498.5 mg, 94%
yield) as a yellow solid solid (m.p. 351−357 °C). 1H NMR (500
MHz, CD3CN): 9.07 (dd, J = 4.5, 1.6 Hz, 4H), 8.64 (dd, J =
8.1, 1.6 Hz, 4H), 8.12 (s, 4H), 7.93 (dd, J = 8.1, 4.5 Hz,
4H).13C{1H}NMR (125 MHz, CD3CN): 152.1, 143.7, 139.3,
130.4, 128.2, 125.7. HRMS (ESI-TOF) m/z: [M – NO3]+
Calcd for C24H16AgN4 467.0420; Found 467.0403.
The threads of a 3 mL borosilicate scintillation vial were
thoroughly taped with Teflon tape. To this vial containing a stir
bar was added quinone (0.2 mmol, 1 equiv), benzylic arene (2.0
mmol, 10 equiv) and Selectfluor (141.7 mg, 0.4 mmol, 2 equiv).
Dichloroethane (1 mL) and H2O (1 mL) were then added and
stirred for approximately 1 min at room temperature. A solid
amount of Ag(4-methoxypyridine)2NO3 (15.5 mg, 0.04 mmol,
20 mol %) was added in one portion. The reaction was capped
with a teflon screw cap and rubber septum (24/40). The
reaction was heated to 50 °C until reaction was completed as
judged by GCMS (up to 24 hours).
bis(2,2′-bipyridine)silver(I) nitrate complex (Ag(byp)2NO3).
The general procedure was employed using AgNO3 (169 mg,
1.0 mmol) and 2,2′-bipyridine (328 mg, 2.1 mmol). The
reaction afforded Ag(bypy)2NO3 (429.2 mg, 89% yield) as a
Upon completion, the reaction was diluted with ethyl acetate (1
mL) and transferred to a test tube containing H2O (3 mL). The
aqueous phase was extracted with ethyl acetate (3 x 3 mL) and
the combined organic layers were dried over MgSO4, filtered
and carefully concentrated in vacuo. The crude material was
purified by silica gel chromatography (ethyl acetate:hexanes) to
yield the desired product.
1
yellow solid solid (m.p. 154−157 °C). H NMR (500 MHz,
CD3CN): 8.67 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.35 (dt, J =
8.1, 0.9 Hz, 1H), 8.01 (td, J = 7.8, 1.7 Hz, 1H), 7.52 (ddd, J
= 7.5, 4.9, 1.0 Hz, 1H). 13C{1H}NMR (125 MHz, CD3CN):
154.5, 151.1, 139.3, 125.9, 122.8. HRMS (ESI-TOF) m/z:
[M – NO3]+ Calcd for C20H16AgN4 419.0420; Found 419.0412.
Experimental Procedures and Characterization Data
General Conditions for the synthesis of bis(pyridine) silver
complexes
To a round bottom containing a stir bar was added AgNO3 (1 –
3.0 mmol) and pyridine (2.1 equiv.) which were mixed in
MeCN (0.15M) and stirred at room temperature overnight
protected from light. The reaction mixture was filtered through
Celite, and the solvent removed from the filtrate under vacuum.
The resulting residue was washed with diethyl ether.
Figure 4 Compounds (1–15)
2-(4-methylbenzyl)cyclohexa-2,5-diene-1,4-dione (1). The
general procedure was employed using 1,4-benzoquinone (22
mg, 0.2 mmol) and p-xylene (247 L, 2.0 mmol). The reaction
afforded 1 (30.1 mg, 71% yield) as a yellow oil separated by
silica gel (3 to 10% ethyl acetate in hexanes).
. 1H NMR (500 MHz, CDCl3): 7.13 (d, J = 7.9 Hz, 2H), 7.07
(d, J = 8.0 Hz, 2H), 6.76 (d, J = 10.1 Hz, 1H), 6.69 (dd, J = 10.1,
2.5 Hz, 1H), 6.38–6.35 (m, 1H), 3.70 (s, 2H), 2.33 (s,3H).
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13C{1H} NMR (125 MHz, CDCl3): 187.9, 187.4, 149.0, 136.8,
136.4, 133.3, 133.3, 129.7, 129.4, 34.9, 21.2. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C14H13O2 213.0910; Found
213.0901.
(22 mg, 0.2 mmol) and 3'-methylacetophenone (266 L, 2.0
mmol). The reaction afforded 7 (13.6 mg, 28% yield) as a
colorless oil separated by silica gel (3 to 10% ethyl acetate in
1
2
3
1
hexanes). H NMR (500 MHz, CDCl3): 6.96 (s, 1H), 6.84 (s,
2-(4-methoxybenzyl)cyclohexa-2,5-diene-1,4-dione (2). The
general procedure was employed using 1,4-benzoquinone (22
mg, 0.2 mmol) and 4-methylanisole (252 L, 2.0 mmol). The
reaction afforded 2 (16.3 mg, 36% yield) as a yellow oil
separated by silica gel (3 to 10% ethyl acetate in hexanes). 1H
NMR (500 MHz, CDCl3): 7.10 (d, J = 8.1 Hz, 2H), 6.86 (d, J
= 8.2 Hz, 2H), 6.76 (d, J = 10.1 Hz, 1H), 6.69 (d, J = 10.0 Hz,
1H), 6.35 (s, 1H), 3.79 (s, 3H), 3.68 (s, 2H). 13C{1H} NMR (125
MHz, CDCl3): 187.9, 187.5, 158.8, 149.2, 136.8, 136.5, 133.2,
130.5, 128.3, 114.4, 55.4, 34.5. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C14H13O3 229.0859; Found 229.0853.
1H), 6.79 (d, J = 10.1 Hz, 1H), 6.70 (dd, J = 10.1, 2.5 Hz, 1H),
6.12 (d, J = 1.9 Hz, 1H), 3.68 (s, 2H), 2.22 (s, 3H), 2.20 (s, 3H),
2.14 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ 187.9, 187.6,
148.8, 136.8, 136.5, 135.7, 134.6, 133.8, 133.1, 132.2, 131.8,
131.5, 32.3, 19.4, 19.3, 18.9. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C16H17O2 241.1223; Found 241.1216.
2-benzylcyclohexa-2,5-diene-1,4-dione (8). The general
procedure was employed using 1,4-benzoquinone (22 mg, 0.2
mmol) and toluene (213 L, 2.0 mmol). The reaction afforded
8 (19.8 mg, 46% yield) as a yellow oil separated by silica gel
(5% ethyl acetate in hexanes). The data matches those
previously reported.3a 1H NMR (500 MHz, CDCl3): 7.33 (t, J =
7.3 Hz, 2H), 7.29–7.23 (m, 1H), 7.19 (d, J = 7.1 Hz, 2H), 6.78
(d, J = 10.1 Hz, 1H), 6.71 (dd, J = 10.1, 2.5 Hz, 1H), 6.37 (dt, J
= 2.4, 1.6 Hz, 1H), 3.75 (d, J = 1.3 Hz, 2H).
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-((3,6-dioxocyclohexa-1,4-dien-1-yl)methyl)phenyl acetate
(3). The general procedure was employed using 1,4-
benzoquinone (22 mg, 0.2 mmol) and p-tolyl acetate (287 L,
2.0 mmol). The reaction afforded 3 (28.6 mg, 56% yield) as a
pale yellow oil separated by silica gel (3 to 10% ethyl acetate in
2-benzyl-3,5-dimethylcyclohexa-2,5-diene-1,4-dione
(9).
1
hexanes). H NMR (500 MHz, CDCl3): 7.19 (d, J = 8.5 Hz,
The general procedure was employed using 2,6-
dimethylbenzoquinone (27 mg, 0.2 mmol) and toluene (213 L,
2.0 mmol). The reaction afforded 9 (22.2 mg, 49% yield) as a
yellow oil separated by silica gel (3% ethyl acetate in hexanes).
1H NMR (500 MHz, CDCl3): 7.29–7.23 (m, 2H), 7.21–7.15 (m,
3H), 6.59 (dd, J = 3.0, 1.4 Hz, 1H), 3.86 (s, 2H), 2.10 (s, 3H),
2.05 (d, J = 1.6 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3):
188.5, 187.3, 145.6, 142.9, 141.9, 138.2, 133.2, 128.7, 128.7,
126.5, 31.9, 16.1, 12.9. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H15O2 227.1067; Found 227.1055.
3-benzyl-2,5-dimethylcyclohexa-2,5-diene-1,4-dione (10).
The general procedure was employed using 2,5-dimethyl-1,4-
benzoquinone (27 mg, 0.2 mmol) and toluene (213 L, 2.0
mmol). The reaction afforded 10 (20.4 mg, 45% yield) as a
yellow oil separated by silica gel (3% ethyl acetate in hexanes).
1H NMR (500 MHz, CDCl3): 7.30–7.23 (m, 2H), 7.22–7.15
(m, 3H), 6.59 (d, J = 1.6 Hz, 1H), 3.87 (s, 2H), 2.09 (s, 3H),
2.04 (d, J = 1.6 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3):
188.0, 187.7, 145.6, 143.1, 141.8, 138.2, 133.3, 128.8, 128.7,
126.6, 32.2, 16.1, 12.6. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H15O2 227.1067; Found 227.1067.
2H), 7.06–7.00 (m, 2H), 6.75 (d, J = 10.1 Hz, 1H), 6.69 (dd, J
= 10.1, 2.5 Hz, 1H), 6.40 (dt, J = 2.6, 1.5 Hz, 1H), 3.72 (d, J =
1.0 Hz, 2H), 2.27 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3):
187.7, 187.1, 169.5, 149.7, 148.3, 136.7, 136.4, 134.0, 133.3,
130.4, 122.0, 34.7, 21.2. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H13O4 257.0808; Found 257.0798.
4-((3,6-dioxocyclohexa-1,4-dien-1-yl)methyl)benzonitrile
(4). The general procedure was employed using 1,4-
benzoquinone (22 mg, 0.2 mmol) and p-tolunitrile (234 mg, 2.0
mmol). The reaction afforded 4 (8.9 mg, 20% yield) as a yellow
resin separated by silica gel (3 to 25% ethyl acetate in hexanes).
1H NMR (500 MHz, CDCl3): 7.62 (d, J = 8.2 Hz, 2H), 7.33 (d,
J = 8.2 Hz, 2H), 6.79 (d, J = 10.1 Hz, 1H), 6.75 (dd, J = 10.1,
2.4 Hz, 1H), 6.46–6.40 (m, 1H), 3.80 (s, 2H). 13C{1H} NMR
(125 MHz, CDCl3): 187.3, 186.8, 147.2, 142.2, 136.8, 136.7,
133.8, 132.8, 130.2, 118.7, 111.3, 35.6. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H9NO2 224.0706; Found 224.0698.
2-(2-methylbenzyl)cyclohexa-2,5-diene-1,4-dione (5). The
general procedure was employed using 1,4-benzoquinone (22
mg, 0.2 mmol) and o-xylene (241 L, 0.4 mmol). The reaction
afforded 5 (24.3 mg, 57% yield) as a yellow oil separated by
2-benzyl-3,5-dichlorocyclohexa-2,5-diene-1,4-dione
(11).
1
silica gel (5% ethyl acetate in hexanes). H NMR (500 MHz,
The general procedure was employed using 2,6-dichloro-1,4-
benzoquinone (35 mg, 0.2 mmol) and toluene (213 L, 2.0
mmol). The reaction afforded 11 (23.9 mg, 45% yield) as a
yellow solid separated by silica gel (3% ethyl acetate in
hexanes). The data matches those previously reported.4c 1H
NMR (400 MHz, CDCl3): 7.30–7.20 (m, 5H), 7.03 (s, 1H), 4.01
(s, 2H).
CDCl3): 7.22–7.14 (m, 3H), 7.12–7.06 (m, 1H), 6.81 (d, J =
10.1 Hz, 1H), 6.71 (dd, J = 10.1, 2.6 Hz, 1H), 6.11 (dd, J = 4.4,
2.0 Hz, 1H), 3.75 (d, J = 1.9 Hz, 2H), 2.21 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3): 187.8, 187.5, 148.4, 136.8, 136.7,
136.5, 134.4, 133.1, 130.8, 130.5, 127.6, 126.6, 32.7, 19.5.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H13O2
213.0910; Found 213.0902.
3-benzyl-2,5-dichlorocyclohexa-2,5-diene-1,4-dione
(12).
2-(3-methylbenzyl)cyclohexa-2,5-diene-1,4-dione (6). The
general procedure was employed using 1,4-benzoquinone (22
mg, 0.2 mmol) and m-xylene (247 L, 2.0 mmol). The reaction
afforded 6 (12.2 mg, 29% yield) as a yellow oil separated by
The general procedure was employed using 2,5-dichloro-1,4-
benzoquinone (35 mg, 0.2 mmol) and toluene (213 L, 2.0
mmol). The reaction afforded 12 (27.7 mg, 52% yield) as a
yellow solid (m.p. 96−98 °C) separated by silica gel (3% ethyl
1
1
silica gel (5% ethyl acetate in hexanes). H NMR (500 MHz,
acetate in hexanes). H NMR (500 MHz, CDCl3): 7.35–7.21
(m, 5H), 7.10 (s, J = 3.3 Hz, 1H), 4.07 (s, 2H). 13C{1H} NMR
(125 MHz, CDCl3): 177.5, 177.5, 144.4, 144.3, 141.6, 136.0,
133.0, 129.4, 129.0, 127.3, 34.1. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C15H15O2 266.9974; Found 266.9972.
CDCl3): 7.21 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.0 Hz, 1H), 7.01–
6.96 (m, J = 8.2 Hz, 2H), 6.77 (dd, J = 10.0, 4.9 Hz, 1H), 6.70
(dd, J = 10.1, 2.5 Hz, 1H), 6.37 (dt, J = 2.4, 1.6 Hz, 1H), 3.70
(d, J = 1.3 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): 187.9, 187.4, 148.9, 138.7, 136.8, 136.5, 136.4, 133.4,
130.2, 128.9, 127.9, 126.5, 35.2, 21.5. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C14H12O2 213.0910; Found 213.0907.
2-(2,4,5-trimethylbenzyl)cyclohexa-2,5-diene-1,4-dione (7).
The general procedure was employed using 1,4-benzoquinone
2-benzylnaphthalene-1,4-dione (13). The general procedure
was employed using 1,4-naphthoquinone (32 mg, 0.2 mmol)
and toluene (213 L, 2.0 mmol). The reaction afforded 13 (21.0
mg, 42% yield) as a yellow solid (m.p. 93−94 °C) separated by
silica gel (3% ethyl acetate in hexanes). The data matches those
ACS Paragon Plus Environment

The Journal of Organic Chemistry
previously reported.3a 1H NMR (500 MHz, CDCl3): 8.12 (dt, J
Page 6 of 7
Davies-Coleman, M. T. Cytotoxic and antioxidant marine
prenylated quinones and hydroquinones. Nat. Prod. Rep. 2012,
29, 513. (c) Khader, M.; Eckl, P. M. Thymoquinone: an
emerging natural drug with a wide range of medical
applications. Iran, J. Basic Med. Sci. 2014, 17, 950–957. (d)
Breyer, S.; Effenberger, K.; Schobert, R. Effects of
Thymoquinone–Fatty Acid Conjugates on Cancer Cells. Chem.
Med. Chem. 2009, 4, 761. (e) Bauer, H.; Fritz-
Wolf, K.; Winzer, A.; Kühner, S.; Little, S.; Yarley, V.; Vezin,
H.; Palfey, B.; Schirmer, R. H.; Davioud-Charvet, E. A Fluoro
Analogue of the Menadione Derivative 6-[2‘-(3‘-Methyl)-1‘,4‘-
naphthoquinolyl]hexanoic Acid Is a Suicide Substrate of
Glutathione Reductase. Crystal Structure of the Alkylated
Human Enzyme. J. Am. Chem. Soc. 2006, 128, 10784–
10794. (f) Nakao, H.; Arakawa, M.; Nakamura, T.; Fukushima,
M. Chem. Pharm. Bull. 1972, 20, 1968. (g) Sunassee, S. N.;
Veale, C. G. L.; Shunmoogam-Gounden, N.; Osoniyi, O.;
Hendricks, D. T.; Caira, M. R. ; de la Mare, J. O., Edkins, A.
L.; Pinto, A. V.; da Silva Júnior, E. N.; Davies-Coleman, M. T.
Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-
naphthoquinones against oesophageal cancer cells. Eur. J. Med.
Chem. 2013, 62, 98. (h) Mukai, A.; Takahashi, K.; Kofujita, H.;
Ashitani, T. Antitermite and antifungal activities of thujopsene
natural autoxidation products. Eur. J. Wood Prod. 2019, 77,
311–317. (i) Ehrhardt, K.; Deregnaucourt, C.; Goetz, A. A.;
Tzanova, T.; Gallo, V.; Arese, P.; Pradines, B.; Adjalley, S. H.;
Bagrel, D.; Blandin, S.; Lanzer, M.; Davioud-Charvet, E. The
Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead
Compound with Pronounced Activity against Sexual and Early
Asexual Blood-Stage Parasites. Antimicrob. Agents Chemother.
2016, 60, 5146–5158. (j) Feng, L.; Lanfranchi, D. A.; Cotos, L.;
Cesar-Rodo, E.; Ehrhardt, K.; Goetz, A. A.; Zimmermann, H.;
Fenaille, F.; Blandin, SA.; Davioud-Charvet, E. Synthesis of
plasmodione metabolites and 13C-enriched plasmodione as
chemical tools for drug metabolism investigation. Org. Biomol.
Chem., 2018, 16, 2647–2665.
1
2
3
4
5
6
7
8
= 5.5, 3.0 Hz, 1H), 8.05 (dt, J = 6.7, 3.1 Hz, 1H), 7.77–7.70 (m,
2H), 7.35 (t, J = 7.3 Hz, 2H), 7.30–7.23 (m, 4H), 6.62 (t, J = 1.5
Hz, 1H), 3.91 (d, J = 1.1 Hz, 2H).
2-benzyl-5-hydroxynaphthalene-1,4-dione (14-C2) and 2-
benzyl-8-hydroxynaphthalene-1,4-dione
(14-C3).
The
general procedure was employed using 5-hydroxy-1,4-
naphthoquinone (35 mg, 0.2 mmol) and toluene (213 L, 2.0
mmol). The regioisomeric ratio of C2:C3 was determined to be
1:1.1 by crude 1H NMR. The reaction afforded 14-C2 (6.0 mg,
11% yield) and 14-C3 (6.1 mg, 11% yield) as yellow solids
separated by silica gel (2% DCM in hexanes). NMR data for
14-C2 1H NMR (500 MHz, CDCl3): 11.92 (s, 1H), 7.67–7.58
(m, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.30–7.21 (m, 4H), 6.55 (t, J
= 1.5 Hz, 1H), 3.89 (d, J = 1.2 Hz, 2H). 13C{1H} NMR (125
MHz, CDCl3): 190.5, 184.4, 161.4, 152.5, 136.6, 136.4, 135.6,
132.2, 129.6, 129.1, 127.2, 124.4, 119.6, 115.1, 35.9. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H13O3 265.0859;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Found 265.0853. NMR data for 14-C3 H NMR (500 MHz,
CDCl3): 12.04 (s, 1H), 7.63–7.56 (m, 2H), 7.37–7.32 (m, 2H),
7.30–7.23 (m, 4H), 6.59 (t, J = 1.5 Hz, 1H), 3.89 (d, J = 1.1 Hz,
2H). 13C{1H} NMR (125 MHz, CDCl3): 190.4, 184.5, 161.8,
150.9, 136.7, 136.7, 136.5, 132.3, 129.5, 129.1, 127.3, 124.5,
119.0, 115.3, 35.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C17H13O3 265.0859; Found 265.0849.
2-benzyl-3-methylnaphthalene-1,4-dione (15). The general
procedure was employed using 2-methyl-1,4-naphthoquinone
(34 mg, 0.2 mmol) and toluene (213 L, 2.0 mmol). The
reaction afforded 15 (11.1 mg, 21% yield) as a yellow solid
(m.p. 104−105 °C) separated by silica gel (10% ethyl acetate in
hexanes). The data matches those previously reported.3h 1H
NMR (400 MHz, CDCl3): 8.14–8.02 (m, 2H), 7.74–7.65 (m,
2H), 7.31–7.15 (m, 5H), 4.04 (s, 2H), 2.25 (s, 3H).
ASSOCIATED CONTENT
(2) Select examples of Pd- catalyzed functionalization of
quinones. (a) Echavarren, A. M.; de Frutos, Ó.; Tamayo, N.;
Noheda, P.; Calle, P. Palladium-Catalyzed Coupling of
Naphthoquinone Triflates with Stannanes. Unprecedented
Supporting Information
19F NMR studies, solvent screen, analogs of featured reaction,
and relevant spectral data. This material is available free of
charge via the internet at http:pubs.acs.org.
Nucleophilic
Aromatic
Substitution
on
a
AUTHOR NFORMATION
Corresponding Author
*E-mail: rbaxter@ucmerced.edu.
ORCID
Ryan D. Baxter: 0000-0002-1341-5315
ACKNOWLEDGMENT
J.D.G. gratefully acknowledges the National Science
Foundation for receipt of a graduate fellowship (NSF Graduate
Research Fellowship Program). This material is based upon
work supported by the National Science Foundation under
Grant No. 1752821 (R.D.B)
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O
Me
O
O
Ag(4-OMePy)2NO3
R
H
Ar
R
Ar
+
Cl
N
O
N
2BF4
F
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