A protocol to generate phthaloyl peroxide in flow for the hydroxylation of arenes

Article abstract of DOI:10.1021/ol501497y

A flow protocol for the generation of phthaloyl peroxide has been developed. This process directly yields phthaloyl peroxide in high purity (>95%) and can be used to bypass the need to isolate and recrystallize phthaloyl peroxide, improving upon earlier batch procedures. The flow protocol for the formation of phthaloyl peroxide can be combined with arene hydroxylation reactions and provides a method for the consumption of peroxide as it is generated to minimize the accumulation of large quantities of peroxide.

Full text of DOI:10.1021/ol501497y

Letter
pubs.acs.org/OrgLett
A Protocol To Generate Phthaloyl Peroxide in Flow for the
Hydroxylation of Arenes
Anders M. Eliasen, Randal P. Thedford, Karin R. Claussen, Changxia Yuan, and Dionicio Siegel*
Department of Chemistry, The University of Texas at Austin, 1 University Station, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: A flow protocol for the generation of phthaloyl peroxide has been developed. This process directly yields
phthaloyl peroxide in high purity (>95%) and can be used to bypass the need to isolate and recrystallize phthaloyl peroxide,
improving upon earlier batch procedures. The flow protocol for the formation of phthaloyl peroxide can be combined with arene
hydroxylation reactions and provides a method for the consumption of peroxide as it is generated to minimize the accumulation
of large quantities of peroxide.
henols are found in all areas of chemical industry including
pharmaceuticals, agrochemicals, and materials. While there
The yield of phthaloyl peroxide (1) prepared in batch is
highly dependent on the rate of stirring and amount of water
present (see Supporting Information). On larger scales the
efficiency of mixing heterogeneous reactions necessitates longer
reaction times. Additionally, a final precipitation is required to
access pure material, removing unreacted phthaloyl chloride
and phthalic anhydride formed as a byproduct (Figure 1).
In order to avoid working with (and storage of) large
quantities of phthaloyl peroxide (1), we developed a
straightforward method to generate phthaloyl peroxide cleanly
in flow. This method when combined with reactions in batch
allows for the hydroxylation of a wide array of arenes without
isolating phthaloyl peroxide (1).
Reactions performed in flow offer several advantages over
reactions in batch, including a small apparatus footprint and
increased safety.6 Batch reactions optimized on bench scale can
be “scaled-out” when attempting to meet high demand while
with flow scale up is more transferable.7 Reactions in flow also
circumvent exposure of toxic,8 air sensitive,9 or inherently
unstable materials10 simplifying chemical processes. Relevant to
our efforts several oxidation reactions have been successfully
performed in flow improving upon their batch counterparts.11
Notably, aerobic oxidation of Grignard reagents has been
P
are diverse approaches for the synthesis of phenols, there are no
broadly applicable methods for directly accessing phenols from
arenes. Peroxides have been extensively studied as oxidants for
the conversion of arenes to phenols and successfully employed
when used in combination with strong acids.1 These additives
are required to both activate the peroxides and deactivate the
resulting phenolic compounds, preventing a secondary
oxidation reaction. The reagent phthlaloyl peroxide (1) alone
converts aryl C−H bonds into C−O bonds.2 The reaction
proceeds in good yields and avoids overoxidation. As the
oxidant does not require additional catalysts or additives, the
procedure is straightforward. Importantly, phthaloyl peroxide
(1) selectively reacts with arenes while possessing little to no
observable reactivity toward a large number of functional
groups including those that are typically susceptible to
oxidation.
However, the use of stoichiometric amounts of peroxides for
oxidative transformations has potential safety drawbacks due to
the high energetics of peroxide containing compounds. As a
result, we report herein the development of a protocol for the
formation of phthaloyl peroxide in flow to circumvent the
discrete formation and isolation of large quantities of pure
phthaloyl peroxide. The formation of phthaloyl peroxide in flow
allows for the direct reaction of phthaloyl peroxide solutions
and the immediate consumption of the reagent as it is formed,
minimizing the accumulation of peroxide.
Received: April 23, 2014
© XXXX American Chemical Society
A
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Table 3. Effect of Water on the Oxidation of
a
Triisopropylbenzene by Phthaloyl Peroxide
b
entry
equiv water
conversion (%)
1.
2.
3.
4.
5.
6.
7.
8.
0
1
94
90
94
94
90
73
59
12
2
8
16
32
64
128
Figure 1. Preparation of phthaloyl peroxide in batch and flow.
Table 1. Solvent Screening for the Synthesis of Phthaloyl
Peroxide from Phthaloyl Chloride Using a Packed Bed
Reactions carried out using the existing batch procedure.2
Determined by NMR.
a
a
Reactor with Sodium Percarbonate
b
b
c
entry
solvent
conversion (%)
1.
2.
3.
4.
5.
ethyl acetate
acetone
68
76
trifluorotoluene
dichloroethane
>95
>95
>95
methylene chloride
a
Reactions conducted with a 167 μL/min flow rate (tr = 11 min) using
b
c
Figure 2. Schematic for the combination of flow and batch reactions
using phthaloyl peroxide.
a 40 psi BPR. ACS reagent grade solvent. Determined by NMR.
Table 2. Optimization of the Synthesis of Phthaloyl Peroxide
a
from Phthaloyl Chloride in Flow
bonate as an in-line reagent, and the contents of the packed bed
reactor are ultimately consumed. After a short induction (a
volume corresponding to twice the volume of the packed bed
reactor) yields were found to fluctuate by 4% over 72 min
(using a flow rate of 167 μL/min). For complete instructions
for constructing the packed bed reactor with sodium
percarbonate please refer to the associated Supporting
Information.
The polar aprotic solvents ethyl acetate and acetone afforded
moderate conversion of phthaloyl chloride (Table 1). However,
in addition to incomplete conversion the use of these solvents
led to the formation of phthalic anhydride in variable amounts.
Halogenated solvents proved optimal with clean conversion
and no detectable amounts of phthalic anhydride. Ultimately
methylene chloride was selected due to its volatility allowing it
to be selectively removed by distillation out of batch reactors.
While variable flow rates provide uniformly high conversion
the isolated yields of peroxide were best achieved using higher
flow rates (Table 2). Unabated, carbon dioxide generated from
the reaction of HCl with sodium carbonate propelled material
through the reactor at rates faster than selected. Therefore, the
feed emanating from the end of the packed bed reactor was
affixed with a back-pressure regulator (BPR) to allow constant
velocity through the reactor. In addition to providing
consistency, an increase in yield was observed after employing
a BPR (Table 2, entry 4).
flow rate
BPR
(psi)
conversion
yield
c
b
entry
(μL min−1
)
CH2CI2
(%)
(%)
1.
2.
3.
4.
5.
6.
50
167
334
167
167
167
anhydrous
anhydrous
anhydrous
anhydrous
wet
40
>95
>95
>95
>95
>95
>95
61
71
72
66
47
57
40
40
none
40
reagent
40
d
grade
a
Flow rate of 50 μL/min, tr = 37 min; flow rate of 167 μL/min, tr = 11
min; flow rate of 334 μL/min, tr = 5.5 min. Determined by NMR.
b
c
d
Isolated yield. ACS reagent grade.
developed in continuous flow providing access to phenolic
compounds.12
We envisioned the construction of a packed bed reactor
containing solid sodium percarbonate to be the key component
to our reaction protocol.13 Fine mesh sodium percarbonate
increased mixing and was found to be required for full
conversion. The use of mesh sieves to control the particle size
in the packed bed reactor proved important.14 Particles smaller
than the frit porosity tended to clog the packed bed reactor,
and the uniformity of particle size of sodium percarbonate
increased reproducibility. This procedure uses sodium percar-
Water-saturated methylene chloride can extract six times the
amount of hydrogen peroxide from sodium percarbonate than
anhydrous methylene chloride.15 Consequently, we found that
B
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Figure 3. Batch arene hydroxylation by phthaloyl peroxide (1) generated in flow.
trace water content in batch reactions was critical to ensure
adequate leaching of hydrogen peroxide. The opposite was
observed for the synthesis of phthaloyl peroxide in flow: yields
increased 24% using anhydrous methylene chloride in place of
wet solvent.
solvents. While methylene chloride and HFIP form an
azeotrope, we found that trifluoroethanol (TFE) and
methylene chloride do not, allowing the selective removal of
methylene chloride. This enabled our reaction design to
provide pure phthaloyl peroxide in TFE in analogy to our
previous reactions in batch.
While the role of water was well understood in the formation
of phthaloyl peroxide (1), the presence of water in the course
of the hydroxylation was investigated (Table 3). The synergistic
effects of water in fluorinated alcohol solvents for an
organocatalytic C−H oxidation reaction has been noted.16
Similarly water has been found to assist the reaction of malonyl
peroxides with styrenes and stillbenes.17 Despite no improve-
ments in the reaction of phthaloyl peroxide with arenes the
hydroxylation reaction is tolerant of water; addition of up to 16
equiv of water did not affect the conversion. This further
supports our previous observation that the direct use of
solvents as supplied from commercial sources is permissible.
The reaction of phthaloyl peroxide with arenes has been
optimized using fluorinated alcoholic solvents. The addition of
cosolvents typically reduces yields. Reaction of mesitylene with
phthaloyl peroxide in a 1:1 solution of methylene chloride/
hexafluoroisopropanol (HFIP) resulted, after hydrolysis, in a
diminished 56% yield of trimethylphenol as compared to the
reaction conducted solely in HFIP generating trimethylphenol
in 97% yield. To remove methylene chloride, boiling point
measurements and analysis of distillates were conducted in
mixtures of methylene chloride and fluorinated alcohol
Combination of the formation of phthaloyl peroxide in flow
with batch reactions was achieved through the setup shown in
Figure 2. Using a syringe pump a 0.2 M solution of phthaloyl
chloride in methylene chloride is passed through a packed bed
reactor with solid sodium percarbonate at a rate of 167 μL/min.
This system empties into a two-neck round-bottom flask
containing the arene of interest at 0.1 M in TFE heated in an
oil bath set to 60 °C. The flask is equipped with a distillation
head to permit the continuous distillation of methylene
chloride as the phthaloyl peroxide solution adds.
Similar to reactions employing isolated, solid phthaloyl
peroxide arenes possessing a variety of functionality are
tolerated by this method. Steric encumbrance bears little effect
on the reaction (4a−d, Figure 3). Groups classically considered
labile toward oxidative conditions are left unreacted. Allylic
(4e), allenic (4h), and propargylic (4i) groups are not oxidized.
Carbonyls derivatives can be hydroxylated with no evidence of
Baeyer−Villiger/Dakin oxidations as seen for the syntheses of
the phenols 4f and 4n.
Molecules possessing more than one benzene ring are
selectively oxidized on the most electronically activated ring
C
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(9) (a) Pellegatti, L.; Buchwald, S. L. Org. Process Res. Dev. 2012, 16,
1442. (b) Shu, W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51,
5355.
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(4f). Naphthalene derivatives are hydroxylated in good yield.
Trimethylsilyl groups (4l) remained intact as well as epoxides
(4k). Finally, phenols of the nonsteroidal anti-inflammatory
drugs (NSAID) nabumetone (4n) and naproxen (4o) were
generated providing potential metabolite standards.
In summary, we have described a method to safely generate
phthaloyl peroxide (1) in flow and use this procedure, in
combination with batch reactions, to hydroxylate arenes. This
procedure circumvents the need to isolate solid phthaloyl
peroxide. The development of a reaction apparatus allows for
the continuous removal of methylene chloride providing
solutions of phthaloyl peroxide in TFE, therefore maximizing
reactivity.
́
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(d) Bourne, S. L.; Ley, S. V. Adv. Synth. Catal. 2013, 355, 1905.
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ASSOCIATED CONTENT
* Supporting Information
■
(12) He, Z.; Jamison, T. F. Angew. Chem., Int. Ed. 2014, 53, 3353.
(13) Bogdan, A.; McQuade, D. T. Beilstein J. Org. Chem. 2009, 5,
No. 17.
S
Detailed instructions for assembling the flow apparatus,
experimental procedures, and characterization data are included
in the Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) (a) Naber, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49,
9469. (b) Noel, T.; Maimone, T. J.; Buchwald, S. L. Angew. Chem., Int.
̈
Ed. 2011, 50, 8900.
(15) Rocha Gonsalves, A.M. d’A.; Johnstone, R. A. W.; Pereira, M.
M.; Shaw, J. J. Chem. Res. (M) 1991, 2101−2118.
(16) Adams, A. M.; Du Bois, J. Chem. Sci. 2014, 5, 656.
(17) Griffith, J. C.; Jones, K. M.; Picon, S.; Rawling, M. J.; Kariuki, B.
M.; Campbell, M.; Tomkinson, N. C. O. J. Am. Chem. Soc. 2010, 132,
14409.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dsiegel@cm.utexas.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors would like to thank Dr. Tom Barton (currently at
Dow Agro sciences) for discussions regarding flow and review
of the final manuscript. The authors would also like to thank
Angela Spangenberg and Steve Sorey for 2D NMR
experimental assistance. Financial support from the Welch
Foundation (F-1694) is gratefully acknowledged.
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