Quinone C-H Alkylations via Oxidative Radical Processes

Article abstract of DOI:10.1055/s-0037-1610005

A brief survey of radical additions to quinones is reported. Carboxylic acids, aldehydes, and unprotected amino acids are compared as alkyl radical precursors for the mono- or bis- C-H alkylation of several quinones. Two methods for radical initiation are discussed comparing inorganic persulfates and Selectfluor as stoichiometric oxidants. Kinetic analysis reveals dramatic differences in the rate of radical initiation depending on the identity of the radical precursor and oxidant. Synthetic strategies for efficiently producing alkyl-quinones are discussed in the context of selecting optimum radical precursors and initiators depending on quinone identity and functional groups present.

Full text of DOI:10.1055/s-0037-1610005

SYNTHESIS
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1
1
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X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
special topic
A
en
A. Hamsath et al.
Special Topic
Synthesis
Quinone C–H Alkylations via Oxidative Radical Processes
Akil Hamsath
O
O
AgNO3 (20 mol%)
oxidant (2 equiv)
Jordan D. Galloway
X
+
Ryan D. Baxter*
0
0
0
0
0-
0
0
2
1-
3
4
1
5-
3
1
5
DCE/H2O (1:1, 0.1 M)
r.t.
O
O
Department of Chemistry & Chemical Biology,
University of California, Merced, 5200 N. Lake
Road, Merced, CA 95343, USA
O
O
OH
3 steps
rbaxter@ucmerced.edu
Published as part of the Special Topic Modern
Radical Methods and their Strategic Applications in
Synthesis
O
O
$0.35/gram
Parvaquone
(antiparasitic)
Received: 01.03.2018
Accepted after revision: 18.04.2018
Published online: 06.06.2018
been utilized as aldehyde equivalents for photocatalyzed
quinone alkylation, further establishing radical C–H func-
tionalization as a robust alternative to precious-metal
catalysis.8
DOI: 10.1055/s-0037-1610005; Art ID: ss-2018-c0139-st
Abstract A brief survey of radical additions to quinones is reported.
Carboxylic acids, aldehydes, and unprotected amino acids are com-
pared as alkyl radical precursors for the mono- or bis- C–H alkylation of
several quinones. Two methods for radical initiation are discussed com-
paring inorganic persulfates and Selectfluor as stoichiometric oxidants.
Kinetic analysis reveals dramatic differences in the rate of radical initia-
tion depending on the identity of the radical precursor and oxidant.
Synthetic strategies for efficiently producing alkyl-quinones are dis-
cussed in the context of selecting optimum radical precursors and initi-
ators depending on quinone identity and functional groups present.
O
OH
O
OH
O
O
Cl
Atovaquone (antiparasite)
Parvaquone (antiparasitic)
O
O
Key words quinones, radicals, alkylation, Selectfluor, kinetics
C16H33
Quinones are versatile reagents that have been used as
oxidants, synthetic intermediates, and chemotherapeutics.1
Because of their highly reducing nature, quinones have
shown notable activity in the context of enzymatic electron
transfers, affecting the levels of reactive oxygen species and
oxidative stress in biological tissues.2 As shown in Figure 1,
a variety of quinone structures display useful biological ac-
tivity.3 Remarkably, even very simple alkyl-quinones such
as thymoquinone display an impressive range of biological
activity, including anticancer properties.4 Studies have
shown that subtle changes to the quinone structure greatly
affect therapeutic efficacy, and so synthetic methods for the
assembly of diverse quinone libraries would be useful for
assessing structure–activity relationships.5 Traditional
methods for quinone functionalization have relied on tran-
sition-metal catalysis, although recent advances in free-
radical chemistry have provided attractive alternatives.6
Boronic acids and esters have been popular as bench-stable
radical precursors for quinone arylation, although alkyla-
tion is also possible from organoboron reagents and car-
boxylic acids.7 More recently, 1,4-dihydropyridines have
O
O
Vitamin K1 (coagulation)
Thymoquinone (anticancer)
Figure 1 Biologically active alkyl-quinones
Our lab has been interested in free-radical chain pro-
cesses using simple and inexpensive radical precursors un-
der mild reaction conditions. Our initial entry into radical
C–H alkylation involved Ag(I)-catalyzed Strecker degrada-
tion of unprotected amino acids to produce nucleophilic
radicals.9 Although this method was suitable to functional-
ize a variety of electron-deficient heteroarenes, our method
required elevated temperatures and strongly oxidizing con-
ditions, limiting functional group compatibility. Through
our subsequent work on radical fluorination, we discovered
that Selectfluor was a suitable oxidant to promote Ag(I)-
catalyzed decarboxylation for heteroarene or quinone C–H
alkylation under mild conditions.10 Through the develop-
ment of this method, we noted significant differences in re-
activity comparing Selectfluor and inorganic persulfates as
oxidants, most notably in the rate of radical initiation. We
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
A. Hamsath et al.
Special Topic
Synthesis
became interested in exploring how this rate difference af-
fects the efficiency of C–H alkylation of quinones depend-
ing on the identity of the oxidant, the radical precursor, and
the quinone.
Our initial efforts focused on comparing several simple,
and widely available, radical precursors for Ag(I)-catalyzed
We postulated that formation of an isopropyl radical
from valine would limit the rate of C–H alkylation due to a
multistep initiation process, allowing unfavorable termina-
tion pathways to compete with a second alkylation. Fur-
thermore, whereas carboxylic acids or aldehydes theoreti-
cally only require one equivalent of oxidant for alkylation,
the Strecker degradation of unprotected amino acids pre-
sumably consumes several equivalents of oxidant per alkyl
radical generated, minimizing the likelihood of bis-alkyla-
tion.11 It is interesting to note that decreasing the stoichi-
ometry of isobutyric acid or isobutyraldehyde decreased
the prevalence for bis-alkylation, but did not suitably im-
prove the overall conversion into mono-alkylated product.
Across the scope of the quinones examined, isobutyric acid
and isobutyraldehyde were viewed as comparable radical
precursors when using ammonium persulfate as a strong
oxidant.
We next sought to compare the same set of isopropyl
radical precursors under identical experimental conditions
by replacing ammonium persulfate with Selectfluor as the
stoichiometric oxidant. As shown in Scheme 2, only mono-
alkylated products were observed regardless of the identity
of the radical precursor. Across the range of quinones stud-
ied, isobutyric acid was shown to be the superior radical
quinone
alkylation
using
ammonium
persulfate
[(NH4)2S2O8] as an oxidant (Scheme 1). Based on our previ-
ous work, we identified the isopropyl radical as being opti-
mum for comparing nucleophilic radical additions to conju-
gated electrophiles.9 Isobutyric acid, isobutyraldehyde, and
valine are all capable of quinone alkylation at room tem-
perature under identical experimental conditions. Because
all the radical precursors examined produce the isopropyl
radical as the reactive species, differences in conversion or
selectivity may be attributed to differences in the rate of
radical formation. Electron-neutral (1, 5), electron-rich (2–
4, 6), and electron-poor (7) quinones are all suitable reac-
tion partners, although the nucleophilic nature of alkyl rad-
icals typically renders electron-poor quinones the most re-
active. Under these strongly oxidizing conditions (Scheme
1), several quinones yield a mixture of mono- and bis-al-
kylated products with isobutyric acid and isobutyralde-
hyde, but not with valine.
O
O
O
AgNO3 (20 mol%)
O
O
O
O
O
O
Selectfluor (2 equiv)
AgNO3 (20 mol%)
(NH4)2S2O8 (2 equiv)
radical
precursor
+
H
+
radical
precursor
DCE/H2O (1:1, 0.1 M)
r.t., up to 24 h
H
+
+
DCE/H2O (1:1, 0.1 M)
r.t., up to 24 h
O
O
O
1–7
1–7
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4
A = 26%
B = 24%
C = 13%
1
2
3
4
1
2
3
A = 47%
B = 9%
C = trace
A = 58%
B = 47%
C = trace
A = 47%
B = 24%
C = 4%
A = 8%
A = 29% (51% bis)
B = 34% (29% bis)
C = 32%
A = 26% (37% bis)
B = 37% (24% bis)
C = 41%
A = 28% (18% bis)
B = 29% (15% bis)
C = 31%
B = trace
C = trace
O
O
O
O
O
O
O
Cl
Cl
Cl
Cl
O
O
O
O
O
5
6
7
5
6
7
A = 57%
B = 43%
C = 31%
A = 34%
B = 33%
C = 25%
A = 36% (22% bis)
B = 40% (20% bis)
C = 32%
A = 42%
B = 24%
C = 5%
A = 17%
B = 15%
C = trace
A = 52%
B = 12%
C = trace
Scheme 1 Comparison of precursors for radical alkylation with ammo-
nium persulfate. Reagents and conditions: quinone (0.2 mmol), radical
precursor (0.4 mmol), ammonium persulfate (0.4 mmol), AgNO3 (0.04
mmol) in DCE/H2O (2 mL, 1:1) at room temperature for up to 24 h.
Yields determined by 1H NMR using 1,3,5-trimethoxybenzene as a stan-
dard. Method ‘A’ radical precursor is isobutyric acid. Method ‘B’ radical
precursor is isobutyraldehyde. Method ‘C’ radical precursor is valine.
Scheme 2 Comparison of precursors for radical alkylation with Select-
fluor. Reagents and conditions: quinone (0.2 mmol), radical precursor
(0.4 mmol), Selectfluor (0.4 mmol), AgNO3 (0.04 mmol) in DCE/H2O (2
mL, 1:1) at room temperature for up to 24 h. Yields determined by 1H
NMR using 1,3,5-trimethoxybenzene as a standard. Method ‘A’ radical
precursor is isobutyric acid. Method ‘B’ radical precursor is isobutyral-
dehyde. Method ‘C’ radical precursor is valine.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
A. Hamsath et al.
Special Topic
Synthesis
precursor, whereas valine was essentially ineffective. These
results suggested that highly reactive quinones are more ef-
fectively mono-alkylated using Selectfluor as an oxidant
with carboxylic acids as radical precursors.
within three hours with ammonium persulfate as the oxi-
dant (plot ‘a’). Under these conditions, the rate of product
formation is higher using isobutyric acid as a radical pre-
cursor compared to isobutyraldehyde (plot ‘b’). This result
suggests that oxidative decarboxylation is faster than de-
carbonylation as all elementary mechanistic steps are ex-
pected to be identical after formation of the isopropyl radi-
cal.14 It is interesting to note that for isobutyric acid, forma-
tion of the bis-alkylated product is not observed until
nearly all of the 1,4-benzoquinone starting material is con-
sumed (the point indicated by the arrow in plot ‘b’). This
suggests that the slightly electron-rich 2-isopropyl-1,4-
benzoquinone (1) is a less effective electrophile, consistent
with the data shown in Scheme 1.
Because the conversions shown in Scheme 2 were gen-
erally lower with isobutyraldehyde, we compared the rates
of C–H alkylation with ammonium persulfate or Selectfluor
using isobutyric acid as the sole radical precursor. Dramatic
differences in the rate of C–H alkylation were observed be-
tween the two oxidants. Whereas persulfate-mediated ini-
tiation consumes 1,4-benzoquinone in approximately three
hours, the Selectfluor-mediated reaction still contains 25%
Based on the proposed mechanism for Ag(I)-catalyzed
radical alkylation with carboxylic acids, we believed that
the lower reduction potential of Selectfluor (E° = –0.04 V)
compared to ammonium persulfate (E° = 2.01 V) would
slow the production of alkyl radicals available to react with
quinones.12 This kinetic difference could explain the pro-
pensity for mono-alkylation via the Selectfluor method and
should be easily tested by comparing global reaction pro-
gressions. It has previously been shown that 1,4-benzoqui-
none is an excellent radical electrophile, and so the rate of
C–H alkylation is likely to be most affected by the rate of
alkyl radical formation.13 We sought to provide experimen-
tal evidence for this hypothesis by comparing the global
rates of 1,4-benzoquinone alkylation when using either
ammonium persulfate or Selectfluor as oxidants.
Due to the heterogeneity of the reaction medium, man-
ual sampling was used to determine reaction progressions.
As shown in Scheme 3, 1,4-benzoquinone is consumed
O
O
O
AgNO3 (20 mol%)
+
radical precursor
+
oxidant
+
DCE/H2O (1:1, 0.1 M)
r.t.
O
O
O
1
Scheme 3 Rate comparisons for isobutyric acid and isobutyraldehyde using ammonium persulfate and Selectfluor. Reagents and conditions: 1,4-benzo-
quinone (0.4 mmol), radical precursor (0.8 mmol), oxidant (0.8 mmol), AgNO3 (0.08 mmol) in DCE/H2O (4 mL, 1:1) at room temperature for up to 24
h. Using a glass microsyringe, 10 μL aliquots were taken from the organic phase at specified time points. Conversions were determined by GCMS
against 4-tert-butylbenzene as an internal standard. Each data point represents the average value of three runs under identical conditions. Plots a) and
b), (NH4)2S2O8 as the oxidant, blue data is isobutyric acid as the radical precursor, red data is isobutyraldehyde as the radical precursor. Plots c) and d),
isobutyric acid as the radical precursor, blue data is (NH4)2S2O8 as the oxidant, red data is Selectfluor as the oxidant.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
A. Hamsath et al.
Special Topic
Synthesis
unreacted starting material after 24 hours (plot ‘c’). Com-
paring the initial rates of product formation for the two
methods reveals that persulfate-mediated alkylation occurs
approximately 30 times faster than when using Selectfluor
as an oxidant (plot ‘d’). This data is consistent with our hy-
pothesis that the formation of bis-alkylation products is
largely controlled by the rate of alkyl radical formation,
which is directly related to the strength of the stoichiomet-
ric oxidant.
dition ineffective, regardless of the oxidant used. In addi-
tion, 2-hydroxy-1,4-naphthoquinone is more than four
times the cost of naphthoquinone, and the hydroxy group is
easily installed through the quinone alkene using straight-
forward chemistry. Either ammonium persulfate or Select-
fluor may be used as the oxidant for the initial reaction, al-
though bis-alkylation is sterically unfavored and so ammo-
nium persulfate was chosen as the cost-effective option.
This simple synthetic sequence could easily be applied to
producing structural analogues of parvaquone simply by
substituting cyclohexanecarboxylic acid for an alternative
radical precursor. In this way, radical alkylation could be
The kinetic data shown in Scheme 3 suggests that pow-
erful oxidants, such as ammonium persulfate, rapidly gen-
erate alkyl radicals via decarboxylation of carboxylic acids.
For highly reactive electrophiles this influx of reactive spe-
cies can lead to over-alkylation, a problem that is not easily
overcome by altering reactant stoichiometry. Conversely,
slow formation of alkyl radicals using Selectfluor as a mild
oxidant leads to suitable conversion of exclusively mono-al-
kylated products over longer reaction times. This assess-
ment is true in the context of the isopropyl radical where
high levels of nucleophilicity ensure efficient reaction with
1,4-benzoquinone. However, we have shown that several
alkyl carboxylic acids are suitable radical precursors for
quinone alkylation using Selectfluor as an oxidant.10b In
many cases, the stability and nucleophilicity of the generat-
ed alkyl radical play large roles in reaction efficiency, and
the choice of oxidant depends on predicting the efficacy of
the nucleophilic radical generated. As shown in Scheme 4,
for highly reactive quinones such as 1,4-benzoquinone,
simple secondary alkyl radicals 8 produce higher yields of
mono-alkylation when using Selectfluor as an oxidant. The
poor stability of primary radicals 9 renders them inefficient
with either oxidant, but the stable tert-butyl radical 10 is
more efficient with a stronger oxidant, likely due to steric
effects slowing the nucleophilic addition. Because of their
decreased nucleophilicity, deactivated secondary radicals
11 are more efficient when rapidly formed using ammoni-
um persulfate. Stabilized benzylic radicals 13 are reactive
enough to produce bis-alkylation with ammonium persul-
fate, but still yield a suitable amount of the mono-alkylated
product.
O
O
O
AgNO3 (20 mol%)
oxidant (2 equiv)
+
R–CO2H
+
H
R
R
R
DCE/H2O (1:1, 0.1 M)
r.t., up to 24 h
O
O
O
8–13
O
O
O
O
O
O
8
9
10
A = 46% (24% bis)
B = 47%
A = 22%
B = 13%
A = 51%
B = 27%
O
O
O
O
F
F
O
O
O
11
12
13
A = 73%
B = 45%
A = 38% (17% bis)
B = 12%
A = 52% (21% bis)
B = 37%
Scheme 4 1,4-Benzoquinone alkylation from various carboxylic acids.
Reagents and conditions: quinone (0.2 mmol), carboxylic acid (0.4
mmol), oxidant (0.4 mmol), AgNO3 (0.04 mmol) in DCE/H2O (2 mL,
1:1) at room temperature for up to 24 h. Yields determined by 1H NMR
using 1,3,5-trimethoxybenzene as a standard. Method ‘A’ oxidant is
(NH4)2S2O8. Method ‘B’ oxidant is Selectfluor.
A possible mechanism for the radical alkylation of qui-
nones is shown in Scheme 5. Single-electron oxidation of
Ag(I) by either persulfate or Selectfluor would produce
Ag(II). Oxidation of the carboxylate by Ag(II) would lead to
radical decarboxylation, liberating a nucleophilic alkyl radi-
cal (R•). Reaction with a quinone would produce a substitut-
ed quinone radical species that likely undergoes an oxida-
tion/deprotonation sequence to form the expected alkylat-
ed quinone product.
Cl
CO2H
N
•-
SO4
Ag(II)
or
R
N
•
– CO2
– H+
Cl
N
2–
Ag(I)
R•
S2O8
or
N
F
O
O
O
O
To demonstrate the utility of quinone C–H alkylation,
we sought to develop a short synthesis of parvaquone from
unfunctionalized 1,4-naphthoquinone as a simple and in-
expensive starting material (Scheme 6). Although 2-hy-
droxy-1,4-naphthoquinone is commercially available, the
electron-donating hydroxy renders nucleophilic radical ad-
R•
oxidize
•
H
– H+
R
R
O
O
Scheme 5 Proposed mechanism for quinone alkylation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
A. Hamsath et al.
Special Topic
Synthesis
used to generate a library of substituted quinones to screen
for structure–activity relationships in the search for a more
potent compound.
Functionalization of Quinones with (NH4)2S2O8 as the Oxidant;
General Procedure A
To a vial containing a stir bar was added the quinone (0.2 mmol, 1
equiv), the radical precursor (0.4 mmol, 2 equiv) and (NH4)2S2O8 (91
mg, 0.4 mmol, 2 equiv) followed by dichloroethane (1 mL) and H2O
(0.9 mL). A solution of AgNO3 (0.1 mL of a 0.4 M solution in H2O, 0.04
mmol) was added in one portion. The reaction vial was capped with a
screw cap and the contents stirred at room temperature for 24 h.
Upon completion, the reaction was transferred to a test tube contain-
ing saturated NaHCO3 (2 mL). The aqueous phase was extracted with
EtOAc (3 × 3 mL) and the combined organic layers were dried over
MgSO4, filtered and carefully concentrated in vacuo. Trimethoxyben-
zene (16.8 mg, 1 mmol) was added and the resulting crude material
was dissolved in CDCl3 for NMR yield analysis.
O
O
AgNO3 (20 mol%)
oxidant (2 equiv)
O
OH
OH
HO
+
DCE/H2O (1:1, 0.1 M)
r.t., up to 24 h
O
$1.54/gram
O
O
parvaquone
O
O
O
OH
(ii), (iii)
(72%)
(i)
(75%)
O
O
Functionalization of Quinones with Selectfluor as the Oxidant;
General Procedure B
$0.35/gram
parvaquone
Scheme 6 A short synthesis of parvaquone. Price comparison for a
100-gram bottle from Sigma-Aldrich. Reagents and conditions: (i) 1,4-
naphthoquinone (0.2 mmol), cyclohexanecarboxylic acid (0.4 mmol),
(NH4)2S2O8 (0.4 mmol), AgNO3 (0.04 mmol) in DCE/H2O (20 mL, 1:1) at
room temperature for 24 h, 75% isolated yield; (ii) 30% H2O2, Na2CO3,
80 °C, 1 h, 93% isolated yield; (iii) concentrated H2SO4, 57% yield.15
To a vial containing a stir bar was added the quinone (0.2 mmol, 1
equiv), the radical precursor (0.4 mmol, 2 equiv) and Selectfluor (142
mg, 0.4 mmol, 2 equiv) followed by dichloroethane (1 mL) and H2O
(0.9 mL). A solution of AgNO3 (0.1 mL of a 0.4 M solution in H2O, 0.04
mmol) was added in one portion. The reaction vial was capped with a
screw cap and the contents stirred at room temperature for 24 h.
Upon completion, the reaction was transferred to a test tube contain-
ing saturated NaHCO3 (2 mL). The aqueous phase was extracted with
EtOAc (3 × 3 mL) and the combined organic layers were dried over
MgSO4, filtered and carefully concentrated in vacuo. Trimethoxyben-
zene (16.8 mg, 1 mmol) was added and the resulting crude material
was dissolved in CDCl3 for NMR yield analysis.
In conclusion, we have described a brief survey of multi-
ple strategies for quinone C–H alkylation via radical pro-
cesses. Carboxylic acids, aldehydes, and unprotected amino
acids are all suitable alkyl radical precursors, although car-
boxylic acids were deemed to be the most generally effec-
tive. Kinetic comparisons showed that carboxylic acids pro-
duce alkyl radicals faster than aldehydes, and ammonium
persulfate is much more reactive than Selectfluor as a stoi-
chiometric oxidant. Depending on the quinone substrate,
the optimum radical precursor and oxidant could be select-
ed by assessing the nucleophilic character of the expected
radical. Finally, we demonstrated the utility of radical al-
kylation by providing a short and inexpensive synthesis of a
biologically active quinone, parvaquone. We look forward
to applying such strategies for library synthesis of simple
alkyl-quinones in the future.
2-Isopropylcyclohexa-2,5-diene-1,4-dione (1), 2,6-Diisopropylcy-
clohexa-2,5-diene-1,4-dione (1-Bis-C2,C6), 2,5-Diisopropylcyclo-
hexa-2,5-diene-1,4-dione (1-Bis-C2,C5) and 2,3-
Diisopropylcyclohexa-2,5-diene-1,4-dione (1-Bis-C2,C3)
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The reaction afford-
ed 1 (8.6 mg, 29%) as a yellow oil. The data matches those previously
reported.1 The same reaction also afforded an inseparable mixture of
1-Bis-C2,C6, 1-Bis-C2,C5 and 1-Bis-C2,C3 (19.5 mg, 51%) as a yellow
oil. When isobutyraldehyde (36 μL, 0.4 mmol) was used, the reaction
afforded 1 (34% NMR yield), 1-Bis-C2,C6 (13% NMR yield), 1-Bis-
C2,C5 (13% NMR yield) and 1-Bis-C2,C3 (3% NMR yield). When valine
(47 mg, 0.4 mmol) was used, the reaction afforded 1 (32% NMR yield)
with no bis product. The data for 1 matches those previously report-
ed.15
Reagents and solvents were purchased at the highest commercial
quality and used without purification. NMR yields were calculated by
selecting proton peaks from products that were previously isolated.
Trimethoxybenzene was used as the NMR standard. The yields de-
scribe the result of a single experiment. Reactions were monitored by
NMR spectroscopy; the spectra were recorded on a Varian-INOVA 400
MHz or 500 MHz spectrometer and calibrated using residual undeu-
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The reaction afford-
ed 1 (47% NMR yield). When isobutyraldehyde (36 μL, 0.4 mmol) was
used, the reaction afforded 1 (9% NMR yield). When valine (47 mg, 0.4
mmol) was used, the reaction afforded 1 (<2% NMR yield). The data
for 1 matches those previously reported.16
Previously isolated NMR data were used as a reference to calculate
NMR yields.
terated solvent as an internal reference (CDCl3: 1H NMR 7.26 ppm, 13
C
NMR 77.16 ppm). The following abbreviations are used to explain
multiplicities (s, singlet; d, doublet; t, triplet; q, quartet; m, multi-
plet). High-resolution mass spectrometry (HRMS) was performed us-
ing a ThermoFisher Q-Exactive instrument. Kinetic data were ob-
tained by GCMS (Agilent Technologies 5975 Series MSD GCMS) with
tert-butylbenzene as the standard.
1-Bis-C2,C6 and 1-Bis-C2,C5
1H NMR (400 MHz, CDCl3): δ = 6.50 (d, J = 1.2 Hz, 2 H), 6.47 (s, 2 H),
3.13–2.95 (m, 4 H), 1.12 (d, J = 6.9 Hz, 24 H).
13C NMR (100 MHz, CDCl3): δ = 188.9, 188.1, 187.0, 155.5, 154.4,
131.0, 129.9, 27.1, 26.6, 21.6, 21.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
A. Hamsath et al.
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Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H18O2+: 193.1223; found:
193.1214 and 193.1213, respectively.
mg, 0.4 mmol) was used, the reaction afforded 3 (31% NMR yield)
with no bis product. The data for 3 matches those previously report-
ed.17
1-Bis-C2,C3
General procedure B was employed using 2,6-dimethyl-1,4-benzo-
quinone (27 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 3 (47% NMR yield). When isobutyraldehyde (36 μL,
0.4 mmol) was used, the reaction afforded 3 (24% NMR yield). When
valine (47 mg, 0.4 mmol) was used, the reaction afforded 3 (4% NMR
yield).
1H NMR (400 MHz, CDCl3): δ = 6.58 (s, 2 H), 3.30–3.18 (m, 2 H), 1.27
(d, J = 7.1 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 188.3, 148.9, 136.6, 27.9, 21.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H18O2+: 193.1223; found:
193.1210.
Previously isolated NMR data were used as a reference to calculate
NMR yields.
2-Isopropyl-5-methylcyclohexa-2,5-diene-1,4-dione (2-C5), 2-Iso-
propyl-6-methylcyclohexa-2,5-diene-1,4-dione (2-C6), 2-Isopro-
pyl-3-methylcyclohexa-2,5-diene-1,4-dione (2-C3), 2,3-
Diisopropyl-5-methylcyclohexa-2,5-diene-1,4-dione (2-Bis-C5,C6)
and 2,6-Diisopropyl-5-methylcyclohexa-2,5-diene-1,4-dione (2-
Bis-C3,C5)
3-Bis
1H NMR (500 MHz, CDCl3): δ = 3.13–3.03 (m, 2 H), 2.02 (s, 6 H), 1.25
(d, J = 7.1 Hz, 12 H).
13C NMR (125 MHz, CDCl3): δ = 188.9, 187.9, 149.3, 139.0, 28.9, 20.7,
11.9.
General procedure A was employed using 2-methyl-1,4-benzoqui-
none (24 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 2-C5 (9% NMR yield), 2-C6 (11% NMR yield), 2-C3
(6% NMR yield), 2-Bis-C3,C6 (19% NMR yield) and 2-Bis-C3,C5 (18%
NMR yield). When isobutyraldehyde (36 μL, 0.4 mmol) was used, the
reaction afforded 2-C5 (13% NMR yield), 2-C6 (16% NMR yield), 2-C3
(8% NMR yield), 2-Bis-C3,C6 (13% NMR yield) and 2-Bis-C3,C5 (11%
NMR yield). When valine (47 mg, 0.4 mmol) was used, the reaction
afforded 2-C5 (14% NMR yield), 2-C6 (16% NMR yield), 2-C3 (11% NMR
yield), with no bis product. The data for 2-C5, 2-C6 and 2-C3 matches
those previously reported.10b
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H22O2+: 221.1536; found:
221.1521.
2-Isopropyl-3,5-dimethoxycyclohexa-2,5-diene-1,4-dione (4)
General procedure A was employed using 2,6-dimethoxy-1,4-benzo-
quinone (34 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 4 (26% NMR yield). When isobutyraldehyde (36 μL,
0.4 mmol) was used, the reaction afforded 4 (24% NMR yield). When
valine (47 mg, 0.4 mmol) was used, the reaction afforded 4 (13% NMR
yield).
General procedure B was employed using 2,6-dimethoxy-1,4-benzo-
quinone (34 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 4 (8% NMR yield). When isobutyraldehyde (36 μL,
0.4 mmol) was used, the reaction afforded 4 (3% NMR yield). When
valine (47 mg, 0.4 mmol) was used, the reaction afforded 4 (<2% NMR
yield).
General procedure B was employed using 2-methyl-1,4-benzoqui-
none (24 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 2-C5 (21% NMR yield), 2-C6 (23% NMR yield), 2-C3
(14% NMR yield), 2-Bis-C3,C6 (19% NMR yield) and 2-Bis-C3,C5 (19%
NMR yield). When isobutyraldehyde (36 μL, 0.4 mmol) was used, the
reaction afforded 2-C5 (14% NMR yield), 2-C6 (16% NMR yield) and 2-
C3 (17% NMR yield). When valine (47 mg, 0.4 mmol) was used, the
reaction afforded 2-C5 (<2% NMR yield), 2-C6 (<2% NMR yield) and 2-
C3 (<2% NMR yield). The data matches those previously reported.10b
Previously isolated NMR data were used as a reference to calculate
NMR yields.
1H NMR (400 MHz, CDCl3): δ = 5.80 (s, 1 H), 3.93 (s, 3 H), 3.78 (s, 3 H),
3.30–3.18 (m, 1 H), 1.20 (d, J = 7.0 Hz, 6 H).
Previously isolated NMR data were used as a reference to calculate
NMR yields.
13C NMR (100 MHz, CDCl3): δ = 187.5, 178.9, 157.1, 154.9, 138.6,
107.6, 61.1, 56.5, 24.8, 20.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H16O4+: 211.0965; found:
211.0964.
2-Bis-C3,C6 and 2-Bis-C3,C5
1H NMR (400 MHz, CDCl3): δ = 6.45 (s, 1 H), 6.38 (s, 1 H), 3.17–3.07
(m, 2 H), 3.07–2.98 (m, 2 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 1.26 (dd, J =
7.1, 2.0 Hz, 12 H), 1.10 (dd, J = 6.9, 2.5 Hz, 12 H).
13C NMR (100 MHz, CDCl3): δ = 188.8, 188.2, 187.7, 187.6, 155.1,
149.0, 145.3, 140.3, 137.4, 135.6, 134.0, 130.5, 53.6, 31.7, 28.9, 26.7,
22.8, 21.6, 20.5, 15.5, 14.3, 11.9.
2-Isopropylnaphthalene-1,4-dione (5)
General procedure A was employed using naphthoquinone (32 mg,
0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The reaction afford-
ed 5 (57% NMR yield). When isobutyraldehyde (36 μL, 0.4 mmol) was
used, the reaction afforded 5 (43% NMR yield). When valine (47 mg,
0.4 mmol) was used, the reaction afforded 5 (31% NMR yield).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H20O2+: 207.1380; found:
207.1350 and 207.1372 respectively.
General procedure B was employed using naphthoquinone (32 mg,
0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The reaction afford-
ed 5 (42% NMR yield). When isobutyraldehyde (36 μL, 0.4 mmol) was
used, the reaction afforded 5 (24% NMR yield). When valine (47 mg,
0.4 mmol) was used, the reaction afforded 5 (5% NMR yield).
2-Isopropyl-3,5-dimethylcyclohexa-2,5-diene-1,4-dione (3) and
2,6-Diisopropyl-3,5-dimethylcyclohexa-2,5-diene-1,4-dione (3-
Bis)
General procedure A was employed using 2,6-dimethyl-1,4-benzo-
quinone (27 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 3 (28% NMR yield) and 3-Bis (18% NMR yield).
When isobutyraldehyde (36 μL, 0.4 mmol) was used, the reaction af-
forded 3 (29% NMR yield) and 3-Bis (15% NMR yield). When valine (47
Previously isolated NMR data were used as a reference to calculate
NMR yields.
1H NMR (400 MHz, CDCl3): δ = 8.14–8.03 (m, 2 H), 7.76–7.68 (m, 2 H),
6.77 (d, J = 1.0 Hz, 1 H), 3.31–3.19 (m, 1 H), 1.20 (d, J = 6.9 Hz, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
A. Hamsath et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3): δ = 185.7, 185.0, 157.4, 133.9, 133.6,
132.7, 132.7, 132.1, 126.8, 126.1, 27.3, 21.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H14O2+: 201.0910; found:
[1,1′-Bi(cyclohexane)]-3,6-diene-2,5-dione (8), [1,1′:4′,1′′-Tercyclo-
hexane]-3′,6′-diene-2′,5′-dione (8-Bis-C2,C5) and [1,1′:3′,1′′-Tercy-
clohexane]-3′,6′-diene-2′,5′-dione (8-Bis-C2,C6)
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and cyclohexanoic acid (51 mg, 0.4 mmol). The reaction af-
forded 8 (17.6 mg, 46%) as a yellow after separation by silica gel chro-
matography (5% EtOAc in hexanes). The data matches those previous-
ly reported.2 The same reaction also afforded a mixture of 8-Bis-
C2,C5 and 8-Bis-C2,C6 (1:1) (14 mg, 24%) as a yellow oil.
201.0913.
2-Isopropyl-3-methylnaphthalene-1,4-dione (6)
General procedure A was employed using 2-methylnaphthoquinone
(34 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The reaction
afforded 6 (34% NMR yield). When isobutyraldehyde (36 μL, 0.4
mmol) was used, the reaction afforded 6 (33% NMR yield). When va-
line (47 mg, 0.4 mmol) was used, the reaction afforded 6 (25% NMR
yield).
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and cyclohexanoic acid (51 mg, 0.4 mmol). The reaction af-
forded 8 (17.9 mg, 47%) as a yellow oil separated by silica gel chroma-
tography (5% EtOAc in hexanes). The data matches those previously
reported.10b
General procedure B was employed using 2-methylnaphthoquinone
(34 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The reaction
afforded 6 (17% NMR yield). When isobutyraldehyde (36 μL, 0.4
mmol) was used, the reaction afforded 6 (15% NMR yield). When va-
line (47 mg, 0.4 mmol) was used, the reaction afforded 6 (<2% NMR
yield). The data matches those previously reported.18
8-Bis-C2,C5 and 8-Bis-C2,C6
1H NMR (400 MHz, CDCl3): δ = 6.46 (d, J = 1.0 Hz, 2 H), 6.42 (s, 2 H),
2.75–2.63 (m, 4 H), 1.86–1.71 (m, 20 H), 1.47–1.30 (m, 10 H), 1.27–
1.08 (m, 10 H).
3,5-Dichloro-2-isopropylcyclohexa-2,5-diene-1,4-dione (7) and
2,6-Dichloro-3,5-diisopropylcyclohexa-2,5-diene-1,4-dione (7-Bis)
13C NMR (100 MHz, CDCl3): δ = 189.0, 188.2, 187.0, 154.5, 153.4,
131.4, 130.3, 36.8, 36.2, 32.3, 32.2, 27.2, 26.5, 26.5, 26.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H26O2+: 273.1849; found:
273.1837 and 273.1842, respectively.
General procedure A was employed using 2,6-dichloro-1,4-benzoqui-
none (35 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 7 (36% NMR yield) and 7-Bis (22% NMR yield); trace
amounts of a product corresponding to a mass of 7-Bis, minus chlo-
rine, were observed (ESI-TOF: m/z calcd 269.1302; found: 269.1351).
When isobutyraldehyde (36 μL, 0.4 mmol) was used, the reaction af-
forded 7 (40% NMR yield) and 7-Bis (20% NMR yield). When valine (47
mg, 0.4 mmol) was used, the reaction afforded 7 (32% NMR yield).
2-Pentylcyclohexa-2,5-diene-1,4-dione (9)
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and n-hexanoic acid (50 μL, 0.4 mmol). The reaction af-
forded 9 (7.7 mg, 22%) as a yellow oil separated by silica gel chroma-
tography (5% EtOAc in hexanes).
General procedure B was employed using 2,6-dichloro-1,4-benzoqui-
none (35 mg, 0.2 mmol) and isobutyric acid (37 μL, 0.4 mmol). The
reaction afforded 7 (52% NMR yield). When isobutyraldehyde (36 μL,
0.4 mmol) was used, the reaction afforded 7 (12% NMR yield). When
valine (47 mg, 0.4 mmol) was used, the reaction afforded 7 (<2% NMR
yield).
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and n-hexanoic acid (50 μL, 0.4 mmol). The reaction af-
forded 9 (4.5 mg, 13%) as a yellow oil separated by silica gel chroma-
tography (5% EtOAc in hexanes). The data matches those previously
reported.10b
Previously isolated NMR data were used as a reference to calculate
NMR yields.
2-(tert-Butyl)cyclohexa-2,5-diene-1,4-dione (10)
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and pivalic acid (41 mg, 0.4 mmol). The reaction afforded
10 (16.7 mg, 51%) as a yellow oil separated by silica gel chromatogra-
phy (5% EtOAc in hexanes).
Compound 7
1H NMR (500 MHz, CDCl3): δ = 7.07 (s, 1 H), 3.55–3.45 (m, 1 H), 1.33
(d, J = 7.1 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 177.6, 177.3, 149.7, 144.9, 140.6,
132.3, 30.9, 19.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H10Cl2O2+: 218.9974; found:
218.9949.
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and pivalic acid (41 mg, 0.4 mmol). The reaction afforded
10 (8.8 mg, 27%) as a yellow oil separated by silica gel chromatogra-
phy (5% EtOAc in hexanes). The data matches those previously report-
ed.19
4′,4′-Difluoro-[1,1′-bi(cyclohexane)]-3,6-diene-2,5-dione (11)
7-Bis
1H NMR (400 MHz, CDCl3): δ = 3.51–3.40 (m, 2 H), 1.32 (d, J = 7.1 Hz,
12 H).
13C NMR (100 MHz, CDCl3): δ = 177.5, 148.6, 140.8, 30.7, 19.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H16Cl2O2+: 261.0444;
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and 4,4-difluorocyclohexane-1-carboxylic acid (66 mg, 0.4
mmol). The reaction afforded 11 (32.9 mg, 73%) as a yellow oil sepa-
rated by silica gel chromatography (10% EtOAc in hexanes).
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and 4,4-difluorocyclohexane-1-carboxylic acid (66 mg, 0.4
mmol). The reaction afforded 11 (20.2 mg, 45%) as a yellow oil sepa-
rated by silica gel chromatography (10% EtOAc in hexanes). The data
matches those previously reported.10b
found: 261.0422.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
A. Hamsath et al.
Special Topic
Synthesis
+
2-(Tetrahydro-2H-pyran-4-yl)cyclohexa-2,5-diene-1,4-dione (12),
2,5-Bis(tetrahydro-2H-pyran-4-yl)cyclohexa-2,5-diene-1,4-dione
(12-Bis-C2,C5) and 2,6-Bis(tetrahydro-2H-pyran-4-yl)cyclohexa-
2,5-diene-1,4-dione (12-Bis-C2-C6)
HRMS (ESI-TOF): calcd for
289.1256
C
20H17O2 [M+H]+ 289.1223 found
13-Bis-C2,C5
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 4H), 7.29–7.22 (m, 4H),
7.21–7.15 (m, 2H), 6.29 (s, 2H), 3.75 (s, 4H)
13C NMR (100 MHz, CDCl3), mixture of all three isomers: δ = 188.0,
187.8, 187.7, 187.3, 148.9, 148.7, 143.9, 137.8, 136.7, 136.6, 136.5,
133.5, 133.3, 129.5, 128.98, 128.97, 128.8, 128.7, 127.13, 127.11,
126.7, 35.6, 35.0, 32.0.
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (56 mg, 0.4
mmol). The reaction afforded 12 (14.4 mg, 38%) as a yellow solid sep-
arated by silica gel chromatography (10% EtOAc in hexanes). The same
reaction also afforded a mixture of 12-Bis-C2,C5 and 12-Bis-C2,C6
(1:1) (9.5 mg, 17%) as a yellow oil.
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (56 mg, 0.4
mmol). The reaction afforded 12 (8.1 mg, 21%) as a yellow solid sepa-
rated by silica gel chromatography (10% EtOAc in hexanes).
HRMS (ESI-TOF): calcd for
289.1226
C
20H17O2 [M+H]+ 289.1223 found
+
13-Bis-C2,C6
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 4H), 7.29–7.22 (m, 4H),
7.21–7.15 (m, 2H), 6.35 (t, J = 1.6 Hz, 2H), 3.71 (d, J = 1.2 Hz, 4H)
13C NMR (100 MHz, CDCl3), mixture of all three isomers: δ = 188.0,
187.8, 187.7, 187.3, 148.9, 148.7, 143.9, 137.8, 136.7, 136.6, 136.5,
133.5, 133.3, 129.5, 128.98, 128.97, 128.8, 128.7, 127.13, 127.11,
126.7, 35.6, 35.0, 32.0.
Compound 12
1H NMR (400 MHz, CDCl3): δ = 6.79–6.70 (m, 2 H), 6.52 (dd, J = 2.3, 1.2
Hz, 1 H), 4.05 (dd, J = 11.6, 4.4 Hz, 2 H), 3.53 (td, J = 11.8, 2.1 Hz, 2 H),
3.01–2.90 (m, 1 H), 1.72–1.64 (m, 2 H), 1.56 (ddd, J = 25.1, 12.5, 4.4
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 187.9, 187.0, 152.0, 137.1, 136.2,
131.3, 67.9, 34.0, 31.6.
+
HRMS (ESI-TOF): calcd for
289.1247
C
20H17O2 [M+H]+ 289.1223 found
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H14O3+: 193.0859; found:
193.0857.
General Kinetic Procedures
To a vial containing a stir bar was added benzoquinone (44 mg, 0.4
mmol, 1 equiv), the radical precursor (0.8 mmol, 2 equiv) and the ox-
idant (0.8 mmol, 2 equiv) followed by dichloroethane (2 mL) and H2O
(1.8 mL). Tetrabutylbenzene (31 μL, 0.2 mmol) was then added as the
internal standard. The reaction mixture was stirred for 1 min without
catalyst. A 10 μL aliquot was then taken using a glass syringe and
transferred into a GC vial. The vial was then filled with EtOAc and
placed into the GCMS (Agilent Technologies 5975 Series MSD GCMS)
for analysis. A solution of AgNO3 (0.2 mL of a 0.4 M solution in H2O,
0.04 mmol) was added to the reaction in one portion. Aliquots (10 μL
) were taken for GCMS analysis every 20 min for the first hour, then
after 30 min for the second hour followed by one one-hour sample (3
hours), two two-hour samples (5 h and 7 h), a four-hour sample (11
h) and finally a twenty-four-hour sample. A previously prepared cali-
bration curve with benzoquinone and tert-butylbenzene as the stan-
dard along with their corresponding GC peak areas from each sample
produced the kinetic data in Scheme 3.
12-Bis-C2,C5 and 12-Bis-C2,C6
1H NMR (400 MHz, CDCl3): δ = 6.51 (s, 2 H), 6.48 (s, 2 H), 4.09–4.01
(m, 8 H), 3.56–3.53 (m, 8 H), 3.00–2.95 (m, 4 H), 1.69–1.66 (m, 8 H),
1.62–1.50 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 188.2, 187.5, 186.5, 152.3, 151.6,
131.7, 130.9, 68.0, 66.0, 34.3, 33.8, 31.7, 31.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H22O4+: 277.1434; found:
277.1419 and 277.1422, respectively.
2-Benzylcyclohexa-2,5-diene-1,4-dione (13), 2,5-Dibenzylcyclo-
hexa-2,5-diene-1,4-dione (13-Bis-C2,C5), 2,6-Dibenzylcyclohexa-
2,5-diene-1,4-dione (13-Bis-C2,C6) and 2,3-Dibenzylcyclohexa-
2,5-diene-1,4-dione (13-Bis-C2,C3)
General procedure A was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and 2-phenylacetic acid (54 mg, 0.4 mmol). The reaction
afforded 13 (20.5 mg, 52%) as a yellow oil separated by silica gel chro-
matography (5% EtOAc in hexanes). The data matches those previous-
ly reported.15 The same reaction also afforded a mixture of 13-Bis-
C2,C3, 13-Bis-C2,C5 and 13-Bis-C2,C6 (1:2:4) (7 mg, 12%) as a yellow
oil.
Parvaquone
2-Cyclohexylnaphthoquinone
To a vial containing a stir bar was added 1,4-naphthoquinone (316
mg, 2.0 mmol, 1 equiv), cyclohexanecarboxylic acid (512 mg, 4 mmol,
2 equiv) and (NH4)2S2O8 (912 mg, 4 mmol, 2 equiv) followed by di-
chloroethane (10 mL) and H2O (10 mL). AgNO3 (68 mg, 0.4 mmol, 20
mol%) was added in one portion. The reaction was capped with a
screw cap and stirred at room temperature for 24 h. Upon completion,
the reaction mixture was transferred into a separatory funnel con-
taining saturated NaHCO3 solution (20 mL). The aqueous phase was
extracted with EtOAc (3 × 3 mL) and the combined organic layers
were dried over MgSO4, filtered and carefully concentrated in vacuo.
The reaction afforded 2-cyclohexylnaphthoquinone (364 mg, 75%
yield) as a yellow solid separated by silica gel chromatography (5%
EtOAc in hexanes). The data matches those previously reported.15
General procedure B was employed using 1,4-benzoquinone (22 mg,
0.2 mmol) and benzoic acid (54 mg, 0.4 mmol). The reaction afforded
13 (12.3 mg, 31%) as a yellow solid separated by silica gel chromatog-
raphy (10% EtOAc in hexanes).
13-Bis-C2,C3
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 4H), 7.29–7.22 (m, 4H),
7.13–7.10 (m, 2H),6.78 (s, 2H), 3.93 (s, 4H)
13C NMR (100 MHz, CDCl3), mixture of all three isomers: δ = 188.0,
187.8, 187.7, 187.3, 148.9, 148.7, 143.9, 137.8, 136.7, 136.6, 136.5,
133.5, 133.3, 129.5, 128.98, 128.97, 128.8, 128.7, 127.13, 127.11,
126.7, 35.6, 35.0, 32.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

I
A. Hamsath et al.
Special Topic
Synthesis
1a,7a-dihydronaphtho[2,3-b]oxirene-2,7-dione
Rogers, M.; Sattler, F. N. Engl. J. Med. 1993, 328, 1521.
(b) Muragur, G. R.; Kiara, H. K.; McHardy, N. Vet. Parasitol. 1999,
87, 25. (c) Shearer, M. J.; Newman, P. Thromb. Haemost. 2008,
100, 530.
EtOH (3.8 mL) was added to a vial containing 2-cyclohexylnaphtho-
quinone (364 mg, 1.5 mmol) and the vial was heated at 80 °C until all
the solid had dissolved. Next, 30% H2O2 (600 μL) and Na2CO3 (950 μL
of a 1.1 M solution in H2O, 1.0 mmol) was added in one portion and
the resulting pink reaction mixture was stirred for 1 h. Upon comple-
tion, the resulting white solution was added to a test tube containing
H2O (3 mL). The aqueous phase was extracted with Et2O (3 × 3 mL)
and the combined organic layers were dried over MgSO4, filtered and
carefully concentrated in vacuo. The reaction afforded 2-cyclohexyl-
(2,3)-oxirane-1,4-naphthoquinone (361 mg, 93% yield) as a pale yel-
low oil. The data matches those previously reported.15
(4) (a) Khader, M.; Eckl, P. M. Iran J. Basic Med. Sci. 2014, 17, 950.
(b) Breyer, S.; Effenberger, K.; Schobert, R. ChemMedChem 2009,
4, 761.
(5) Nasiri, H. R.; Madej, M. G.; Panisch, R.; Lafontaine, M.; Bats, J.
W.; Lancaster, C. R. D.; Schwalbe, H. J. Med. Chem. 2013, 56,
9530.
(6) (a) Ge, B.; Wang, D.; Dong, W.; Ma, P.; Li, Y.; Ding, Y. Tetrahedron
Lett. 2014, 55, 5443. (b) Yu, X.; Wan, H.; Xu, Z.; Xu, X.; Wang, D.
RSC Adv. 2016, 6, 62298. (c) Wang, D.; Ge, B.; Li, L.; Shan, J.;
Ding, Y. J. Org. Chem. 2014, 79, 8607. (d) Walker, S. E.; Jordan-
Hore, J. A.; Johnson, D. G.; Macgregor, S. A.; Lee, A.-L. Angew.
Chem. Int. Ed. 2014, 53, 13876. (e) Gan, X.; Jiang, W.; Wang, W.;
Hu, L. Org. Lett. 2009, 11, 589. (f) Echavarren, A. M.; de Frutos,
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Parvaquone
Concentrated H2SO4 (2.5 mL) was added to a vial containing 2-cyclo-
hexyl-(2,3)-oxirane-1,4-naphthoquinone (361 mg, 1.4 mmol). The re-
sulting blood-red solution was then stirred in an ice bath for 1 h.
Upon completion, the reaction was transferred to a separatory funnel.
A solution of NaOH (4 M) was added until the pH tested approximate-
ly 7. The reaction mixture was then extracted multiple times with
Et2O. The combined organic layers were dried over MgSO4, filtered
and carefully concentrated in vacuo. The reaction afforded parva-
quone (220 mg, 57%) as a yellow solid separated by silica gel chroma-
tography (10% Et2O in hexanes). The data matches those previously
reported.15
Funding Information
(8) Gutiérrez-Bonet, Á.; Remeur, C.; Matsui, J. K.; Molander, G. A.
J. Am. Chem. Soc. 2017, 139, 12251.
(9) Mai, D. N.; Baxter, R. D. Org. Lett. 2016, 18, 3738.
(10) (a) Hua, A. M.; Mai, D. N.; Martinez, R.; Baxter, R. D. Org. Lett.
2017, 19, 2949. (b) Galloway, J. D.; Mai, D. N.; Baxter, R. D. Org.
Lett. 2017, 19, 5772.
We gratefully acknowledge the University of California, Merced for
funding. R.D.B acknowledges funding from the University of Califor-
nia, Merced MACES Center, NASA parent.
)(
(11) Schonberg, A.; Moubacher, R. Chem. Rev. 1952, 50, 261.
(12) (a) Minisci, F.; Citterio, A.; Giordano, C. Acc. Chem. Res. 1983, 16,
27. (b) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed.
2013, 52, 8214.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610005.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(13) Baxter, R. D.; Liang, Y.; Hong, X.; Brown, T. A.; Zare, R. N.; Houk,
K. N.; Baran, P. S.; Blackmond, D. G. ACS Cent. Sci. 2015, 1, 456.
(14) Radical formation is believed to occur via a hydrogen-atom
abstraction/decarbonylation sequence rather than an oxida-
tion/decarboxylation sequence. Evidence for this mechanism is
provided via the presence of acylated products from aldehydes
in reference 9 above.
(15) Patil, C. P.; Akamanchi, G. K. RSC Adv. 2014, 4, 58214.
(16) Murahashi, S.-I.; Miyaguchi, N.; Noda, S.; Naota, T.; Fujii, A.;
Inubushi, Y.; Komiya, N. Eur. J. Org. Chem. 2011, 5355.
(17) Yue, Y.; Novianti, M. L.; Tessensohn, M. E.; Hirao, H.; Webster, R.
D. Org. Biomol. Chem. 2015, 13, 11732.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I