Computational and Experimental Studies of Phthaloyl Peroxide-Mediated Hydroxylation of Arenes Yield a More Reactive Derivative, 4,5-Dichlorophthaloyl Peroxide

Article abstract of DOI:10.1021/acs.joc.5b01079

The oxidation of arenes by the reagent phthaloyl peroxide provides a new method for the synthesis of phenols. A new, more reactive arene oxidizing reagent, 4,5-dichlorophthaloyl peroxide, computationally predicted and experimentally determined to possess enhanced reactivity, has expanded the scope of the reaction while maintaining a high level of tolerance for diverse functional groups. The reaction proceeds through a novel "reverse-rebound" mechanism with diradical intermediates. Mechanistic insight was achieved through isolation and characterization of minor byproducts, determination of linear free energy correlations, and computational analysis of substituent effects of arenes, each of which provided additional support for the reaction proceeding through the diradical pathway.

Full text of DOI:10.1021/acs.joc.5b01079

Page 1 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Computational and Experimental Studies of the Phthaloyl
Peroxide-Mediated Hydroxylation of Arenes Yield a More Re-
active Derivative 4,5-Dichlorophthaloyl Peroxide
Andrew M. Camelio,† Yong Liang,‡ Anders M. Eliasen,†,§ Trevor C. Johnson,†,§ Changxia Yuan,† Alex
W. Schuppe,† K. N. Houk*,‡,ǁ and Dionicio Siegel*,†,§
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
† Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States
‡ Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
§ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92037,
United States
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, United
States
ǁ
ABSTRACT
The oxidation of arenes by the reagent phthaloyl peroxide proꢀ
vides a new method for the synthesis of phenols. A new, more
reactive arene oxidizing reagent, 4,5ꢀdichlorophthaloyl peroxꢀ
ide, computationally predicted and experimentally determined
to possess enhanced reactivity, has expanded the scope of the
reaction while maintaining a high level of tolerance for diverse functional groups. The reaction proceeds through a
novel “reverseꢀrebound” mechanism with diradical intermediates. Mechanistic insight was achieved through the isolaꢀ
tion and characterization of minor byproducts, the determination of linear free energy correlations, and computational
analysis of substituent effects of arenes, each of which provided additional support for the reaction proceeding through
the diradical pathway.
INTRODUCTION
The incorporation of oxygen into organic molecules in place of hydrogen is a fundamental transformation in organic
synthesis. These transformations provide functional groups that can be readily manipulated, as well as atoms required
in the final compounds. While significant efforts and advancements have been made in this area, there is no broadly
applicable methodology for the straightforward conversion of arenes to phenols. One of the major challenges in develꢀ
oping hydroxylation reactions of aromatic compounds is that the products of the reactions are, under most conditions,
more reactive than the starting material and as a result overꢀoxidation is a competitive process.1, 2 Peroxides have been
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 35
extensively used as reagents to effect oxidation and early hydroxylation reactions employing peroxides have had partial
success generating monoꢀhydroxylated products. However, significant limitations remain, largely due to the restricted
scope of the oxidation reactions employing simple unfunctionalized arenes frequently used in excess.3-14 Additionally,
the use of super acids to activate the oxidant and subsequently deactivate the products through protonation of the new
phenolic oxygen were subsequently investigated thereby circumventing the need for excess starting material usage.15-18
This approach, however, cannot be broadly applied due to the requirement of exceptionally strong Brønsted acids and,
under some conditions, concentrated (95%) hydrogen peroxide solutions.19 This combination reduces functional group
tolerance to only those that can withstand both strongly acidic and powerful oxidizing conditions. As a result broadly
applicable methods for phenol synthesis from arenes remains a challenge.
1
2
3
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
Scheme 1. Reaction of phthaloyl peroxide (1) with mesitylene generating an intermediate aryl phthaloyl mono-ester 2 hydrolyzed to generate
mesitol (3).
O
O
O
Me
O
O
1
Me
O
CO2H
HFIP, 40°C
Me
Me
Me
Me
Me
2
NaHCO3
OH
Me
MeOH/H2O, 40 °C
Me
3
Using phthaloyl peroxide (1), a reagent extensively studied by Greene in the 1950’s,20-25 we have developed a new
synthetic method for arene hydroxylation. Phthaloyl peroxide, in the absence of other reagents, enables the selective
oxidation of arenes with a variety of pendant functional groups.26 The reaction can be conducted in commercial grade
solvents, i.e., fluorinated alcohols, with no need for the special exclusion of air or water. The oxidation reaction proꢀ
ceeds only once and an excess of reagent can be employed, if needed, without overꢀoxidation becoming a competitive
process. The controlled oxidation is enabled by the intermediate phthaloyl esterꢀacid 2, which deactivates the arene
product toward a second oxidation (indicative of a radical process, vida infra). The typical transformation is shown for
the reaction of mesitylene and phthaloyl peroxide (1) in Scheme 1. Following the reaction of phthaloyl peroxide and
ACS Paragon Plus Environment

Page 3 of 35
The Journal of Organic Chemistry
arene the intermediate phthaloyl group is cleaved under neutral to slightly basic conditions, liberating the phenolic
product mesitol (3).
1
2
3
Quantum mechanical calculations26 have shown that the reaction of phthaloyl peroxide (1) with arenes proceeds
through a “reverseꢀrebound” mechanism (Figure 1), as opposed to the rebound mechanism27,28 observed with metalꢀ
oxo and dioxirane oxidants. Homolysis of the peroxide generates a diradical 4 that is in equilibrium with the parent
peroxide 1. Addition of the diradical 4 to the arene generates an intermediate diradical 5 that undergoes aromatization
to provide the phthaloyl esterꢀacid 6. Within this mechanism there is the possibility of a moleculeꢀassisted homolysis
wherein the arene and the peroxide react directly to generate the same diradical intermediate 5. Through these mechaꢀ
nistic considerations, a new arene hydroxylation reagent 4,5ꢀdichlorophthaloyl peroxide was conceived, subsequently
developed, and the scope of the reaction expanded. Additional mechanistic insight was also gained through the deterꢀ
mination of linear free energy relationships, byproduct characterization, and the calculations of substituent effects of
arenes in both radical and ionic processes. Insights obtained through these experiments and calculations further support
the diradical “reverseꢀrebound” mechanism. The key feature of this mechanism is that the hydrogen abstraction comes
last, instead of first, as in the “oxygen rebound” mechanism.
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
Figure 1. The reverse-rebound mechanism for the phthaloyl peroxide oxidation of arenes.
RESULTS AND DISCUSSION
Subsequent to reporting on the ability of phthaloyl peroxide to hydroxylate functionalized arenes, we sought to imꢀ
prove the scope of the reaction by developing more reactive conditions and/or alternative cyclic peroxideꢀbased reaꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 35
gents. The major limitations of phthaloyl peroxide as a reagent is that arenes with the electronics of anisaldehyde and
those more electron deficient fail to react, returning unchanged starting material. A computational study demonstrated
that the rateꢀdetermining step of the reaction was the carbonꢀoxygen bond formation (Figure 1). The frontier molecular
orbital (FMO) analysis shows that the interaction between the HOMO of arene and the SOMO of diradical 4 is domiꢀ
nant in the carbonꢀoxygen bonding transition state. Elevating the HOMO energy of the arene can increase the favorable
interaction in the transition state, lowering the barrier for oxidation. Alternatively, lowering the SOMO energy of the
diradical generated from cyclic peroxide will also increase the favorable interaction, improving the reactivity. Further
FMO analysis indicates that the 4,5ꢀdichloroꢀsubstitution decreases the SOMO energy by 0.3 eV (Figure 2a), suggestꢀ
ing that 4,5ꢀdichlorophthaloyl peroxide (7), previously prepared,29 would have improved reactivity relative to the parꢀ
ent phthaloyl peroxide (1) (Figure 2a).
1
2
3
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
Figure 2. (a) Structures of phthaloyl peroxide and 4,5-dichlorophthaloyl peroxide, the SOMO energies of the corresponding diradicals, and the
computed barriers for the reactions with mesitylene in trifluoroethanol (TFE). (b) The computed barrier for the competing benzylic hydrogen
abstraction of mesitylene by the diradical generated from 4,5-dichlorophthaloyl peroxide.
The barriers for the reactions of 4,5ꢀdichlorophthaloyl peroxide (7) with different arenes are calculated to be lowꢀ
ered by 1ꢀ2 kcal/mol relative to phthaloyl peroxide (1) in trifluoroethanol (for mesitylene, 19.1 versus 20.3 kcal/mol,
Figure 2a; for others, see the Supporting Information). In addition, calculations show that the competing benzylic
ACS Paragon Plus Environment

Page 5 of 35
The Journal of Organic Chemistry
hydrogen abstraction (Figure 2b) has a much higher barrier than the desired aryl oxidation, indicating that 4,5ꢀ
dichlorophthaloyl peroxide will be selective for aromatic carbonꢀhydron bonds.
1
2
3
4
5
6
7
8
9
Preliminary safety testing of 4,5ꢀdichlorophthaloyl peroxide achieved by thermogravimetric analysis (TGA)
demonstrated improved thermal stability relative to the parent compound (phthaloyl peroxide has been found to deꢀ
compose at 125 °C) with 4,5ꢀdichlorophthaloyl peroxide undergoing exothermic decomposition at 135 °C (see the
Supporting Information). For safety consideration reactions were conducted below the threshold for thermal decompoꢀ
sition and, as described herein, using a maximal oil bath temperature of 75 °C.
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
Figure 3. Arene hydroxylation mediated by 4,5-dichlorophthaloyl peroxide. The minor regioisomer(s) are labeled with the respective carbon
number, if three regioisomers are produced the ratios are given major product : lowest carbon number isomer : highest carbon number iso-
mer. a1.0 equivalent of p-toluenesulfonic acid monohydrate added.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 35
This new reagent allows arenes to be converted to phenols that were not previously reactive toward phthaloyl perꢀ
oxide, including pꢀanisaldehyde which reacts regioselectively with 4,5ꢀdichlorophthaloyl peroxide to generate phenol 9
(Figure 3). Arenes with strong electronꢀwithdrawing groups can react with the new reagent. The phenols 10–18 were
prepared from corresponding arenes conjugated to ketones and esters. When the groups on the arene are cooperative,
the reaction is highly regioselective. Importantly, the new reagent maintains broad tolerance to a variety of functional
groups. Successfully transformed substrates are shown to include diols, carbonates, and carbamates, as demonstrated
by the reaction of a series of chlorphenesin derivatives which formed the phenolic products 19, 20, and 21. Testing the
regioselectivity of the reaction with a series of halogenated alkyl benzene derivatives showed the influence of the subꢀ
stituents relative to alkanes on the site of reaction providing phenols 22, 23, and 24 with increasing levels of selectiviꢀ
ty. The reaction was also used for the synthesis of triclosan (25) directly from 2,4,4’ꢀtrichloroꢀdiphenyl ether, resulting
in an improvement on the existing methods.30, 31 Triclosan is an antibacterial/antifungal agent which is included in
many commonly used household products and is currently being reinvestigated by the FDA. The hydroxylation of
monoꢀalkyl benzenes was improved by using the new reagent, generating the hydroxylated products 26, 27, and 28 in
improved yields relative to those obtained with phthaloyl peroxide (yields for 26 and 27 obtained by reactions with
phthaloyl peroxide were 49% and 36%, respectively). Basic distal amines are tolerated if they are first reacted with
toluene sulfonic acid monohydrate, as was observed for amine 29. Sulfonamideꢀphenol 30 and trifluroacetamideꢀ
phenol 31 were also successfully generated from the corresponding arenes.
1
2
3
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
The second step in the reaction sequence, hydrolysis of the intermediate phthaloyl esterꢀacid to liberate the phenol,
was initially reported using a warmed mixture of methanol and saturated aqueous sodium bicarbonate solution. This
allowed rapid hydrolysis of the intermediate esters. However, the intermediate esters are highly labile, and have been
dubbed “self immolative”.32, 33 If needed, exceedingly mild hydrolysis is possible under neutral conditions (pH = 7.0)
at 23 °C with prolonged reaction times (Figure 4). The dichlorophthaloyl esters 30 and 31 hydrolyze faster than the
phthaloyl adduct 3 and, as the cleavage reaction is intramolecular, hindered esters hydrolyze at approximately the same
rate as less bulky esters (30 versus 31, Figure 4).
ACS Paragon Plus Environment

Page 7 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
Figure 4. Half-lives for the hydrolysis of phthaloyl esters at 23 °C in a 1:1 solution of pH 7.0 aqueous phosphate buffer and THF.
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
Coꢀproduct analysis of the remnants of the reaction from the hydroxylation of mesitylene using either phthaloyl
peroxide (1) or 4,5ꢀdichlorophthaloyl peroxide (7) revealed benzylic functionalized products at low levels of approxiꢀ
mately 1% (Figure 5). To permit full characterization, reactions for both of the peroxide regents were scaled up to proꢀ
duce sufficient amounts of the benzylic functionalized products 32 and 33. The formation of these products, derived by
replacing benzlic hydrogens with phthaloyl esters is highly suggestive of radicals. These esters are significantly more
stable than the corresponding arylꢀphthaloyl esters.
Figure 5. Structures of minor co-products of benzylic oxidation esters 32 and 33 derived from, respectively, the reactions of phthaloyl perox-
ide (1) or 4,5-dichlorophthaloyl peroxide (7) with mesitylene.
The improved reactivity of 4,5ꢀdichlorophthaloyl peroxide enables the hydroxylation of benzene and chlorobenꢀ
zene. By using substituted arenes and evaluating linear free energy relationships, investigation into the reaction mechaꢀ
nism was possible. Reaction rates for monoꢀsubstituted benzenes in comparison to benzene were obtained through diꢀ
rect competition reactions. Experiments were conducted with an excess of benzene and an excess of the appropriate
substituted benzene with one equivalent of 4,5ꢀdichlorophthaloyl peroxide (Figure 6). Comparison of the ratios of the
paraꢀ and orthoꢀphthaloylated substituted benzene adducts (36 and 37), versus the peroxide adduct with benzene 35,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 35
provided relative rates of reaction. Hammett plots using either σ or σ+ values were then constructed, and in a notable
departure from electrophilic aromatic substitution, the data fits σ values (R2 = 0.92) better than σ+ values (R2 = 0.78).
In addition, the ρ value generated (–3.9) is notably less than those obtained for electrophilic aromatic substitution reacꢀ
tions where the stability of the cationic charge in the ring is strongly influenced by contributions of substituents (e.g. ρ
value for arene bromination using Br2 in acetic acid is –13).34
1
2
3
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
X
O
Cl
O
X
O
Cl
X
O
O
O
O
O
O
7
O
CO2H
CO2H
CO2H
1.0 equiv.
+
+
+
HFIP, 75 °C
Cl
Cl
Cl
34
Cl
Cl
Cl
5.0 equiv.
5.0 equiv.
35
36
37
Figure 6. Linear free energy correlations derived for the reactions of 4,5-dichlorophthaloyl peroxide and arenes.
The stronger correlation with σ values as opposed to σ+ values also provides insight into the reaction’s propensity
to only undergo one oxidation reaction. By using phenyl benzoate (39), which has known σ and σ+ values,35 as a surꢀ
rogate for phthaloylated benzene 38, the σ value of 0.13 predicts the phthaloylated benzene to be less reactive than
benzene (Figure 7). Therefore, after the first addition, the ring becomes deactivated and overꢀoxidation does not occur.
Indeed, the reaction of benzene (1 equiv.) with 4,5ꢀdichlorophthaloyl peroxide (2 equiv.) in HFIP only provides the
monoꢀoxidized product 35 (40% yield) with no evidence of double addition. However, if resonance contributions were
important for the reaction, as is the case for electrophilic aromatic substitution, the σ+ value (–0.07 for phenyl benzoꢀ
ate) would predict that phthaloylated benzene would be more reactive than benzene. As a consequence, the products of
the reaction, if it were similar to EAS, would be expected to be more reactive than the starting material and undergo
ACS Paragon Plus Environment

Page 9 of 35
The Journal of Organic Chemistry
subsequent oxidation reactions. That stated, in reactions where phthaloyl peroxideꢀbased reagents are used in excess
over oxidation is not a competitive process.
1
2
3
4
5
σ = 0.13
(less reactive
6
than benzene)
CO2H
7
8
9
O
O
O
O
σ+ = –0.07
(more reactive
than benzene)
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
38
39
Figure 7. Phenyl benzoate σ and σ+ values.
To better understand the “reverseꢀrebound” mechanism and the substituent effects of arenes on reaction rates, we
conducted the following DFT calculations. First, we located the carbonꢀoxygen bonding transition states via a radical
or ionic process for the reaction of 4,5ꢀdichlorophthaloyl peroxide and benzene (Figure 8a). Computational results
showed that the radical addition pathway requires an activation free energy of 26.2 kcal/mol in trifluoroethanol, which
is 5.7 kcal/mol lower than that for the electrophilic aromatic substitution (an ionic mechanism). The possibility of “reꢀ
bound” mechanism initiated by the aromatic hydrogen abstraction was evaluated. As shown in Figure 8b, the barrier
for this process is close to 40 kcal/mol which is significantly higher than those calculated for the radical (26.2
kcal/mol) and ionic (31.9 kcal/mol) processes.
Figure 8. (a) The computed barriers for the radical addition and electrophilic aromatic substitution processes for the reaction of 4,5-
dichlorophthaloyl peroxide and benzene, and the charge analysis of the corresponding transition states (NBO charge in parentheses and
mulliken charge in brackets). (b) The computed barrier for the aromatic hydrogen abstraction of benzene by the diradical generated from 4,5-
dichlorophthaloyl peroxide.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 35
1
2
3
4
5
6
7
8
9
The use of fluorinated alcohol solvents in the optimized oxidation conditions is suggestive of the need for stabiliꢀ
zation of polar species. The charge analysis indicates that the diradical transition state is highly polarized (Figure 8a),
which charge separation is only slightly smaller than that of the zwitterionic electrophilic aromatic substitution transiꢀ
tion state. Therefore, the most accurate description is that the reaction involves a polarized diradical, which is not unuꢀ
sual in radical chemistry involving electronegative radicals.36 Tomkinson has recently proposed an ionic mechanism
for the related arene oxidation by a spirocyclopropyl malonyl peroxide, but the data preseneted in that work are fully
consistent with the polarized diradical mechanism proposed here.37
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
Table 1. Computed activation free energies for radical addition and electrophilic aromatic substitution reactions using 4,5-dichlorophthaloyl
peroxide.a
X
TSꢀRꢀoꢀX
21.7
TSꢀRꢀpꢀX TSꢀIꢀoꢀX TSꢀIꢀpꢀX
OMe
Me
H
20.8
24.1
25.0
28.5
22.7
28.1
23.5
26.2
31.9
F
27.4
27.9
27.1
26.6
27.3
27.0
33.3
32.9
33.0
31.8
31.8
32.8
OBz
Cl
a Computed at CPCM(CF3CH2OH)ꢀ(U)B3LYPꢀD3/6ꢀ31+G(d)//(U)B3LYP/6ꢀ31+G(d).
ACS Paragon Plus Environment

Page 11 of 35
The Journal of Organic Chemistry
We computed activation free energies in trifluoroethanol for the radical additions and electrophilic aromatic subꢀ
1
2
stitutions using 4,5ꢀdichlorophthaloyl peroxide. As shown in Table 1, while they have similar reactivity trends for the
substituted benzenes, the calculated barriers for the electrophilic aromatic substitution are higher by 2ꢀ6 kcal/mol. In
addition, computational data predict that electrophilic aromatic substitution is more sensitive to the electronics of
arenes, with an activation free energy difference of approximately 9 kcal/mol for anisole and benzene (22.7 versus 31.9
kcal/mol, Table 1). The corresponding activation free energy difference for the radical addition is predicted to be about
5 kcal/mol (20.8 versus 26.2 kcal/mol, Table 1). The reduced influence of the groups on the reaction rates in the diradiꢀ
cal mechanism matches the experimental study of linear free energy correlations (Figure 6). Further, the electrophilic
aromatic substitution mechanism would predict a high para/ortho ratio for anisole based on the energy difference of 2.3
kcal/mol. However, a poor regioselectivity (the reaction of 4,5ꢀdichlorophthaloyl peroxide with anisole provided a 1.2 :
1 o : p ratio of products) was observed, thus supporting the computational prediction on the basis of the radical addition
mechanism. More importantly, for the benzoate substitution, calculations show that it is a deactivated group, as comꢀ
pared to hydrogen only in the diradical mechanism. This is in conformity with the experimental observation of no overꢀ
oxidation.
3
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
CONCLUSIONS
The new reagent 4,5ꢀdichlorophthaloyl peroxide for the hydroxylation of arenes, predicted to possess enhanced reactivꢀ
ity relative to the parent oxidant phthaloyl peroxide has expanded the scope of the arene hydroxylation reaction. The
heightened reactivity of this peroxide enables mechanistic inquiry and allows the determination of linear free energy
relationships. Both experiment and theory support the reverseꢀrebound mechanism.
EXPERIMENTAL SECTION
Safety Information. Research entailing the use of peroxides requires that the proper precautions be
taken and knowledgeable and experienced practitioners of organic synthesis should carry out the followꢀ
ing procedures. At 130 °C there is a rapid loss of mass (see Section V). Earlier work using phthaloyl
peroxide describes the stability and proper handling of these compounds.1ꢀ6
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 35
General Information. Commercial reagents were purchased at the highest purity available and
used without further purification. While reactions using 4,5ꢀdichlorophthaloyl peroxide were performed
without exclusion of air, other reactions were conducted under an atmosphere of N2 unless otherwise
indicated. Solvents (CH2Cl2 and Et2O) were purified using a PureꢀSolv MDꢀ5 Solvent Purification Sysꢀ
tem (Innovative Technology). Hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) were purꢀ
chased from Oakwood Products and used without purification. Analytical thinꢀlayer chromatography
(TLC) was carried out using 0.2 mm commercial glassꢀcoated silica gel plates (silica gel 60, F254,
EMD chemical). Thin layer chromatography plates were visualized by exposure to ultraviolet light
and/or exposure to iodine, an acidic solution of ceric ammonium molybdate, or a basic solution of poꢀ
tassium permanganate followed by heating on a hot plate. The chromatographic purification of products
was achieved using silica gel chromatography with positive N2 pressure as described by Still.7 Infrared
spectra were recorded using neat thin film technique. Highꢀresolution mass spectra (HRMS) were obꢀ
tained using time of flight and quadrupole and reported as m/z (relative intensity). Accurate masses are
reported for the molecular ion [M+Na]+, [M+H]+, [M−] or [M+]. Nuclear magnetic resonance spectra
1
2
3
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
1
(1H NMR and 13C NMR) were recorded with at 400 MHz, H at 400 MHz, 13C at 100 MHz, 500 MHz,
13
1
13
1H at 500 MHz, C at 125 MHz, H at 600 MHz, C at 150 MHz. For CDCl3, C6D6, CD3OD, and
C3D6O solutions, chemical shifts are reported as parts per million (ppm) referenced to residual protium
or carbon of the solvent; CHCl3 δ 7.26 ppm, CDCl3 δ 77.00 ppm, C6D5H δ 7.15 ppm, C6D6
δ 128.00 ppm, CD2HOD δ 3.31 ppm, CD3OD δ 47.60 ppm, C3D5HO δ 2.05 ppm, and C3D6O δ 29.00
ppm. Coupling constants are reported in Hertz (Hz). Data for 1H NMR spectra are reported as follows:
chemical shift (ppm, referenced to protium); bs = broad singlet, s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublets, dt = doublet of triplets, ddd = doublet of doublet of doublets, tt = triꢀ
plet of triplets, tq = triplet of quartets, qt = quartet of triplets, m = multiplet, integration, and coupling
constant (Hz). Melting points were measured on a MELꢀTEMP device with calibration using benzoic
acid (M.P. = 122 °C) as the standard.
ACS Paragon Plus Environment

Page 13 of 35
The Journal of Organic Chemistry
4,5-Dichlorophthaloyl Peroxide (7). Solid 4,5ꢀdichlorophthalic acid (50.0 g, 213 mmol, 1.0 equiv.) and
solid phosphorus pentachloride (89.0 g, 427 mmol, 2.0 equiv.) were added to a flameꢀdried flask
equipped with a stir bar. The reaction vessel was placed under a continuous flow of N2 and equipped
with an outport leading to a saturated aqueous NaHCO3 mixture. The solid mixture was then placed in
an oil bath heated to 160 °C and stirred (600 rpm). Caution: a copious amount of HCl is evolved during
this procedure. After 4.5 hours the reaction vessel was equipped with a fractional distillation apparatus
and the resulting dark grey liquid was purified by distillation in vacuo (b.p. = 155–160 °C at 1.0 mbar)
to provide the 4,5ꢀdichlorophthaloyl chloride (55.1 g, 192 mmol, 90%, 95% pure) as a clear colorless oil
which solidified upon cooling to 23 °C. The spectral and physical properties matched those reported for
4,5ꢀdichlorophthaloyl chloride.38 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 2H). m.p. = 34 °C. A mixture
of solid 4,5ꢀdichlorophthaloyl chloride (25.5 g, 94 mmol, 1.0 equiv.) and solid sodium percarbonate
(16.2 g, 103 mmol, 1.1 equiv.) were covered with reagent grade (not anhydrous) CH2Cl2 (470 mL). The
white heterogeneous mixture was placed under an atmosphere of N2 and stirred vigorously (1000 rpm).
After 24 hours the mixture was filtered through a pad of celite and carefully concentrated by rotary
evaporation at 23 °C to provide a pale yellow solid. This solid was dissolved in benzene (110 mL) and
then pentane (220 mL) was slowly added, initiating the precipitation of a white solid. The mixture was
placed in an ice water cooling bath for 1 hour and then filtered while cold to provide peroxide 7 as a
white flakey solid (9.3 g, 40 mmol, 43%, 86% purity with 14% 4,5ꢀdichlorophthalic anhydride). A seꢀ
cond precipitation after partial (1/2 the volume) concentration in vacuo of the filtrate solution provided a
pale yellow solid peroxide 7 (2.7 g, 12 mmol, 13%, 86% purity with 14% 4,5ꢀdichlorophthalic anhyꢀ
dride). Further concentration of the solution provided the starting 4,5ꢀdichlorophthaloyl dichloride (5.7
g, 21 mmol, 22%). The spectral data for 7 matches that reported for 4,5ꢀdichlorophthaloyl peroxide.29
This preparation afforded material of 86 to 99% purity with the remainder of the material being 4,5ꢀ
dichlorophthalic anhydride. We have tested the addition 4,5ꢀdichlorophthalic anhydride to the oxidation
1
2
3
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
1
reaction and found that it does not affect the outcome of the reaction. H NMR (400 MHz, CDCl3) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 35
8.34 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 160.4, 142.4, 131.8, 122.6; IR (neat film, cmꢀ1) 1748, 906
1
2
3
cmꢀ1.
4
5
6
7
General Procedure A. To a flameꢀdried borosilicate flask equipped with a magnetic stir bar was
8
9
added the corresponding arene followed by syringe addition of HFIP to provide a clear homogeneous
solution diluting the substrate to a final concentration of 0.1 M. In some cases, when noted, CHCl3 was
added to make the solution homogeneous. Solid 4,5ꢀdichlorophthaloyl peroxide was then added in one
portion. After stirring at a rate of 500 rpm at 23 °C for 1 minute the peroxide was fully dissolved, the
reaction vessel was capped with a polyethylene stopper and placed in an oil bath heated to 50 °C and
stirred at a rate of 500 rpm. After 24 or 48 hours, the reaction was removed from the oil bath and alꢀ
lowed to cool to 23 °C. The solvent was evaporated by a continuous flow of N2 to provide a crude yelꢀ
low, orange, or deep red solid. The crude mixture was then placed under an atmosphere of N2, and a deꢀ
oxygenated mixture of MeOH / saturated aqueous NaHCO3 solution (9 / 1) was added by syringe under
N2 to provide an overall reaction concentration of 0.1 M relative to the starting substrate. The heterogeꢀ
neous mixture was then placed in an oil bath heated to 50 °C and stirred at a rate of 500 rpm. After 1
hour the methanol was removed by a continuous flow of N2, and to the mixture was added Et2O or
EtOAc (10 mL) and aqueous phosphate buffer (10 mL, 0.2 M, pH = 7). The mixture was vigorously
stirred (800 rpm) at 23 °C for 2 minutes to form a biphasic solution which was poured into a separatory
funnel and partitioned. The organic layer was washed with aqueous phosphate buffer (4 x 30 mL, 0.2
M, pH = 7) or with an aqueous saturated solution of NaHCO3 and brine (3 x 30 mL). The residual
aqueous extracts were back extracted with Et2O (3 x 25 mL) or EtOAc (3 x 25 mL), combined with the
first extract, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel
chromatography using the noted solvent mixture to provide the phenolic products.
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
General Procedure B. To a flameꢀdried borosilicate flask equipped with a magnetic stir bar was added
the starting arene followed by syringe addition of HFIP to provide a clear homogeneous solution dilutꢀ
ACS Paragon Plus Environment

Page 15 of 35
The Journal of Organic Chemistry
ing the substrate to a final concentration of 0.1 M. In some cases, when noted, CHCl3 was added to
make the solution homogeneous. Solid 4,5ꢀdichlorophthaloyl peroxide was added in one portion. After
stirring at a rate of 500 rpm at 23 °C for 1 minute the peroxide dissolved, the reaction vessel was capped
with a polyethylene stopper and placed in an oil bath heated to 75 °C and stirred at a rate of 500 rpm.
After 36 or 48 hours, the reaction was removed from the oil bath and allowed to cool to 23 °C. The solꢀ
vent was evaporated by a flow of N2 to provide a yellow, orange, or deep red solid. The crude mixture
was placed under an atmosphere of N2, and a deꢀoxygenated mixture of MeOH / saturated aqueous Naꢀ
HCO3 (9 / 1) solution was added via syringe under N2 to provide 0.1 M solution relative to the amount
of starting substrate. The heterogeneous mixture was placed in an oil bath heated to 50 °C and stirred at
a rate of 500 rpm. After 1 hour the methanol was removed by a continuous flow of N2, and to the mixꢀ
ture Et2O or EtOAc (10 mL) was added and an aqueous phosphate buffer (10 mL, 0.2 M, pH = 7). The
mixture was vigorously stirred (800 rpm) at 23 °C for 2 minutes to provide a biphasic solution which
was poured into a separatory funnel and partitioned. The organic layer was collected and washed with
an aqueous phosphate buffer (4 x 30 mL, 0.2 M, pH = 7) or with the combination of an aqueous saturatꢀ
ed NaHCO3 solution and brine (3 x 30 mL). The aqueous extracts were back extracted with Et2O (3 x
25 mL) or EtOAc (3 x 25 mL), combined with the initial extracts, dried over Na2SO4, filtered, and conꢀ
centrated. The crude material was then purified by silica gel chromatography using the noted solvent
mixture to provide the phenolic products.
1
2
3
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
General Procedure C. To flameꢀdried borosilicate flask equipped with a magnetic stir bar was added
the starting arene neat followed by the syringe addition of HFIP to provide a clear homogeneous soluꢀ
tion with the substrate diluted to a final concentration of 0.1 M. Solid 4,5ꢀdichlorophthaloyl peroxide
was then added in one portion. After stirring at a rate of 500 rpm at 23 °C for 1 minute a homogeneous
solution formed, and the reaction vessel was capped with a polyethylene stopper, placed in an oil bath
heated to 75 °C, and stirred at a rate of 500 rpm. After 36 hours the reaction was removed from the oil
bath and allowed to cool to 23 °C. The solvent was evaporated to dryness by a continuous flow of N2 to
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 35
provide a yellow solid. The crude mixture was then dissolved in a methanol / benzene (2 / 7) solution
providing an overall substrate concentration of 0.1 M and the clear yellow homogeneous solution was
stirred at a rate of 500 rpm. TMSCHN2 solution (5.0 equiv., 0.2 M in Et2O) was added dropwise over 1
minute with gas evolution. After 30 minutes the yellow–orange solution was evaporated by a continuous
flow of N2 to provide a yellow–orange viscous oil; which was purified by silica gel chromatography usꢀ
ing the noted solvent mixture, yielding the mixed phthalate ester products.
1
2
3
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
3-hydroxy-4-methoxybenzaldehyde (9). Prepared following General Procedure B using anisaldehyde
(30.0 mg, 0.22 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (239 mg, 0.88 mmol, 4.0 equiv.,
(using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride)), and HFIP (2.2 mL) at 75 °C
for 36 hours. The crude brown viscous oil was purified by silica gel chromatography; 1 – 10% Et2O in
CH2Cl2 / hexanes (1 / 1) to provide aldehyde 9 (23.0 mg, 0.15 mmol, 69%) as a deep yellow solid. The
spectra of the phenol matched that reported for 9.39,40 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 7.45 –
7.43 (m, 2H), 6.98 (d, J = 8.9 Hz, 1H), 6.72 (s, 1H), 3.99 (s, 3H).
1-(3-hydroxy-4-methoxyphenyl)ethan-1-one (10). Prepared following General Procedure B using 4ꢀ
methoxy acetophenone (100 mg, 0.67 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (446 mg,
1.67 mmol, 2.5 equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride)), and
HFIP (6.7 mL) at 75 °C for 36 hours. The crude brown viscous oil was purified by silica gel chromaꢀ
tography; 1 – 10% Et2O in CH2Cl2 / hexanes (1 / 1) to provide ketone 10 (68.5 mg, 0.41 mmol, 62%) as
a yellow solid and the starting acetophenone (18.8 mg, 0.13 mmol, 19%) as a white solid. The spectra
of the phenol matched that reported for 10.41 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.52 (m, 2H), 6.89
(d, J = 8.2 Hz, 1H), 5.64 (bs, 1H), 3.97 (s, 3H), 2.55 (s, 3H).
Methyl 3-hydroxy-4-methoxybenzoate (11). Prepared following General Procedure B using 4ꢀ
methoxy methylbenzoate (100 mg, 0.60 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (408 mg,
1.50 mmol, 2.5 equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride)), and
ACS Paragon Plus Environment

Page 17 of 35
The Journal of Organic Chemistry
HFIP (6.0 mL) at 75 °C for 36 hours. The crude brown viscous oil was purified by silica gel chromaꢀ
tography; 1 – 20% Et2O in CH2Cl2 / hexanes (1 / 1) to provide phenol 11 (70.0 mg, 0.39 mmol, 64%) as
a yellow solid and the starting benzoate (5.0 mg, 0.03 mmol, 5%) as a white solid. The spectra of the
phenol matched that reported for 11.42 1H NMR (400 MHz, CDCl3): δ 7.62 (dd, J = 2.0, 8.6 Hz, 1H),
7.59 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 5.61 (s, 1H), 3.95 (s, 3H), 3.88 (s, 3H).
1
2
3
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
5-hydroxy-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (12a) and 7-hydroxy-6-methoxy-3,4-
dihydronaphthalen-1(2H)-one (12b). Prepared following General Procedure B using 6ꢀmethoxy teꢀ
tralone (100 mg, 0.57 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (367 mg, 1.42 mmol, 2.5
equiv., (using material of 90% purity with 10% 4,5ꢀdichlorophthalic anhydride)), and HFIP (5.7 mL) at
75 °C for 36 hours. The crude brown viscous oil was purified by silica gel chromatography; 1 – 20%
Et2O in CH2Cl2 / hexanes (1 / 1) to provide phenols 12a (41.0 mg, 0.21 mmol, 38%) and 12b (29.0 mg,
0.15 mmol, 48%) as yellow solids and the starting tetralone (13.0 mg, 0.07 mmol, 13%) as a pale yellow
1
solid. The spectra of the phenols match that reported for 12a and 12b.43,44 Major Isomer (12a): H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.71 (bs, 1H), 3.96 (s,
3H), 2.93 (t, J = 6.2 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H), 2.11 (tt, J = 6.2, 6.2 Hz, 2H). Minor Isomer (12b):
1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1), 6.66 (s, 1H), 5.52 (bs, 1H), 3.95 (s, 3H), 2.88 (t, J = 6.2 Hz,
2H), 2.59 (t, J = 6.8 Hz, 2H), 2.10 (tt, J = 6.2, 6.8 Hz, 2H).
Methyl 3-hydroxy-2-methoxybenzoate (13a) and methyl 5-hydroxy-2-methoxybenzoate (13b). Preꢀ
pared following General Procedure A using methyl salicylate (100 mg, 0.60 mmol, 1.0 equiv.), 4,5ꢀ
dichlorophthaloyl peroxide 7 (212 mg, 0.78 mmol, 1.3 equiv., (using material of 86% purity with 14%
4,5ꢀdichlorophthalic anhydride)), and HFIP (6.0 mL) at 50 °C for 24 hours. The crude brown viscous
oil was purified by silica gel chromatography; 1 – 20% Et2O in CH2Cl2/ hexanes (1 / 1) to provide pheꢀ
nols 13a (31.0 mg, 0.17 mmol, 28%), 13b (27.2 mg, 0.15 mmol, 25%) as yellow solids and the starting
salicylate (25.6 mg, 0.15 mmol, 26%) as a clear colorless oil. The spectra of the phenols match that reꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 35
ported for 13a and 13b.45,46 Major Isomer (13a): H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 1.7, 7.9
Hz, 1H), 7.15 (dd, J = 1.7, 8.2 Hz, 1H), 7.05 (dd, J = 7.9, 8.2 Hz, 1H), 5.91 (bs, 1H), 3.93 (s, 3H), 3.92
(s, 3H). Minor Isomer (13b): 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 3.4 Hz, 1H), 6.97 (dd, J = 3.1,
8.9 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 4.52 (bs, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
1
1
2
3
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
Methyl 4-hydroxy-3-methoxybenzoate (14a), methyl 2-hydroxy-3-methoxybenzoate (14b), methyl
2-hydroxy-5-methoxybenzoate (14c). Prepared following General Procedure A using 3ꢀmethoxy
methylbenzoate (100 mg, 0.60 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (212 mg, 0.78
mmol, 1.3 equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride), and HFIP
(6.0 mL) at 50 °C for 24 hours. The crude brown viscous oil was purified by silica gel chromatography;
1 – 20% Et2O in CH2Cl2 / hexanes (1 / 1) to provide phenols 14a (22.1 mg, 0.12 mmol, 20%), 14b (19.7
mg, 0.11 mmol, 18%), 14c (18.8 mg, 0.10 mmol, 17%) as pale yellow solids and the starting benzoate
(20.9 mg, 0.13 mmol, 21%) as a clear colorless oil. The spectra of the phenols match that reported for
14a, 14b, and 14c.39,47,48 Major Isomer (14a): 1H NMR (400 MHz, CDCl3) δ 10.37 (bs, 1H), 7.29 (d, J =
3.2 Hz, 1H), 7.08 (dd, J = 3.1, 8.9 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 3.95 (s, 3H), 3.78 (s, 3H). Minor
Isomer (14b): 1H NMR (400 MHz, CDCl3) δ 11.00 (bs, 1H), 7.43 (dd, J = 1.5, 8.2 Hz, 1H), 7.04 (d, J =
1
7.9 Hz, 1H), 6.83 (dd, J = 8.2, 7.9 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H). Minor Isomer (14c): H NMR
(400 MHz, CDCl3) δ 7.64 (dd, J = 2.1, 8.2 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H),
5.97 (bs, 1H), 3.95 (s, 3H), 3.89 (s, 3H).
Methyl 3-hydroxy-2,6-dimethylbenzoate (15). Prepared following General Procedure B using 2,6ꢀ
dimethyl methylbenzoate (100.0 mg, 0.61 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (422.0
mg, 1.52 mmol, 2.5 equiv., 84%), and HFIP (6.1 mL) at 75 °C for 48 hrs. The crude orange foam was
purified by silica gel chromatography; pentane and then hexane → 15% acetone in hexane to afford the
phenol 15 as a pale yellow amorphous oil (63.0 mg, 0.35 mmol, 58%). Rf = 0.46 (50% Et2O in hexane);
1H NMR (400 MHz, CDCl3): δ 6.91 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.64 (bs, 1H), 3.91 (s,
ACS Paragon Plus Environment

Page 19 of 35
The Journal of Organic Chemistry
3H), 2.22 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 170.8, 151.8, 135.1, 128.3, 126.5,
1
2
3
ꢀ1
121.1, 116.1, 52.1, 18.9, 12.9; IR (neat film, cm ): 3399, 2360, 2341, 1706, 1293, 1047; HRMS (ECꢀ
4
5
6
CI): calcd. for C10H12O3 [M] 180.0786, found 180.0787.
7
8
9
Methyl 5-hydroxy-2,4-dimethylbenzoate (16a) and methyl 3-hydroxy-2,4-dimethylbenzoate (16b).
Prepared following General Procedure B using 2,4ꢀdimethyl methylbenzoate (150.0 mg, 0.91 mmol, 1.0
equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (649.0 mg, 2.28 mmol, 2.5 equiv., 82%), and HFIP (9.1 mL)
at 75 °C for 48 hrs. The crude orange foam was purified by silica gel chromatography; pentane and
then hexane → 30% EtOAc in hexane to afford the phenol 16a as a pale yellow amorphous oil (63.2
mg, 0.35 mmol, 38%) and phenol 16b as a pale yellow oil (57.4 mg, 0.22 mmol, 35%). The spectral
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
data for the title compound matches that of phenol 16a.44 Major Isomer (16a): H NMR (400 MHz,
1
CDCl3): δ 7.36 (s, 1H), 6.99 (s, 1H), 3.86 (s, 3H), 2.48 (s, 3H), 2.25 (s, 3H). Minor Isomer (16b): H
NMR (400 MHz, CDCl3): δ 7.37 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 4.91 (bs, 1H), 3.87 (s,
3H), 2.48 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.4, 152.6, 133.0, 129.1, 127.6,
ꢀ1
124.7, 122.5, 51.9, 16.4, 12.6; IR (neat film, cm ): 3477, 2952, 1702, 1435, 1273, 1054; HRMS (ECꢀ
CI): calcd. for C10H13O3 [M+H]+ 181.0865, found 181.0865.
Methyl 4-hydroxy-2,3-dimethylbenzoate (17a), methyl 6-hydroxy-2,3-dimethylbenzoate (17b), me-
thyl 5-hydroxy-2,3-dimethylbenzoate (17c). Prepared following General Procedure B using 2,3ꢀ
dimethyl methylbenzoate (100.0 mg, 0.61 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (422.0
mg, 1.52 mmol, 2.5 equiv., 84%), and HFIP (6.1 mL) at 75 °C for 48 hrs. The crude orange foam was
purified by silica gel chromatography; 1 – 5% Et2O in hexane / CH2Cl2 (1:1) to afford the phenols 17a
as a pale yellow amorphous oil (25.9 mg, 0.14 mmol, 24%), 17b as a pale yellow amorphous oil (21.8
mg, 0.12 mmol, 20%), and 17c as a pale yellow foam (14.9 mg, 0.08 mmol, 14%). The spectral data for
the title compounds matches that for phenols 17a and 17b.44,47 Major Isomer (17a): 1H NMR (400 MHz,
CDCl3): δ 7.65 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 3.85 (s, 3H), 2.51 (s, 3H), 2.20 (s, 3H).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 35
Minor Isomer (17b): 1H NMR (400 MHz, CDCl3): δ 10.58 (bs, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.13 (d, J
1
2
3
1
= 7.8 Hz, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.32 (s, 3H). Minor Isomer (17c): H NMR (400 MHz,
4
5
6
7
8
CDCl3): δ 7.10 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 5.25 (bs, 1H), 3.87 (s, 3H), 2.35 (s, 3H),
2.26 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 168.7, 152.6, 139.7, 131.7, 129.8, 120.4, 114.1, 52.0, 20.7,
15.8; IR (neat film, cmꢀ1): 3398, 1718, 1436, 1225; HRMS (ECꢀCI): calcd. for C10H12O3 [M] 180.0786,
found 180.0785.
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
Methyl 3-hydroxy-2,5-dimethylbenzoate (18a), methyl 4-hydroxy-2,5-dimethylbenzoate (18b), me-
thyl 2-hydroxy-3,6-dimethylbenzoate (18c). Prepared following General Procedure B using 2,5ꢀ
dimethyl methylbenzoate (100.0 mg, 0.61 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (422.0
mg, 1.52 mmol, 2.5 equiv., 84%), and HFIP (6.1 mL) at 75 °C for 48 hrs. The crude orange foam was
purified by silica gel chromatography; pentane and then hexane → 15% acetone in hexane to afford the
phenols 18a (27.7 mg, 0.15 mmol, 25%) and 18b (14.5 mg, 0.08 mmol, 13%) as pale yellow foams, and
18c as a pale yellow solid (13.9 mg, 0.08 mmol, 13%). The spectral data for the title compounds
1
matches that for phenols 18a, 18b, and 18c.49,50 Major Isomer (18a): H NMR (400 MHz, CDCl3): δ
7.23 (s, 1H), 6.77 (s, 1H), 5.22 (bs, 1H), 3.88 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H). Minor Isomer (18b): 1H
NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 6.62 (s, 1H), 5.57 (bs, 1H), 3.85 (s, 3H), 2.52 (s, 3H), 2.22 (s,
3H). Minor Isomer (18c): 1H NMR (400 MHz, CDCl3): δ 11.58 (bs, 1H), 7.15 (d J = 7.5 Hz, 1H,), 6.62
(d, J = 7.5 Hz, 1H), 3.95 (s, 3H), 2.50 (s, 3H), 2.22 (s, 3H).
3-(4-chloro-2-hydroxyphenoxy)propane-1,2-diol (19). Prepared following General Procedure A using
chlorphenesin (95 mg, 0.47 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (165 mg, 0.61 mmol,
1.3 equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride), and HFIP (4.7 mL)
at 50 °C for 24 hours. After removal of the HFIP by continuous positive flow of N2, the mixed
phthalate acid was placed under an atmosphere of N2 and a deꢀoxygenated mixture of methanol / satuꢀ
rated aqueous NaHCO3 (9 / 1, 4.7 mL) was added via syringe under N2. The resulting redꢀorange susꢀ
ACS Paragon Plus Environment

Page 21 of 35
The Journal of Organic Chemistry
pension was placed in an oil bath heated to 50 °C and stirred (700 rpm). After 1 hour the methanol was
removed by a continuous flow of N2 from the red solution, diluted with EtOAc (15 mL), an aqueous
phosphate buffer (5 mL, 0.2 M, pH = 7), and brine (5 mL). The biphasic mixture was stirred (700 rpm)
for 5 minutes and then poured into a separatory funnel containing brine (10 mL) and aqueous phosphate
buffer (10 mL, 0.2 M, pH = 7). After the layers were partitioned the organic layer was collected and
washed with a saturated aqueous mixture of NaHCO3 and brine (1:1, 3 x 30 mL). The aqueous layers
were back extracted with EtOAc (4 x 30 mL). The combined organics were dried over Na2SO4, filtered,
and concentrated to provide a brown solid which was purified by silica gel chromatography; 5 ꢀ 50 %
acetone in hexanes to provide triol 19 (53.0 mg, 0.24 mmol, 52%) as a pale yellow viscous oil and
1
2
3
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
1
chlorphenesin (11.0 mg, 0.05 mmol, 12%) as a white solid. Rf = 0.47 (50% acetone in hexanes); H
NMR (400 MHz, C3D6O) δ 8.21 (bs, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.79 (dd, J
= 2.7, 8.6 Hz, 1H), 4.39 (bs, 1H), 4.14 (m, 1H), 4.01 (m, 2H), 3.84 (m, 1H), 3.67 (t, J = 5.5 Hz, 2H); 13C
NMR (125 MHz, C3D6O) δ 148.2, 145.9, 125.8, 119.1, 115.5, 114.6, 71.4, 70.4, 62.9; IR (neat film, cmꢀ
1) 3410, 2935, 1634, 1592, 1504, 1268, 1215; HRMS (ECꢀESI) calcd. for C9H11ClNaO4 [M+Na]+
241.0238, found 241.0234.
Chlorphenesin carbonate. The solid mixture of chlorphenesin (0.40 g, 1.97 mmol, 1.0 equiv.), 1,1’ꢀ
carbonyl diimidazole (0.48 g, 3.0 mmol, 1.5 equiv.), and 4ꢀN,N’ꢀdimethyl aminopyridine (0.01 g, 0.10
mmol, 0.05 equiv.) were added under N2 into a flameꢀdried reaction vessel. Purified CH2Cl2 (19.7 mL)
was added under N2 followed by the addition of freshly distilled Et3N (1.0 g, 1.39 mL, 9.87 mmol, 5.0
equiv.). The homogeneous, clear pale yellow solution was allowed to stir (300 rpm) for 18 hours at 23
°C, diluted with Et2O (30 mL), and an aqueous phosphate buffer (50 mL, 0.2 M, pH = 7) was added.
The mixture was poured into a separatory funnel and the layers were separated. The organics layer was
removed and the residual organics were back extracted from aqueous layer with Et2O (4 x 20 mL), dried
over Na2SO4, filtered, and concentrated to provide an off white solid which was purified by column
chromatography; 5 – 25% acetone in hexanes to provide the carbonate as a white solid (0.30 g, 1.31
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 35
mmol, 67%). The spectra of the carbonate matches that reported.51 Rf = 0.56 (40% acetone in hexanes);
1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 5.02 (m, 1H), 4.62 (dd,
J = 7.6, 8.6 Hz, 1H), 4.52 (dd, J = 5.81, 8.5 Hz, 1H), 4.22 (dd, J = 4.1, 10.6 Hz, 1H), 4.12 (dd, J = 3.4,
1
2
3
4
5
6
7
8
13
10.6 Hz, 1H); C NMR (125 MHz, CDCl3) δ 156.3, 154.5, 129.6, 127.0, 115.9, 73.9, 67.3, 66.1; IR
9
(neat film, cmꢀ1) 1790, 1492, 1243, 1169.
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-((4-chloro-2-hydroxyphenoxy)methyl)-1,3-dioxolan-2-one (20). Prepared following General Proceꢀ
dure A using carbonate (50 mg, 0.22 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (138 mg, 0.51
mmol, 2.5 equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride)), and HFIP
(2.0 mL) at 50 °C for 24 hours. The crude brown viscous oil was purified by silica gel chromatography;
5 ꢀ 30% acetone in hexanes to provide the carbonate 20 (28.0 mg, 0.11 mmol, 52%) as a pale orange
1
solid. Rf = 0.46 (40% acetone in hexanes); H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 2.4 Hz, 1H),
6.84 (dd, J = 2.4, 8.6 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 5.48 (bs, 1H), 5.07 (m, 1H), 4.66 (dd, J = 8.2,
8.9 Hz, 1H), 4.47 (dd, J = 5.8, 8.9 Hz, 1H), 4.30 (dd, J = 3.4, 10.9 Hz, 1H), 4.20 (dd, J = 4.4, 10.9 Hz,
1
1H); H NMR (400 MHz, C3D6O) δ 8.39 (bs, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 2.6 Hz, 1H),
6.80 (dd, J = 2.5, 8.5 Hz, 1H), 5.20 (m, 1H), 4.71 (t, J = 8.5 Hz, 1H), 4.56 (dd, J = 6.9, 8.5 Hz, 1H),
13
4.39 (dd, J = 3.4, 11.2 Hz, 1H), 4.33 (dd, J = 4.7, 11.2 Hz, 1H); C NMR (150 MHz, C3D6O) δ 155.5,
148.9, 146.3, 127.2, 120.0, 116.8, 115.8, 75.7, 69.5, 66.7; IR (neat film, cmꢀ1) 3400, 2922, 1783, 1634;
HRMS (ECꢀCI) calcd. for C10H9ClO5 [MꢀH]+ 244.0139, found 244.0141; M.P. = 122 ꢀ 125°C.
3-(4-chloro-2-hydroxyphenoxy)-2-hydroxypropyl carbamate (21). Prepared following General Proꢀ
cedure A using chlorphenesin carbamate (85 mg, 0.35 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxꢀ
ide 7 (122 mg, 0.45 mmol, 1.3 equiv., (using material of 86% purity with 14 % 4,5ꢀdichlorophthalic anꢀ
hydride)), and HFIP (3.5 mL) at 50 °C for 24 hours. After removal of the HFIP by continuous positive
flow of N2, the intermediate phthalate esterꢀacid was placed under an atmosphere of N2 and a deꢀ
oxygenated mixture of methanol / saturated aqueous NaHCO3 (9 / 1, 3.5 mL) was added via syringe unꢀ
ACS Paragon Plus Environment

Page 23 of 35
The Journal of Organic Chemistry
der N2. The resulting redꢀorange suspension was placed in an oil bath heated to 50 °C and stirred vigorꢀ
ously (500 rpm). After 1 hour the methanol was removed by a continuous flow of N2, diluted with
EtOAc (15 mL), and an aqueous phosphate buffer (5 mL, 0.2 M, pH = 7) and brine (5 mL) were added.
The biphasic mixture was stirred vigorously (700 rpm) for 5 minutes and then poured into a separatory
funnel containing additional brine (10 mL) and an aqueous phosphate buffer (10 mL, 0.2 M, pH = 7).
After the layers were separated the organics were washed with a saturated aqueous mixture of NaHCO3
and brine (1 : 1, 3 x 30 mL). The residual organics were back extracted from the aqueous layer repeatꢀ
edly with EtOAc (4 x 30 mL). The combined organics were dried over Na2SO4, filtered, and concenꢀ
trated to provide a brown solid which was purified by silica gel chromatography; 5 ꢀ 35% acetone in
hexanes to yield the carbamate 21 (57.0 mg, 0.22 mmol, 63%) as an offꢀwhite solid. Rf = 0.45 (50%
acetone in hexanes); 1H NMR (400 MHz, CD3OD) δ 6.88 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H),
6.74 (dd, J = 2.4, 8.6 Hz, 1H), 4.16 (m, 3H), 4.06 (m, 1H), 3.98 (m, 1H); 13C NMR (100 MHz, CD3OD)
δ 158.3, 147.6, 145.6, 126.0, 118.9, 115.5, 113.8, 70.0, 68.1, 64.9; IR (neat film, cmꢀ1) 3369, 1706,
1501; HRMS (ECꢀESI) calcd. for C10H12ClNNaO5 [M+Na]+ 284.0296, found 284.0293; M.P. = 124 ꢀ
127°C.
1
2
3
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
5-fluoro-2-pentylphenol (22a) and 2-fluoro-5-pentylphenol (22b). Prepared following General Proꢀ
cedure B using 4ꢀpentyl fluorobenzene (100 mg, 0.60 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide
7 (403 mg, 1.50 mmol, 2.5 equiv., (using material of 87% purity with 13% 4,5ꢀdichlorophthalic anhyꢀ
dride), and HFIP (6.0 mL) at 75 °C for 36 hours. The crude brown viscous oil was purified by silica gel
chromatography; 1 % Et2O in CH2Cl2 / hexanes (1 / 1) to provide fluorophenols 22a and 22b (64.3 mg,
0.35 mmol, 59%, 22a : 22b = 2.5 : 1) as a yellow oil. The spectra of phenols matched that reported for
22b.51 Rf = 0.57 (3% Et2O in 49% hexanes and 48% CH2Cl2); Major Isomer (22a): 1H NMR (400 MHz,
CDCl3) δ 7.03 (dd, J = 6.8, 8.6 Hz, 1H), 6.57 (ddd, J = 5.8, 8.2, 10.0 Hz, 1H), 6.52 (dd, J = 2.4, 9.9 Hz,
13
1H), 4.82 (bs, 1H), 2.53 (t, J = 8.2 Hz, 2H), 1.58 (m, 2H), 1.35 (m, 4H), 0.90 (m, 3H); C NMR (100
MHz, CDCl3) δ161.4 (d, JCF = 243.4 Hz), 154.2 (d, JCF = 10.7 Hz), 130.7 (d, JCF = 9.9 Hz), 124.2 (d, JCF
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 35
= 3.8 Hz), 107.5, 103.0, 31.6, 29.5, 29.3, 22.5, 14.0; IR (neat film, cmꢀ1) 3391, 2929, 1609, 1514, 1279,
1
2
3
1
1112; HRMS (ECꢀCI) calcd. for C11H15OF [M+H]+ 182.1107, found 182.1106. Minor Isomer (22b): H
4
5
6
NMR (400 MHz, CDCl3) δ 6.95 (dd, J = 8.2, 10.3 Hz, 1H), 6.84 (dd, J = 2.1, 8.6 Hz, 1H), 6.66 ꢀ 6.63
7
8
13
(m, 1H), 5.01 (bs, 1H), 2.53 (t, J = 8.2 Hz, 2H), 1.58 (m, 2H), 1.35 (m, 4H), 0.90 (m, 3H); C NMR
9
(100 MHz, CDCl3) δ 149.3 (d, JCF = 234.2 Hz), 142.9 (d, JCF = 14.5 Hz), 139.9 (d, JCF = 3.1 Hz), 120.5
(d, JCF = 6.1 Hz), 117.0 (d, JCF = 1.5 Hz), 115.0 (d, JCF = 1.6 Hz), 35.3, 31.4, 31.1, 22.5, 14.0; IR (neat
film, cmꢀ1) 3391, 2929, 1609, 1514, 1279, 1112; HRMS (ECꢀCI) calcd. for C11H15OF [M+H]+
182.1107, found 182.1106.
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
2-butyl-5-chlorophenol (23a) and 5-butyl-2-chlorophenol (23b). Prepared following General Proceꢀ
dure B using 4ꢀbutyl chlorobenzene (100 mg, 0.59 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7
(406 mg, 1.48 mmol, 2.5 equiv., (using material of 85% purity with 15% 4,5ꢀdichlorophthalic anhyꢀ
dride)), and HFIP (5.9 mL) at 75 °C for 36 hours. The crude brown viscous oil was purified by silica
gel chromatography; 1 % Et2O in CH2Cl2 / hexanes (1 / 1) to provide chlorophenols 23a and 23b (64.4
mg, 0.35 mmol, 59%, 23a : 23b = 4 : 1) as a yellow oil. Rf = 0.57 (3% Et2O in 49% Hexanes and 48%
CH2Cl2); Major Isomer (23a): 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 7.9 Hz, 1H), 6.5 (dd, J = 2.1,
8.2 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 4.69 (bs, 1H), 2.56 (t, J = 7.5 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.37
(m, 2H), 0.94 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ154.2, 132.0, 131.2, 127.4, 121.1,
115.8, 32.0, 29.4, 22.7, 14.2; IR (neat film, cmꢀ1) 3412, 2957, 2930, 1603, 1588, 1413; HRMS (ECꢀCI)
1
calcd. for C10H13OCl [M+H]+ 184.0655, found 184.0653. Minor Isomer (23b): H NMR (400 MHz,
CDCl3) δ 7.19 (d, J = 8.2 Hz, 1H), 6.86 – 6.83 (m, 1H), 6.69 (dd, J = 2.1, 8.2 Hz, 1H), 5.43 (bs, 1H),
2.54 (t, J = 7.5 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.37 (tq, J = 7.5, 7.9 Hz, 2H), 0.92 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 151.0, 143.8, 128.5, 121.5, 116.9, 116.1, 35.1, 33.3, 22.2, 13.9; IR (neat
film, cmꢀ1) 3412, 2957, 2930, 1603, 1588, 1413; HRMS (ECꢀCI) calcd. for C10H13OCl [M+H]+
184.0655, found 184.0653.
ACS Paragon Plus Environment

Page 25 of 35
The Journal of Organic Chemistry
5-bromo-2-butylphenol (24a) and 2-bromo-5-butylphenol (24b). Prepared following General Proceꢀ
dure B using 4ꢀbutyl bromobenzene (100 mg, 0.47 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7
(321 mg, 1.17 mmol, 2.5 equiv., (using material of 85% purity with 15% 4,5ꢀdichlorophthalic anhyꢀ
dride), and HFIP (4.7 mL) at 75 °C for 36 hours. The crude brown viscous oil was purified by silica gel
chromatography; 1 % Et2O in CH2Cl2 / hexanes (1 / 1) to provide bromophenols 24a and 24b (58.3 mg,
0.25 mmol, 54%, 24a : 24b = 10 : 1) as a dark yellow oil. Rf = 0.57 (3% Et2O in 49% Hexanes and
1
2
3
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
1
48% CH2Cl2); H NMR (400 MHz, C6D6) δ 6.88 (dd, J = 2.0, 8.2 Hz, 1H), 6.58 (d, J = 8.2 Hz, 1H),
6.29 (s, 1H), 3.90 (bs, 1H), 2.36 (t, J = 7.9 Hz, 2H), 1.40 (tt, J = 7.5, 7.9 Hz, 2H), 1.17 (qt, J = 7.5, 7.5
1
Hz, 2H), 0.80 (t, J = 7.52 Hz, 3H); H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 1.7 Hz, 1H), 6.97 (bs,
1H), 6.93 (d, J = 1.7 Hz, 1H), 4.72 (bs, 1H), 2.55 (t, J = 7.5 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.42 – 1.33
13
(qt, J = 7.5, 7.5 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H); C NMR (100 MHz, CDCl3) δ 154.5, 131.6, 128.0,
124.0, 119.6, 118.6, 31.9, 29.5, 22.7, 14.2; IR (neat film, cmꢀ1) 3390, 2957, 2928, 1408, 1123; HRMS
(ECꢀCI) calcd. for C10H12OBr [M+H]+ 228.0150, found 228.0149.
2-nitro-4-dichlorobenzene. Concentrated H2SO4 (6.7 mL, 18 M, 98%) was slowly added to fuming
HNO3 (6.7 mL, 90%) in a cold bath (0 °C). After 5 minutes pꢀdichlorobenzene (2.0 g, 13.6 mmol, 1.0
equiv.) was added in one portion. After 2 minutes the cooling bath was removed and the yellow heteroꢀ
geneous mixture was stirred vigorously (700 rpm) at 23 °C. After 15 minutes the yellow homogeneous
solution was poured into ice water (250 mL), and the resulting yellow solid was filtered. The yellow
solid was dried in vacuo with heating (100 °C) for 30 minutes to remove excess H2O to provide 2ꢀnitroꢀ
4ꢀdichlorobenzene (2.43 g, 12.7 mmol, 93%) as a pure yellow solid.53 1H NMR (400 MHz, CDCl3) δ
7.89 (s, 1H), 7.50 (m, 2H).
2-nitro-4,4’-phenyl ether: The solid mixture of 2ꢀnitroꢀ4ꢀdichlorobenzene (2.40 g, 12.5 mmol, 1.0
equiv.), KOH (0.74 g, 13.1 mmol, 1.1 equiv.), and 4ꢀchlorophenol (1.77 g, 13.8 mmol, 1.1 equiv.) was
suspended in water (1 mL), placed in a hot oil bath heated to 170 °C, and stirred (400 rpm). After 2.5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 35
hours the reddishꢀbrown solution was removed from the oil bath, cooled to 23 °C, diluted with Et2O (20
mL), and diluted with 4 N NaOH (20 mL). The biphasic mixture was then poured into a separatory
funnel. Water (20 mL) and Et2O (20 mL) were added to dissolve residual solids and, following soniꢀ
cation, the yellowꢀorange mixture was added to the separatory funnel. The layers were separated and
the organic layer was washed with 4 N NaOH (3 x 20 mL) to remove excess 4ꢀchlorophenol. The aqueꢀ
ous phase was extracted with Et2O (3 x 20 mL), combined with the initial organic extract, dried over
Na2SO4, filtered, and concentrated to provide the 2ꢀnitroꢀ4,4’ꢀdichlorophenyl ether (3.43 g, 12.1 mmol,
97%) as a pure yellowꢀorange solid.53 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.4 Hz, 1H), 7.48 (dd,
J = 2.7, 8.9 Hz, 1H), 7.35 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 9.2 Hz, 3H).
1
2
3
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
2-amino-4,4’-dichloro phenyl ether: To a suspension of the nitro phenyl ether (3.43 g, 12.1 mmol, 1.0
equiv.) in ethanol (48.3 mL) and water (48.3 mL) solid iron powder (1.82 g, 32.6 mmol, 2.7 equiv.) and
solid NH4Cl (2.91 g, 54.3 mmol, 4.5 equiv.) were added. The reaction vessel was equipped with a reꢀ
flux condenser, purged with N2, and the black mixture was placed in an oil bath heated to 110 °C with
vigorous stirring (1000 rpm). After 12 hours the black mixture was filtered over celite and the EtOH
was removed in vacuo. The resulting yellow mixture was diluted with CH2Cl2 (50 mL) and an aqueous
phosphate buffer solution (50 mL, 0.2 M, pH = 10), poured into a separatory funnel, and the layers were
separated. The organic extract was washed with an aqueous phosphate buffer (1 x 25 mL, 0.2 M, pH =
10). The aqueous layer was extracted with CH2Cl2 (2 x 30 mL), combined with the previous organic
extract, dried over Na2SO4, filtered, and concentrated to provide the aniline (2.96 g, 11.65 mmol, 96%)
pure as a yellow solid.53 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 9.2 Hz,
2H), 6.80 (d, J = 2.4 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 2.4, 8.6 Hz, 1H), 3.86 (bs, 2H).
2,4,4’-trichloro phenyl ether: To the dichloroꢀaniline (2.96 g, 11.7 mmol, 1.0 equiv.) water (9.0 mL)
and concentrated HCl (7.0 mL, 87.0 mmol, 7.5 equiv., 38%, 12.4 M) were added. The orange mixture
was placed in an ice water bath and stirred vigorously (400 rpm). After 5 minutes solid NaNO2 (0.88 g,
ACS Paragon Plus Environment

Page 27 of 35
The Journal of Organic Chemistry
12.8 mmol, 1.1 equiv.) was added in one portion and the mixture changed to deep redꢀorange solution.
After 25 minutes, CuCl (1.73 g, 17.5 mmol, 1.5 equiv.) was added in one portion followed by concenꢀ
trated HCl solution (1.5 mL, 18.0 mmol, 1.6 equiv., 38%, 12.4 M). The dark redꢀorange solution was
removed from the cooling bath and stirred vigorously (400 rpm) at 23 °C. After 30 minutes the dark
orange biphasic mixture was diluted with Et2O (20 mL), poured into a separatory funnel, and the layers
were partitioned. The organic layer was washed with 1 N HCl (3 x 25 mL). The aqueous layer was exꢀ
tracted with Et2O (3 x 25 mL), combined with the first organic extract, dried over Na2SO4, filtered, conꢀ
centrated, and the crude yellowꢀorange solid was purified by silica gel chromatography using hexanes to
provide the trichloride (1.34 g, 4.90 mmol, 42%) as a white crystalline solid. The spectra of the trichloꢀ
ride matched that reported for 2,4,4’ꢀtrichloro phenyl ether.54 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J =
2.7 Hz, 1H), 7.29 (d, J = 8.9 Hz, 2H), 7.21 (dd, J = 2.4, 8.6 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 6.88 (d, J
= 8.9 Hz, 2H).24
1
2
3
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
Triclosan (25). Prepared following General Procedure A using trichloride (95 mg, 0.35 mmol, 1.0
equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (188 mg, 0.70 mmol, 2.0 equiv., (using material of 86% purity
with 14% 4,5ꢀdichlorophthalic anhydride)), and HFIP (3.5 mL) at 60 °C for 24 hours. The crude brown
viscous oil was purified by silica gel chromatography; 1 – 10% Et2O in pentane to provide triclosan (25)
(52.0 mg, 0.18 mmol, 52%) as a paleꢀyellow viscous oil and the starting trichloride (8.4 mg, 0.03 mmol,
9%). The spectra of the phenol matched that reported for triclosan (25).55 1H NMR (400 MHz, CDCl3)
δ 7.48 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 2.4, 8.6 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 8.9 Hz,
1H), 6.81 (dd, J = 2.4, 8.9 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 5.63 (bs, 1H).
4-butylphenol (26a) and 2-butylphenol (26b). Prepared following General Procedure A using butyl
benzene (100 mg, 0.75 mmol, 1.0 equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (262 mg, 0.97 mmol, 1.3
equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride), and HFIP (7.5 mL) at
50 °C for 24 hours. The crude orange viscous oil was purified by silica gel chromatography; 1 – 5%
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 35
Et2O in CH2Cl2 / hexanes (1 / 1) to provide phenols 26a and 26b (81.1 mg, 0.54 mmol, 73%, 26a : 26b
= 1.2 : 1) as a pale yellow viscous oil. The spectra of phenols matched that reported for 26a and
1
2
3
4
5
6
1
26b.26,39 Major Isomer (26a): H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.4
7
8
9
Hz, 2H), 4.56 (bs, 1H), 2.54 (t, J = 7.8 Hz, 2H), 1.64 – 1.52 (m, 2H), 1.44 – 1.31 (m, 2H), 0.92 (t, J =
7.1 Hz, 3H) Minor Isomer (26b): 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.05 (m, 2H), 6.87 (ddd, J = 1.1,
7.4, 8.6 Hz, 1H), 6.77 – 6.74 (m, 1H), 4.64 (bs, 1H), 2.61 (t, J = 7.9 Hz, 2H), 1.64 – 1.52 (m, 2H), 1.44
– 1.31 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H).
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
Methyl 3-(4-hydroxyphenyl)propanoate (27a) and methyl 3-(2-hydroxyphenyl)propanoate (27b).
Prepared following General Procedure B using the hydrocinnamyl methyl ester (100 mg, 0.61 mmol, 1.0
equiv.), 4,5ꢀdichlorophthaloyl peroxide 7 (399 mg, 1.52 mmol, 2.5 equiv., (using material of 89% purity
with 11% 4,5ꢀdichlorophthalic anhydride)), and HFIP (6.1 mL) at 75 °C for 36 hours. The crude brown
viscous oil was purified by silica gel chromatography; 1 – 5% Et2O in CH2Cl2 / hexanes (1 / 1) to proꢀ
vide esters 27a and 27b (81.3 mg, 0.55 mmol, 74%, 27a : 27b = 1.4 : 1) as a pale yellow viscous oil and
the starting ester (5.1 mg, 0.03 mmol, 5%) as a clear colorless oil. The spectra of the phenols match that
reported for 27a and 27b.50,56 Major Isomer (27a): 1H NMR (400 MHz, CDCl3) δ 7.26 (bs, 1H), 7.06 (d,
J = 8.6 Hz, 2H), 6.88 (d, J = 7.9 Hz, 2H), 3.69 (s, 3H), 2.91 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H).
Minor Isomer (27b): 1H NMR (400 MHz, CDCl3) δ 7.11 (m, 2H), 6.75 (m, 2H), 3.66 (s, 3H), 2.88 (t, J
= 7.9 Hz, 2H), 2.59 (t, J = 6.9 Hz, 2H).
3-(4-hydroxyphenyl)propanoic acid (28a) and 3-(2-hydroxyphenyl)propanoic acid (28b). Preꢀ
pared following General Procedure B using hydrocinnamic acid (100 mg, 0.67 mmol, 1.0 equiv.), 4,5ꢀ
dichlorophthaloyl peroxide 7 (451 mg, 1.67 mmol, 2.5 equiv., (using material of 86% purity with 14%
4,5ꢀdichlorophthalic anhydride)), CHCl3 (1.7 mL), and HFIP (5.0 mL) at 75 °C for 48 hours. After
removal of the HFIP and CHCl3 by continuous positive flow of N2, the mixed phthalate acidꢀester
was placed under an atmosphere of N2, suspended in 1,4ꢀdioxane (6.0 mL) and then a saturated aqueꢀ
ACS Paragon Plus Environment

Page 29 of 35
The Journal of Organic Chemistry
ous solution of NaHCO3 (0.7 mL) was added. The redꢀorange suspension was placed in an oil bath
heated to 50 °C and stirred (700 rpm). After 1 hour the red solution was removed from the oil bath,
acidified to a pH = 2 using 1 N HCl (3 mL), then diluted with EtOAc (20 mL), poured into a separatoꢀ
ry funnel containing brine (20 mL), and the layers were separated. The organic extract was washed
with an aqueous phosphate buffer (2 x 20 mL, 0.2 M, pH = 4) and the aqueous layer was combined
with the brine and back extracted with EtOAc (4 x 30 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated to provide an orange solid. The orange solid was suspended
in CH2Cl2 (30 mL), heated for 5 minutes, and sonicated for 1 minute. The residual orange mixture
was filtered to remove the insoluble 4,5ꢀdichlorophthalic acid. The orange filtrate solution was conꢀ
centrated to provide an orange solid which was purified by silica gel chromatography; 1% CH3OH +
1% AcOH in CH2Cl2 to provide acids 28a and 28b (71.8 mg, 0.43 mmol, 65%, 28a : 28b = 1 : 1) as
an orange solid. The starting acid (12.0 mg, 0.08 mmol, 12%) was isolated as a white solid. The specꢀ
tra of the phenols match that reported for 28a and 28b.57,58 Isomer 28a: 1H NMR (400 MHz, CDCl3) δ
7.08 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 2.90 (t, J = 8.2 Hz, 2H), 2.65 (t, J = 7.9 Hz, 2H).
1
2
3
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
1
Isomer 28b: H NMR (400 MHz, CDCl3) δ 7.11 (m, 2H), 6.82 – 6.89 (m, 2H), 2.92 (t, J = 6.5 Hz,
2H), 2.78 (t, J = 6.5 Hz, 2H).
Methyl 4-(2-(diethylamino)ethoxy)-3-methoxybenzoate. To a stirred solution of known methyl 4ꢀ(3ꢀ
chloropropoxy)ꢀ3ꢀmethoxybenzoate26 (1.37 g, 5.3 mmol, 1.0 equiv.) in dimethylformamide (28.5 mL)
was added NaI (1.59 g, 10.6 mmol, 2.0 equiv.) and diethylamine (1.64 mL, 15.9 mmol, 3.0 equiv.). The
flask was purged with N2 and placed in an oil bath heated to 80 °C. After 24 hours the solution was reꢀ
moved from the oil bath and allowed to cool to 23 °C, poured into a separatory funnel containing 3 N
LiCl (150 mL), and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed
with 3 N LiCl (1 x 50 mL) to remove residual DMF, brine (1 x 50 mL), dried over Na2SO4, concentratꢀ
ed in vacuo, and the crude mixture was purified by silica gel chromatography; 1% CH3OH and 1% Et3N
in CH2Cl2 to provide the amine as an amber oil (1.25 g, 80%). Rf = 0.40 (2% CH3OH + 2% Et3N in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 30 of 35
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.64 (dd, J =2.0, 8.6 Hz, 1H), 7.53 (d, J =2.0 Hz, 1H), 6.90 (d,
J = 8.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.61 (t, J = 7.1 Hz, 2H), 2.54 (q, J
1
2
3
4
5
6
13
= 7.4 Hz, 4H), 1.99 (m, 2H), 1.01 (t, J = 7.4 Hz, 6H); C NMR (100 MHz, CDCl3) δ 166.9, 152.5,
7
8
ꢀ1
148.8, 123.5, 122.4, 112.3, 111.5, 67.4, 56.0, 51.9, 49.1, 46.9, 26.6, 11.7; IR (neat film, cm ): 2967,
9
2809, 1717, 1293; HRMS (ECꢀCI): [M+Na]+ calc’d for C16H25NO4Na: 318.16758. Found: 318.16729.
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
Methyl 4-(2-(diethylamino)ethoxy)-2-hydroxy-3-methoxybenzoate (29). To a stirred (500 rpm) soluꢀ
tion of amine (75.0 mg, 0.25 mmol, 1.0 equiv.) in HFIP (2.5 mL) at 23 °C was added pꢀtoluenesulfonic
acid (43.7 mg, 0.25 mmol, 1.0 equiv.) and then 4,5ꢀdichlorophthaloyl peroxide 7 (89.0 mg, 0.33 mmol,
1.3 equiv., (using material of 86% purity with 14% 4,5ꢀdichlorophthalic anhydride)). After 4 hours, the
solvent was removed by a continuous flow of N2 providing the mixed phthalate esterꢀacid as a red solid.
The crude solid was placed under an atmosphere of N2, suspended in a deꢀoxygenated mixture of methꢀ
anol and saturated aqueous NaHCO3 (9 / 1, 2.5 mL), and placed in an oil bath heated to 50 °C. After 1
hour the reaction was poured into an aqueous phosphate buffer solution (5 mL, 0.2 M, pH = 10) and
then into a separatory funnel and the layers were separated. The residual organics were back extracted
from the aqueous layer with EtOAc (3 x 5 mL). The combined organic layers were washed with an
aqueous phosphate buffer (1 x 5 mL, 0.2 M, pH = 10), brine (1 x 5 mL), dried over Na2SO4, concentratꢀ
ed. The crude mixture was purified by silica gel chromatography; 1% methanol and 1% triethylamine in
CH2Cl2 providing phenol 29 as a clear colorless oil (67.7 mg, 0.22 mmol, 86%). Rf = 0.40 (2% methaꢀ
1
nol and 2% triethylamine in CH2Cl2). H NMR (400 MHz, CDCl3): δ 10.79 (s, 1 H), 7.55 (d, J = 9.0
Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 4.12 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.65 (t, J = 7.0 Hz, 2H), 2.57
(q, J = 7.0 Hz, 4H), 1.99 (t, J = 7.4 Hz, 2H), 1.04 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
170.1, 157.3, 155.7, 136.4, 125.3, 106.5, 103.9, 66.8, 60.3, 51.8, 48.9, 46.7, 26.4, 11.2; IR (neat film,
cm ꢀ1): 3369, 2966, 2917, 1720, 1240; HRMS (ECꢀCI): [M+H]+ calcd. for C16H26NO5: 312.1806; found:
312.1800.
ACS Paragon Plus Environment