Progress towards metal-free radical alkylations of quinones under mild conditions

Article abstract of DOI:10.1016/j.tet.2019.130665

A new method for the radical alkylation of quinones is reported. Lewis basic nitrogen additives increase the efficacy of quinone alkylations from carboxylic acids using catalytic AgNO₃ and Selectfluor as a mild oxidant. Electrochemical data sug

Full text of DOI:10.1016/j.tet.2019.130665

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Progress towards metal-free radical alkylations of quinones under mild conditions
Jordan D. Galloway, Ryan D. Baxter
PII:
S0040-4020(19)31034-8
https://doi.org/10.1016/j.tet.2019.130665
TET 130665
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 February 2019
Revised Date: 25 September 2019
Accepted Date: 30 September 2019
Please cite this article as: Galloway JD, Baxter RD, Progress towards metal-free radical alkylations of
quinones under mild conditions, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130665.
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Progress towards metal-free radical
alkylations of quinones under mild
conditions
Leave this area blank for abstract info.
Jordan D. Galloway and Ryan D. Baxter
5200 N. Lake Road, Merced, CA 95343

1
Tetrahedron
journal homepage: www.elsevier.com
Progress towards metal-free radical alkylations of quinones under mild conditions.
Jordan D. Galloway, Ryan D. Baxter ∗
Department of Chemistry & Chemical Biology, University of California, Merced, 5200 N. Lake Road, Merced, CA, 95343, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
A new method for the radical alkylation of quinones is reported. Lewis basic nitrogen additives
increase the efficacy of quinone alkylations from carboxylic acids using catalytic AgNO and
3
Received in revised form
Accepted
Available online
Selectfluor as a mild oxidant. Electrochemical data suggests that certain Lewis basic additives
are capable of directly reducing Selectfluor through a single-electron transfer, presumably via a
charge-transfer complex. This process yields intermediates capable of promoting oxidative
decarboxylation of alkyl carboxylic acids without an added metal initiator. Using this strategy,
we have demonstrated progress towards a metal-free C–H quinone alkylation reaction that
proceeds at room temperature under mild conditions.
Keywords:
radical
quinones
alkylation
metal-free
2
019 Elsevier Ltd. All rights reserved.
∗
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

A) Original Minisci Reaction Conditions
CN
CN
N
CN
N
1
0-20 mol% AgNO
3
O
+
+
(NH
4
)S
2
O
8
+
H
2
SO
4
/ H
2
O (2.0 M)
o
HO
R
2
R
70 - 90 C
N
R
R
1
. Introduction
B) Notable Developments for Improved Minisci-Type Reactions
In the past decade, significant progress has been made in the
development of synthetic methods that combine nucleophilic
radicals with unsaturated π-electrophiles. Renewed interest in
established chemically-initiated methods, such as the Minisci
O
R–B(OR)
(aryl radical precursors)
2
, R = aryl
O
H
or
H
R
or
R
Cl
reaction, have led to improvements in scope, efficiency, and
N
N
N
Ag(I) catalyst,
1
N
F
O
O
operational simplicity (Scheme 1A).
One significant
advancement in this area has been the use of boronic acids and
esters as radical precursors, enabling the generation of aryl
radicals from widely available materials. The ‘Borono-Minisci’
reaction was shown to be effective for nucleophilic arylation of
both electron-deficient heterocycles and several 1,4 quinones,
although alkylation from alkylboronic acids was generally less
(milder oxidant)
C) Metal-Free Conditions for Quinone Alkylation (This Work)
O
O
O
metal free
O
2 equiv. Selectfluor
+
+
N
2
H
HO
R
effective (Scheme 1B). Our own recent work in this area has
DCE / H
2
O (1:1, 0.1M)
R
rt, up to 24hrs
focused on identifying alternative oxidants to promote oxidative
decarboxylation or deborylation for heterocycle and quinone
O
Hünig’s Base
AgNO alone (black curve), AgNO with glycine added (red curve).
3
3
3
o
functionalization. We found that Selectfluor (E = -0.04 V)
Right: AgNO alone (black curve), AgNO with pyridine added (red
3
3
served as a suitable replacement for the traditionally used
o
curve). E values are determined as the minimum voltage producing
100 µA of current in the oxidizing direction (left-to-right).
2-
o
inorganic persulfate oxidants (S O , E = 2.01 V), although
2
8
diminished reactivity generally accompanied the milder reaction
4
Because the Ag(I)/Ag(II) couple is implicated in radical
decarboxylation and deborylation, we used the electrochemical
information above to guide our development of a Minisci
conditions. In spite of these improvements, little progress has
been made in reducing or eliminating the requirement of metal
5
initiators while maintaining mild reaction conditions. In the
3
reaction that uses Selectfluor as a mild oxidant. We believed the
interest of modernizing all aspects of Minisci-type reactions, we
sought to develop a metal-free variant that utilizes a mild oxidant
under ambient conditions. Progress towards this goal has been
achieved by promoting single-electron reduction of Selectfluor
using Hunig’s base, presumably via a charge-transfer complex
presence of a heterocyclic substrate would be sufficient to
promote Ag(I) oxidation, as even electron-deficient heteroarenes
yielded Ag(I) species with lower oxidation potentials than
AgNO3 alone (vide infra). During the development of that
previous work, we were surprised to discover that quinone
alkylation and arylation was also possible with Selectfluor in the
absence of any suitable heterocyclic ligands for Ag(I).
Reasonable yields were observed for quinone alkylation using
Selectfluor as an oxidant, although subsequent work from our
group showed that Minisci conditions using persulfate oxidants
were generally superior for alkylations from carboxylic acids,
except for select cases where undesired bis-alkylation was
(Scheme 1C).
Scheme 1. Historical development of Minisci-type reactions.
2
. Results and Discussion
Our interest in metal-free Minisci-type processes resulted from
mechanistic findings that bridged several distinct projects in our
H
2
N
2
CO H
4
b
Cl
or
observed (Scheme 3).
N
Cl
Ag(I)
+
Ag(II)
+
N
+
F–
N
N
Eo = 1.71 V
Scheme 3. Comparison of (NH ) S O and Selectfluor as oxidants.
F
4 2
2
8
N
Select examples from Synthesis, 2018;50:2915–2923. General
reaction conditions: quinone (0.2 mmol), carboxylic acid (0.4 mmol),
oxidant (0.4 mmol), AgNO (0.04 mmol) in 2 ml of DCE/H O (1:1)
0
0
0
0
.004
.003
.002
.001
0
AgNO3 with glycine
Eo = 1.58 V
0.004
AgNO3 with pyridine
Eo = 1.31 V
3
2
0.003
0.002
0.001
0
at room temperature for up to 24 hours. Isolated yields of
chromatographically pure materials are shown. Method ‘A’ oxidant
is (NH ) S O . Method ‘B’ oxidant is Selectfluor.
4
2
2
8
1
.20
1.80
2.40
3.00
1.20
1.80
2.40
3.00
Several methods for quinone functionalization are available;
E (volts vs. Pt)
E (volts vs. Pt)
7
including palladium-catalyzed couplings , alkylation/oxidation of
8
research group. Through our work on radical fluorination we had
shown that Selectfluor was capable of promoting Ag(I) to Ag(II)
oxidation (E = 1.71 V) when unprotected amino acids, such as
glycine, served as electron-donating ligands for Ag(I). This
effect could be reproduced with various pyridines, which altered
the oxidation potential of Ag(I) to an even greater extent
hydroquinones and phenols , and direct radical functionalizations
9
10
from allylic alcohols , organotellurium reagents , and
o
11
diaryliodonium salts. To further complement these established
6
quinone functionalization methods, we sought to improve the
efficacy of our Selectfluor-mediated protocol while maintaining
mild reaction conditions. Because we observed enhanced
reactivity using pyridine additives in the context of Ag(I)-
initiated radical fluorination, we wondered whether a similar
strategy would improve the moderate yields observed for quinone
(
Scheme 2).
Scheme 2. Ligand-dependent oxidation potentials for Ag(I).
Electrochemical experimental conditions: AgNO (0.4 mmol) in 5
mL CH CN, tetrabutylammonium tetrafluoroborate supporting
electrolyte (0.1 M), additive, where applicable, (0.4 mmol). Left:
3
0
0
0
.004
.003
.002
0.004
0.003
0.002
0.001
o
o
3
E
= 1.31, 1.34 V
E
= 1.60 V
(R = H, OCH
3
)
(R = CF
3
)
O
O
O
O
O
O
O
0.001
O
O
2
0 mol % AgNO
3
R
20 mol % AgNO
equiv. Selectfluor
1.20 1.80
3
H
+
R–CO
2
H
R
+
R
R
O
0
H
20
4 2 2 8
A = (NH ) S O
+
1.20
+
2.40
B = Selectfluor
H
1
O
.80
3.00
2.40
3.00
DCE / H O (1:1, 0.1M)
2
E (volts vs. Pt)
E (volts vs. Pt)
1
–4
N
rt, up to 24hrs
O
0
.004
0.004
0.003
1
F
F
Eo = 1.65 V
Eo = 1.63 V
(no reaction)
O
O
O
F
F
F
NC
F
O
O
0.003
CO
(
no reaction)
H
3
N
H
F
3
C
N
CN
0
.002
0.002
F
N
F
N
N
F
N
0
.001
0.001
O
O
F
F
30% yield of 1
33% yield of 1
57% yield of 1
66% yield of 1
O
O
0
0
1
2
3
4
1
.20
1.80
2.40 pyri
3
d
.
i
0
n
0
e additive1.20
1.80
electron-poor
2.40 3.00
electron-rich
A = 29% (51% bis)
B = 54%
A = 46% (26% bis)
B = 47%
A = 38% (17% bis)
B = 21%
A = 73%
B = 45%
poor conversionE (volts vs. Pt)
E (volts vs. Pt)
high conversion

3
1
alkylation. We began by exploring a small series of electronically
diverse pyridines for the reaction of 1,4-benzoquinone with
up to 24 hours. Yields determined by H NMR using 1,3,5-
trimethoxybenzene as a standard. Yields in parenthesis are for
reactions run without 4-cyanopyridine as an additive.
isobutyric acid, catalytic AgNO , and 2.0 equivalents of
3
Selectfluor as the oxidant. As shown in Scheme 4, an unexpected
trend in reaction efficiency was observed. Although cyclic
voltammetry suggests that electron-rich pyridines form Ag(I)
species that are most easily oxidized, electron-poor pyridines are
the most effective additives for enhancing reaction conversion.
There is a clear limit to this effect that can be visually
With optimized conditions in hand, we explored a brief scope
of carboxylic acids that would alkylate 1,4-benzoquinone using
one equivalent of 4-cyanopyridine as an additive. In all cases
examined, significant improvement was observed compared to
running the reaction without 4-cyanopyridine. We were pleased
to note that the efficiency of these reactions is similar to
alkylation via standard Minisci conditions, suggesting we had
improved the reactivity of the Selectfluor-mediated oxidation
while maintaining mild reaction conditions. These results are
especially intriguing considering that 4-cyanopyridine itself is a
suitable electrophile for the isopropyl radical (albeit typically as
demonstrated by cyclic voltammetry.
Very electron-poor
pyridines, such as pentafluoropyridine or tetrafluoro-4-
pyridinecarbonitrile, are not Lewis basic enough to sufficiently
bind Ag(I), producing a Ag(I)/Ag(II) waveform that is nearly
identical to AgNO alone.
3
12
Scheme 4. Pyridine additives in quinone alkylation. General reaction
conditions: quinone (0.2 mmol), carboxylic acid (0.4 mmol),
the protonated pyridinium) , demonstrating that 1,4-
benzoquinone is far more electrophilic under the given reaction
conditions.
Selectfluor (0.4 mmol), pyridine additive (0.2 mmol), AgNO (0.04
3
mmol), in 2 ml of DCE/H O (1:1) at room temperature for up to 24
2
1
The use of 4-cyanopyridine was advantageous for several
alkylations of 1,4-benzoquinone, but becomes problematic when
moving to less reactive quinone substrates. As stated above,
electron-poor pyridines are good substrates for radical alkylation
via Minisic-type reactions, resulting in an unintended
competition between pyridine and quinone alkylation. This
unwanted side-reaction was observed when examining 4-
cyanopyridine as an additive for the alkylation of 1,4-
naphthoquinone using isobutyric acid (Scheme 7). Significant
conversion to alkylated pyridine 7 was observed, eliminating the
additive effect for the desired quinone alkylation. It was clear we
needed to explore Lewis basic additives that were capable of
enhancing the reactivity of the Ag(I)/Selectfluor system without
participating as an electrophilic radical quencher. A small screen
hours. Yields determined by
H
NMR using 1,3,5-
trimethoxybenzene as a standard. Electrochemical experimental
conditions: AgNO3 (0.4 mmol) in mL CH CN,
5
3
tetrabutylammonium tetrafluoroborate supporting electrolyte (0.1
M), additive, where applicable, (0.4 mmol). Top Left: AgNO alone
3
(
black curve), AgNO with pyridine added (maroon curve), AgNO
3
3
with 4-methoxypyridine added (red curve). Top Right: AgNO alone
3
(black curve), AgNO3 with 4-trifluoromethylpyridine added (red
curve). Bottom Left: AgNO3 alone (black curve), AgNO3 with
pentafluoropyridine added (red curve). Bottom Right: AgNO alone
3
(
black curve), AgNO3 with 4-cyanoperfluoropyridine added (red
o
curve). E values are determined as the minimum voltage producing
00 µA of current in the oxidizing direction (left-to-right).
1
O
CN
O
With pyridines having a clear effect on the efficiency of 1,4-
benzoquinone alkylation, we sought to optimize solvent
conditions to maximize the additive effect and further improve
reaction conversion. Scheme 5 shows that the additive effect was
not universal across solvents examined (yield without 4-
cyanopyridine is shown in parenthesis). We were intrigued to
find that alkylation was not effective in polar solvents that were
miscible with water, although these conditions were suitable for
radical fluorination (entries 2-3, 10, 12). Heterogeneous solvent
conditions gave the highest conversion, although a clear trend
20 mol % AgNO3
O
2
equiv. Selectfluor
H
+
+
HO
R
Solvent / H2O (1:1, 0.1M)
rt, up to 24hrs
N
R
O
O
2
equiv.
1 equiv.
O
O
O
O
O
O
O
1
2
3
23% (21%)
6
6% (54%)
68% (47%)
O
O
O
O
O
O
CN
20 mol % AgNO
equiv. Selectfluor
3
O
2
H
+
+
HO
2
Solvent / H
2
O (1:1, 0.1M)
N
rt, up to 24hrs
O
O
F
F
equiv.
1 equiv.
1
4
5
entry
deviation from standard conditions
yield of 1
6
5% (45%)
51% (48%)
1
2
3
4
5
6
7
8
9
dichloroethane
acetone
acetonitrile
66% (54%)
17% (25%)
3% (3%)
of such additives is shown in Scheme 8.
benzene
52% (41%)
14% (43%)
12% (43%)
22% (57%)
4% (40%)
4% (37%)
0% (12%)
15% (23%)
0% (4%)
perfluorobenzene
trifluorotoluene
1,2-dichlorobenzene
n-hexane
perfluorohexane
isopropanol
Scheme 6. Scope of radicals highlighting additive effect. General
reaction conditions: quinone (0.2 mmol), carboxylic acid (0.4 mmol),
Selectfluor (0.4 mmol), 4-cyanopyridine (0.2 mmol), AgNO (0.04
3
mmol), in 2 ml of DCE/H O (1:1) at room temperature for up to 24
2
1
0
hours. Isolated yields of chromatographically pure material are
shown. Yields in parenthesis are for reactions run without 4-
cyanopyridine as an additive.
1
1
hexafluoroisopropanol
ethanol
1
1
1
2
3
4
trifluoroethanol
1,4-dioxane
15% (2%)
10% (8%)
Scheme 7. Additive effect with 1,4-naphthoquinone. General
reaction conditions: 1,4-napthoquinone (0.2 mmol), carboxylic acid
(0.4 mmol), Selectfluor (0.4 mmol), 4-cyanopyridine (0.2 mmol),
AgNO (0.04 mmol), in 2 ml of DCE/H O (1:1) at room temperature
for up to 24 hours. Yields determined by H NMR using 1,3,5-
trimethoxybenzene as a standard.
regarding solvent properties was not obvious.
Scheme 5. Solvent screen for quinone alkylation. General reaction
conditions: quinone (0.2 mmol), carboxylic acid (0.4 mmol),
Selectfluor (0.4 mmol), 4-cyanopyridine (0.2 mmol), AgNO (0.04
3
2
1
3
mmol), in 2 ml of organic solvent/H O (1:1) at room temperature for
2
O
O
20 mol % AgNO
2 equiv. Selectfluor
3
O
CN
O
+
+
HO
2
2
DCE / H O (1:1, 0.1M)
rt, up to 24hrs
1 equiv. 4-cyanopyridine
N
O
equiv.
6
7
40%
40%

4
Many of the Lewis basic additives screened had either no
effect or were deleterious to reaction conversion compared to the
Figure 1. Cyclic voltammetry of Hünig’s base. Electrochemical
experimental conditions: AgNO , where applicable, (0.4 mmol) in 5
3
O
O
O
O
2
0 mol % AgNO
3
metal free
O
O
2
equiv. Selectfluor
2 equiv. Selectfluor
H
+
+
additive
H
+
+
N
HO
HO
2
DCE / H
2
O (1:1, 0.1M)
DCE / H
2
O (1:1, 0.1M)
rt, up to 24hrs
rt, up to 24hrs
O
O
O
O
equiv.
1.0 equiv.
2
equiv.
1 equiv.
1
1
entry
deviation from standard conditions
yield of 1
additive
CN
1
2
3
4
5
none
n-hexane
18%
11%
38%
13%
5%
H
N
NH
2
NH
2
dichloroethane, 5.0 equiv Hünig’s base
acetone, no water
N
no additive
4
7%
23%
56%
6
6%
54%
acetonitrile, no water
mL CH CN, tetrabutylammonium tetrafluoroborate supporting
N
3
N
N
N
electrolyte (0.1 M), Hünig’s base, where applicable, (0.4 mmol).
Left: AgNO alone (black curve), AgNO with Hünig’s base added
N
3
3
0
%
37%
33%
71%
(red curve). Right: AgNO alone (black curve), Hünig’s base alone
(red curve). E values are determined as the minimum voltage
3
o
standard reaction with no additive. From our screen, Hünig’s
base (N,N-diisopropylethylamine) was the only additive with
activity surpassing that of 4-cyanopyridine. This was an
especially promising lead due to its low cost and status as a
common reagent in many organic laboratories. In addition,
Hünig’s base is not expected to electrophilically sequester
radicals intended for quinone alkylation, theoretically enhancing
reaction efficiency for substrates less electrophilic than 1,4-
benzoquinone. At this point we became interested in exploring
the scope of carboxylic acids and quinones that would efficiently
react in the presence of Hünig’s base but were troubled by an
oddity observed when monitoring the time course of a standard
experiment. Our typical experimental procedure for kinetic
analysis involved removing an aliquot of the reaction medium
prior to adding the Ag(I) initiator to get an accurate analytical
measurement of initial concentrations. This ‘time-zero’ data point
consistently displayed a notable amount of product in the
reaction mixture prior to the addition of any metal initiator. To
us, this suggested that a radical process is initiated via electron-
transfer between two organic species present within the reaction
medium.
producing 100 µA of current in the oxidizing direction (left-to-right).
Based on these results we sought to optimize metal-free
alkylations of quinones using Hünig’s base as a single-electron
reductant for Selectfluor. As shown in Scheme 9, dichloroethane
is the optimum co-solvent when using Hünig’s base, although
only moderate yields can be achieved with just one equivalent of
the additive (entry 1). Increasing the equivalents of Hünig’s base
led to higher conversion, suggesting that the protocol may be
amenable to further optimizations. New stir bars and disposable
glassware were used to minimize the possibility of trace metal
contaminants initiating the radical reaction. No desired product is
observed in the absence of Hünig’s base, and trace metal analysis
of this reagent suggests the reaction is occurring without metal-
initiators (see Supporting Information for details). Although this
work is in its early stages, these preliminary results show promise
for developing a general strategy for Minisci-type reactions that
do not rely on metal initiators. A brief screen of quinones and
carboxylic acids showed that modest conversion to the alkylated
quinone could be achieved for a variety of structures (Scheme
1
0).
Scheme 8. Amine additive screen. General reaction conditions:
quinone (0.2 mmol), carboxylic acid (0.4 mmol), Selectfluor (0.4
Scheme 9. Metal-free radical addition to 1,4-benzoquinone. General
reaction conditions: quinone (0.2 mmol), carboxylic acid (0.4 mmol),
Selectfluor (0.4 mmol), Hünig’s base (0.2 – 1.0 mmol), in 2 ml of
mmol), nitrogen-additive (0.2 mmol), AgNO (0.04 mmol), in 2 ml
3
of DCE/H O (1:1) at room temperature for up to 24 hours. Yields
2
organic solvent/H O (1:1) at room temperature for up to 24 hours.
1
2
determined by H NMR using 1,3,5-trimethoxybenzene as a
1
Yields determined by H NMR using 1,3,5-trimethoxybenzene as a
standard.
standard.
We have recently reported spectroscopic evidence fo+r
Scheme 10. Metal-free radical addition to 1,4-benzoquinone.
General reaction conditions: quinone (0.2 mmol), carboxylic acid
interactions between pyridines and Selectfluor via an [N–F–N]
13
halogen bonding motif. In addition, a report by Van Humbeck
proposed a single-electron transfer event between electron-rich
(
0.4 mmol), Selectfluor (0.4 mmol), Hünig’s base (1.0 mmol), in 2
ml of DCE/H O (1:1) at room temperature for up to 24 hours.
Isolated yields of chromatographically pure material are shown.
14
2
pyridines and Selectfluor via a charge-transfer intermediate. An
analogous electron-transfer between Hünig’s base and Selectfluor
seemed reasonable based on the precedence of using
trialkylamines as reductive quenchers in photocatalysis due to
2
+
II*/I
their favorable redox potentials compared to Ru(bpy) (E1/2
3
15
O
O
O
metal free
=
0.77 V vs SCE). Electrochemical analysis confirmed that
O
2
equiv. Selectfluor
Hünig’s base possessed an onset oxidation potential lower than
H
+
+
N
HO
R
DCE / H
2
O (1:1, 0.1M)
R
rt, up to 24hrs
O
0
0
0
0
.004
.003
.002
.001
0
0.004
0.003
0.002
0.001
0
2.0 equiv.
5.0 equiv.
Hünig's Base with AgNO
Eo = 0.50, 1.87 V
3
Hünig's Base Alone
Eo = 0.87 V
O
O
O
O
O
0
.50 1.10 1.70 2.30 2.90
E (volts vs. Pt)
0.50 1.00 1.50 2.00 2.50 3.00
E (volts vs. Pt)
O
O
1
2
3
38%
36%
24%
that of AgNO (Figure 1).
3
O
O
O
O
Cl
*
*
F
F
O
O
4
5
8
20%
35%
32%
(1.1:1:1)

5
3
. Conclusions
H O, 0.04 mmol) was added in one portion.The reaction was
2
capped with a screw cap and stirred at room temperature for 24
hours. Upon completion, the reaction was transferred to a test
tube containing saturated sodium bicarbonate (2 mL). The
aqueous phase was extracted with ethyl acetate (3 x 3 mL) and
In summary, we have described progress towards the
development of metal-free radical additions to quinones under
mild conditions. We have demonstrated that Lewis basic
additives affect the Ag(I)/Ag(II) redox couple that is common to
many reactions relying on radical decarboxylation, allowing for
mild oxidants to promote this transformation. Through the course
of this work we have identified Hünig’s base as an optimum
additive to facilitate Ag(I)/Ag(II) mediated decarboxylation with
Selectfluor due to its low cost, commonplace presence in most
laboratories, and resistance to unwanted side reactions. In
addition, we found that an unexpected single-electron transfer
event between Hünig’s base and Selectfluor promotes oxidative
decarboxylation without a metal initiator. Future work will
involve further optimization of the metal-free protocol, including
examination of the scope of radical precursors and quinone
substrates that will participate in the reaction.
the combined organic layers were dried over MgSO , filtered and
4
carefully concentrated in vacuo.
2-isopropylcyclohexa-2,5-diene-1,4-dione (1): The general
procedure was followed using 1,4-benzoquinone (22 mg, 0.2
mmol) and isobutyric acid (37 µL, 0.4 mmol, 2 equiv). The
reaction afforded 1 (19.8 mg, 66% yield) as a yellow oil. The
3
1
data for 1 matches those previously reported. H NMR (400
MHz, CDCl ) 6.75 (d, J = 10.1 Hz, 1H), 6.69 (dd, J = 10.1, 2.3
Hz, 1H), 6.53 (s, 1H), 3.03 (dt, J = 13.7, 6.8 Hz, 1H), 1.13 (d, J =
.9 Hz, 6H).
3
6
[1,1'-bi(cyclohexane)]-3,6-diene-2,5-dione (2): The general
procedure was followed using 1,4-benzoquinone (22 mg, 0.2
mmol) and cyclohexanoic acid (51 mg, 0.4 mmol, 2 equiv). The
reaction afforded 2 (25.8 mg, 68% yield) as a pale yellow oil.
4
. Experimental section
3
1
Reagents and solvents were purchased at the highest
The data for 2 matches those previously reported. H NMR (400
commercial quality and used without purification. NMR Yields
were calculated by selecting proton peaks from products that
were previously isolated. 1,3,5–trimethoxybenzene was used as
the NMR standard. The yields describe the result of a single
experiment. Reactions were monitored by NMR spectra which
were recorded on a Varian-INOVA 400 MHz or 500 MHz
spectrometer and calibrated using residual undeuterated solvent
MHz, CDCl ): 6.74 (d, J = 10.1 Hz, 1H), 6.69 (dd, J = 10.1, 2.4
Hz, 1H), 6.50 (dd, J = 2.4, 1.1 Hz, 1H), 2.74 – 2.62 (m, 1H), 1.88
– 1.69 (m, 5H), 1.47 – 1.31 (m, 2H), 1.27 – 1.09 (m, 3H).
3
2
-(tetrahydro-2H-pyran-4-yl)cyclohexa-2,5-diene-1,4-dione
(3): The general procedure was followed using 1,4-benzoquinone
(22 mg, 0.2 mmol) and tetrahydropyran4-yl-carboxylic acid (52
1
13
mg, 0.4 mmol, 2 equiv). The reaction afforded 3 (8.8 mg, 23%
yield) as a yellow solid (m.p. 95 – 98 °C). The data for 3 matches
as an internal reference (CDCl – H NMR 7.26 ppm, C NMR
3
7
7.16 ppm). The following abbreviations were used to explain
4b 1
those previously reported. H NMR (400 MHz, CDCl ): 6.77
3
multiplicities (s – singlet, d – doublet, t – triplet, q – quartet, m –
multiplet). GCMS data was obtained using an Agilent
Technologies 5975 Series MSD GCMS with tert-butylbenzene as
the standard.
(
=
1
(
d, J = 10.1 Hz, 1H), 6.73 (dd, J = 10.1, 2.3 Hz, 1H), 6.52 (dd, J
2.3, 1.2 Hz, 1H), 4.05 (dd, J = 11.6, 4.4 Hz, 2H), 3.53 (td, J =
1.8, 2.1 Hz, 2H), 3.01–2.90 (m, 1H), 1.72–1.64 (m, 2H), 1.56
ddd, J = 25.1, 12.5, 4.4 Hz, 2H).
4
.1 General electrochemical conditions
4
',4'-difluoro-[1,1'-bi(cyclohexane)]-3,6-diene-2,5-dione (4):
AgNO3 (0.4 mmol) in 5 mL CH CN, tetrabutylammonium
hexafluorophosphate supporting electrolyte (0.1 M), glycine (0.4
The general procedure was followed using 1,4-benzoquinone (22
mg, 0.2 mmol) and 4,4-difluorocyclohexanecarboxylic acid (66
mg, 0.4 mmol, 2 equiv). The reaction afforded 4 (29.4 mg, 65%
yield) as a yellow solid. The data for 4 matches those previously
3
mmol) or pyridine (0.4 mmol) where appropriate. AgNO alone
3
o
is given as the black curve in Scheme 2 for reference (E = 1.71
o
3 1
V) E values are determined as the minimum voltage producing
reported. H NMR (400 MHz, CDCl ): 6.78 (d, J = 10.1 Hz,
3
1
00 uA of current in the oxidizing direction.
1H), 6.73 (dd, J = 10.1, 2.4 Hz, 1H), 6.55 (dd, J = 2.2, 1.0 Hz,
1
2
H), 2.79 (t, J = 12.5 Hz, 1H), 2.20 (ddd, J = 14.9, 5.6, 2.9 Hz,
H), 1.97 – 1.76 (m, 4H), 1.63 – 1.48 (m, 2H).
4
.2 General procedure for the functionalization of 1,4-
benzoquinone with Selectfluor as the oxidant with pyridine
additives shown in Scheme 4
2-cyclobutylcyclohexa-2,5-diene-1,4-dione (5): The general
procedure was followed using 1,4-benzoquinone (22 mg, 0.2
mmol) and cyclobutane carboxylic acid (39 µL, 0.4 mmol, 2
equiv). The reaction afforded 5 (16.5 mg, 51% yield) as a yellow
To a vial containing a stir bar was added 1,4-benzoquinone (22
mg, 0.2 mmol), isobutyric acid (37 µL, 0.4 mmol, 2 equiv),
pyridine additive (0.2 mmol), and Selectfluor (142 mg, 0.4 mmol,
3 1
oil. The data for 5 matches those previously reported. H NMR
2
equiv). Dichloroethane (1 mL) and H O (0.9 mL) were then
2
(400 MHz, CDCl ): 6.70 (s, 2H), 6.54 (s, 1H), 3.51 (t, J = 8.3 Hz,
3
added and stirred for approximately 1 minute at room
temperature. A solution of AgNO (0.1 mL of a 0.4M solution in
H O, 0.04 mmol) was added in one portion. The reaction was
1
1
H), 2.33 – 2.23 (m, 2H), 2.12 – 1.93 (m, 3H), 1.84 (ddd, J =
6.4, 7.4, 4.4 Hz, 1H).
3
2
capped with a screw cap and stirred at room temperature for 24
4.4 General procedure for the functionalization of 1,4-
naphthoquinone with Selectfluor as the oxidant with 4-
cyanopyridine shown in Scheme 7
1
hours.
Yields determined by
H NMR using 1,3,5-
trimethoxybenzene as a standard. (see Supporting Information for
spectra).
To a vial containing a stir bar was added 1,4-naphthoquinone (32
mg, 0.2 mmol), isobutyric acid (37 µL, 0.4 mmol, 2 equiv), 4-
cyanopyridine (21 mg, 0.2 mmol, 1 equiv), and Selectfluor (142
4
.3 General procedure for the functionalization of quinones with
selectfluor as the oxidant with 4-cyanopyridine
mg, 0.4 mmol, 2 equiv). Dichloroethane (1 mL) and H O (0.9
mL) were then added and stirred for approximately 1 minute at
2
To a vial containing a stir bar was added quinone (0.2 mmol, 1
equiv), carboxylic acid (0.4 mmol, 2 equiv), 4-cyanopyridine (21
mg, 0.2 mmol, 1 equiv) and Selectfluor (142 mg, 0.4 mmol, 2
room temperature. A solution of AgNO (0.1 mL of a 0.4 M
3
solution in H O, 0.04 mmol) was added in one portion. The
2
equiv). Dichloroethane (1 mL) and H O (0.9 mL) were then
2
reaction was capped with a screw cap and stirred at room
added and stirred for approximately 1 minute at room
1
temperature for 24 hours. Yields determined by H NMR using
temperature. A solution of AgNO (0.1 mL of a 0.4M solution in
3

6
1
,3,5-trimethoxybenzene as
a
standard (see Supporting
185.0, 179.7, 149.8, 140.3, 137.6, 135.2, 30.0, 19.7. HRMS
+
Information for spectra).
(ESI-TOF): calcd for C H ClO [M+H] 185.0364 found
85.0349. Data for 8-C5: H NMR (500 MHz, CDCl ): 6.97 (s,
1H), 6.66 (d, J = 1.2 Hz, 1H), 3.08 – 2.98 (m, 1H), 1.14 (d, J =
9
9
2
1
1
3
2
-isopropylnaphthalene-1,4-dione (6): Previously reported
3
methods were used to synthesize compound 6. The data for 6
matches those previously reported.
CDCl ): 8.14 – 8.09 (m, 1H), 8.08 – 8.03 (m, J = 6.9, 2.7 Hz,
1
13
4b
1
6.9 Hz, 6H). C NMR (125 MHz, CDC
43.7, 134.2, 130.2, 27.1, 21.5. HRMS (ESI-TOF): calcd for
C H ClO [M+H]+ 185.0364 found 185.0347. Data for 8-C6:
3
): 185.1, 180.3, 155.9,
H NMR (400 MHz,
1
3
9
9
2
H), 7.76 – 7.68 (m, 2H), 6.77 (s, 1H), 3.31 – 3.20 (m, 1H), 1.20
1
H NMR (500 MHz, CDCl ): 6.95 (d, J = 2.5 Hz, 1H), 6.56 (dd, J
2.4, 1.2 Hz, 1H), 3.15 – 3.06 (m, 1H), 1.16 (d, J = 6.9 Hz, 7H).
C NMR (125 MHz, CDC ): 185.7, 179.6, 155.3, 144.6, 133.3,
3
3
(d, J = 6.9 Hz, 6H).
=
13
2
-isopropylisonicotinotrile (7): Previously reported methods
3
were used to synthesize compound 7. The data for 7 matches
those previously reported. H NMR (500 MHz, CDCl ) δ 8.71
130.8, 27.8, 21.6. HRMS (ESI-TOF): calcd for C
[M+H]+ 185.0364 found 185.0347.
H ClO
9 9 2
3
1
3
(
(
d, J = 4.9 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 4.5 Hz, 1H), 3.12
dt, J = 13.8, 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H).
Acknowledgments
4
.5 General procedure for the functionalization of quinones with
JDG gratefully acknowledges an NSF Graduate Research
Fellowship for funding. This material is based upon work
supported by the National Science Foundation under Grant No.
selectfluor as the oxidant metal-free
To a vial containing a stir bar was added quinone (0.2 mmol, 1
equiv), carboxylic acid (0.4 mmol, 2 equiv), hünig’s base (174
1
752821 (RDB).
ꢀ
L, 1.0 mmol, 5 equiv) and Selectfluor (142 mg, 0.4 mmol, 2
equiv) followed by 1 mL of H O and 1 mL of 1,2-dichloroethane.
References
2
The reaction was capped with a screw cap and stirred at room
temperature for 24 hours. Upon completion, the reaction was
transferred to a test tube containing saturated sodium bicarbonate
1
.
For the seminal contribution from Minisci and co-workers, see: (a)
Minisci F, Barnardi R, Bertini F, Galli R, Perchinummo M.
Tetrahedron 1971;27:3575–3579. For subsequent reports by
Minisci, see: (b) Minisci F. Synthesis 1973;1:1–24. (c) Minisci F,
Vismara E, Fontana F. Heterocycles 1989;28:489–519. (d) Minisci
F, Fontana F, Vismara E. J. Heterocycl. Chem. 1990;27:79–96.
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see: (e) Harrowven DC, Sutton BJ. Prog. Heterocycl. Chem.
2005;16:27–53. (f) Duncton MAJ. Med. Chem. Comm.
(2 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.
2
-isopropylcyclohexa-2,5-diene-1,4-dione (1): The general
procedure was followed using 1,4-benzoquinone (22 mg, 0.2
mmol) and isobutyric acid (37 µL, 0.4 mmol, 2 equiv). The
reaction afforded 1 (11.5 mg, 38% yield) as a yellow oil.
2
011;2:1135–1161. (g) Proctor, RSJ, Phipps, RJ. Ang. Chem. Int.
Ed. 2019;10.1002/anie.201900977.
(a) Seiple IB, Su S, Rodriguez RA, Gianatassio R, Fujiwara Y,
Sobel AL, Baran PS. J. Am. Chem. Soc. 2010;132:13194-13196.
2
3
.
.
[1,1'-bi(cyclohexane)]-3,6-diene-2,5-dione (2): The general
(b) Fujiwara Y, Domingo V, Seiple IB, Gianatassio R, Del Bel M,
procedure was followed using 1,4-benzoquinone (22 mg, 0.2
mmol) and cyclohexanoic acid (51 mg, 0.4 mmol, 2 equiv). The
reaction afforded 2 (13.5 mg, 36% yield) as a pale yellow oil.
Baran PS. J. Am. Chem. Soc. 2011;133:3292–3295. (c) Haslam, E.
Shikimic Acid Metabolism and Metabolites, John Wiley & Sons:
New York, 1993.
Galloway JD, Mai DN, Baxter RD. Org. Lett. 2017;19:5772–
2
-(tetrahydro-2H-pyran-4-yl)cyclohexa-2,5-diene-1,4-dione
5
775.
(3): The general procedure was followed using 1,4-benzoquinone
4. (a) Minisci F, Citterio A, Giordano C. Acc. Chem. Res. 1983;16:
27–32 (b) Hamsath A, Galloway JD, Baxter RD. Synthesis,
(22 mg, 0.2 mmol) and tetrahydropyran4-yl-carboxylic acid (52
2
018;50:2915–2923.
mg, 0.4 mmol, 2 equiv). The reaction afforded 3 (9.1 mg, 24%
yield) as a yellow solid (m.p. 95 – 98 °C).
5
.
For select examples of metal-free Minisci-type radical initiations
using strong oxidants, see: (a) Siddaraju Y, Lamani M, Prabhu
KR. J. Org. Chem. 2014;79:3856–3865. (b) Sutherland DR,
Veguillas M, Oates CL, Lee A-L. Org. Lett. 2018;20:6863–6867.
4
',4'-difluoro-[1,1'-bi(cyclohexane)]-3,6-diene-2,5-dione (4):
The general procedure was followed using 1,4-benzoquinone (22
mg, 0.2 mmol) and 4,4-difluorocyclohexanecarboxylic acid (66
mg, 0.4 mmol, 2 equiv). The reaction afforded 4 (9.0 mg, 20%
yield) as a yellow solid.
(c) Matcha K, Antonchick AP. Angew. Chem., Int. Ed.
2
013;52:2082–2086. (d) Zhang X-Y, Weng W-Z, Liang H, Yang
H, Zhang B. Org. Lett. 2018;20:4686-4690. (e) Gutiérrez-Bonet
Á, Remeur C, Matsui JK, Molander GA. J. Am. Chem. Soc.
2
017;139:12251−12258.
2
-cyclobutylcyclohexa-2,5-diene-1,4-dione (5): The general
6. Hua AM, Mai DN, Martinez R, Baxter RD. Org. Lett.
procedure was followed using 1,4-benzoquinone (22 mg, 0.2
mmol) and cyclobutane carboxylic acid (39 µL, 0.4 mmol, 2
equiv). The reaction afforded 5 (11.4 mg, 35% yield) as a yellow
oil. The data for 5 matches those previously reported.
2017;19:2949–2952.
7
.
Select examples of Pd- catalyzed functionalization of quinones.
a) Echavarren AM, de Frutos Ó, Tamayo N, Noheda P, Calle P. J.
(
Org. Chem. 1997;62:4524−4527. (b) Gan X, Jiang W, Wang W,
Hu L, Org. Lett. 2009;11:589−592. (c) Rao MLN, Giri S. RSC
Adv. 2012; 2:12739−12750.
2
-chloro-3-isopropylcyclohexa-2,5-diene-1,4-dione (8-C3), 2-
8
.
Select examples of alkylation/oxidation of phenols and
hydroquinones leading to functionalized quinones. (a) Murahashi
S-I, Miyaguchi N, Noda S, Naota T, Fujii A, Inubushi Y, Komiya
N. Eur. J. Org. Chem. 2011:5355–5365. (b) Miyamura H,
Shiramizu M, Matsubara R, Kobayashi S. Angew. Chem. Int. Ed.
chloro-5-isopropylcyclohexa-2,5-diene-1,4-dione (8-C5), 2-
chloro-6-isopropylcyclohexa-2,5-diene-1,4-dione (8-C6): The
general procedure was followed using 2-Chloro-1,4-
benzoquinone (29 mg, 0.2 mmol) and isobutyric acid (37 µL, 0.4
mmol, 2 equiv). The reaction afforded 8-C3 (4.0 mg, 11% yield)
as a yellow oil, 8-C5 (4.1 mg, 11% yield) as a yellow solid (m.p.
2
008;47:8093–8095.
Han Q, Jiang K, Wei Y, Su W. Asian J. Org. Chem. 2018;7:1385–
389.
9
.
1
4
8 – 51 °C) , and 8-C6 (3.8 mg, 10% yield) as a yellow oil. The
10. Yamago S, Hashidume M, Yoshida J-I. Tetrahedron.
2002;58:6805.
11. Wang D, Ge B, Li L, Shan J, Ding Y. J. Org. Chem.
regioisomeric ratio of C3:C5:C6 was determined to be 1.1:1.0:1.1
by crude H NMR. Data for 8-C3: H NMR (400 MHz, CDCl ):
6
1
1
3
2
014;79:8607.
.84 (d, J = 10.0 Hz, 1H), 6.74 (d, J = 10.0 Hz, 1H), 3.53 – 3.37
1
2. O'Hara F, Blackmond DG, Baran PS. J. Am. Chem. Soc.
13
(m, 1H), 1.31 (d, J = 7.1 Hz, 6H). C NMR (100 MHz, CDC3):
2013;135:12122–12134.

7
1
1
3. Hua AM, Bidwell SL, Baker SI, Hratchian HP, Baxter RD. ACS
Catal. 2019;9:3322–3326.
4. Danahy KE, Cooper JC, Van Humbeck JF. Angew. Chem. Int. Ed.
2
018;57:5134–5138.
1
1
5. Kalyanasundaram K. Coord Chem Rev. 1982;46:159–244
6. Complete spectral data for compound 1-4 and 6 are provided in
the Supporting Information of reference 4b. Complete spectral
data for compounds 5 and 7 are provided in the Supporting
Information for reference 3.