Dearomatization Reactions Using Phthaloyl Peroxide

Article abstract of DOI:10.1021/acs.orglett.5b02008

A new oxidative dearomatization reaction has been developed using phthaloyl peroxide to chemoselectively install two oxygen-carbon bonds into aromatic precursors. The oxidation reaction proceeds only once; addition of superstoichiometric equivalents of ph

Full text of DOI:10.1021/acs.orglett.5b02008

Letter
pubs.acs.org/OrgLett
Dearomatization Reactions Using Phthaloyl Peroxide
Anders M. Eliasen,†,‡ Mitchell Christy,‡ Karin R. Claussen,‡ Ronald Besandre,‡ Randal P. Thedford,‡
and Dionicio Siegel*,†,‡
†Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC0756, La Jolla,
California 92093, United States
‡Department of Chemistry, University of Texas at Austin, Norman Hackerman Building, Austin, Texas 78701, United States
S
* Supporting Information
ABSTRACT: A new oxidative dearomatization reaction has
been developed using phthaloyl peroxide to chemoselectively
install two oxygen−carbon bonds into aromatic precursors.
The oxidation reaction proceeds only once; addition of
superstoichiometric equivalents of phthaloyl peroxide does
not react further with the newly generated 1,3-cyclohexadiene.
The reaction has been challenged by the addition of different
functional groups and shown to maintain chemoselectivity.
Due to the broad reactivity with 1,2-methylenedioxybenzene
derivatives, linear free energy correlations were determined
and support a mechanism proceeding through diradicals
analogous to arene-hydroxylation reactions using phthaloyl
peroxide.
ature has evolved a diverse set of enzymes to transform
aromatic compounds with a key reaction involving the
typically consumed in preference to the starting material.
Herein, we report that the reagent phthaloyl peroxide alone can
oxidatively dearomatize benzodioxole and dihydrobenzofuran
derivatives forming oxygenated 1,3-cyclohexadienes without
over oxidation.
N
insertion of oxygen into arenes, thereby disrupting aromatic
stabilization and allowing further enzymatic digestion of the
newly formed 1,3-cyclohexadiene system.1 These enzymes,
oxygenases, are divided based upon whether one or both atoms
of dioxygen are incorporated into the aromatic precursor
(Figure 1).2 The enzymes can use an iron heme cofactor as the
Oxidative dearomatization has proven to be an effective tool
in synthesis, rapidly converting commercial and easily prepared
arenes into highly functionalized cyclohexadienes and cyclo-
hexadienone derivatives.4−6 These products undergo subse-
quent functionalization, including carbon−carbon bond for-
mation, annulation, and hydrogenation. This strategy increases
structural complexity and aligns well with synthetic targets
identified from natural sources and enables the syntheses of
chemically diverse compound collections derived from
privileged core structures. Recently, the Njardarson group
utilized hypervalent iodine to perform an oxidative dearoma-
tization followed by Diels−Alder reaction to assemble the core
of vinigrol.7 Relatedly, Pettus and co-workers utilized oxidative
dearomatization to convert (−)-sophoracarpan A into
( )-kushecarpin A.8 Dearomatization also enables access to
privileged molecular scaffolds, demonstrated by Doyle,9 Tan,10
Hergenrother,11 and Porco.12
Figure 1. Metabolism of benzene. Two oxidative metabolic pathways
for benzene include dioxygenation and monooxygenation.
reactive center with the catalytically active state being either an
iron(V)−oxo or iron(III)−peroxo complex.3 The resulting
epoxide or 1,2-dioxetane is degraded further through hydrolytic
or reductive steps.
From a chemical reactivity standpoint, the lack of over-
oxidation in these enzymatic systems is noteworthy as the first
oxidation step overcomes the barrier of aromaticity and
generates a product that is more easily oxidized. The analogous
reaction in chemical synthesis has not been possible as the
products are more reactive than the starting material. The
majority of reagents fail to react with arenes, and if the reagents
do possess sufficient reactivity the newly generated products are
Phthaloyl peroxide was first reported by Russell in 195513
and extensively studied by Greene for the ability to add to
alkenes or alkynes with pendant aryl groups.14 Recently, 4,5-
dichlorophthaloyl peroxide was demonstrated to be a more
reactive oxidant than the parent phthaloyl peroxide.15 The first
Received: July 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
demonstration of arene-selective reactivity enabling the
conversion of arenes to phenols followed.16 The mechanism
of the reaction of arenes with phthaloyl peroxide was explored
computationally and shown to proceed via a reverse-rebound
mechanism in contrast to the established rebound mecha-
nism.17
Table 1. Optimization of the Reaction of 1,3-Benzodioxole
with Phthaloyl Peroxide
In a marked divergence in the reactivity previously observed
with phthaloyl peroxide (2), the reaction with 1,3-benzodioxole
(1) provides a diastereomeric mixture of cyclohexadiene
bisketals (3a and 3b) shown in Figure 2. This unprecedented
Figure 2. Reaction of 1,3-benzodioxole (1) with phthaloyl peroxide
(2).
The reaction is compatible with diverse substituents on the
arene, demonstrating the reaction to be chemoselective (Figure
3). As outlined in the methods development 1,3-benzodioxole
performed well under the optimized conditions providing a
74% yield of the dearomatized products (3a and 3b). Electron-
rich arenes (generating 5 and 6) readily dearomatize in
minutes; however, these reactive substrates necessitated the use
of trifluorotoluene, as the fluorinated alcohol solvents
hexafluoro-2-propanol and trifluoroethanol led to additional
unproductive reactions. Halogenated arenes possessing chlorine
(10) or bromine (11) reacted well and can be envisioned to
provide synthetic handles for further synthetic manipulation.
Appended phenyl (17) and benzyl (18) groups were left
unreacted, demonstrating the selectivity phthaloyl peroxide has
for the 1,3-benzodioxole. Other functionality susceptible to
oxidation including aldehydes and ketones (19, 20, and 25)
remained unchanged under the reaction conditions. Substitu-
ents ortho to the methylenedioxy proceed with only a slight
erosion in yield relative to meta isomers regardless of whether
the substituent is electron donating (15 and 16) or with-
drawing (19 and 20). Substrates with esters (6 and 21), amides
(22), and carbamates (23) all reacted selectively on the arene.
Nitriles (13) provided the corresponding cyano diene, albeit in
low yield. The 1,3-benzodioxole core with a nitro provided the
nitrodiene 12 in 57% yield. If the nitro is connected through a
vinyl spacer the yields increased for the formation of 8.
Remarkably, the reaction generating the styrene derivative 7
provided the dearomatized product in 67% with phthaloyl
peroxide selecting to react at the arene rather than the olefin.
Given that the reaction tolerates a wide variety of
substituents on the benzodioxole aryl ring, the methylenedioxy
was examined. The geminal dimethyl groups of an acetonide
(as in products 24 and 25), while providing a lower yield, do
not preclude oxidative dearomatization. The importance of
both oxygen atoms of the methylenedioxy was investigated, and
it was found that subjecting 2,3-dihydrobenzofuran to the
reaction provided the dearomatized product (26) in 40% yield
(with recovery of 26% of starting material), indicating that
while lower yields are achieved the system still reacts to provide
the oxygenated cyclohexadiene product. The substrate 3-
reactivity establishes two carbon−oxygen bonds, dearomatizing
the arene, and forms a 1,3-cyclohexadiene. Full NMR and
single-crystal X-ray diffraction analysis confirms these types of
structures.
The reaction is proposed to be driven by the strain associated
with the ring fusion and reactivity directed by oxygen. To
estimate the strain energy present in (methylenedioxy)benzene,
the difference in the calculated ΔHf° (using the Benson group
increment method) and that found experimentally was
determined.18 Benson group additivity parameters suggest
that benzodioxole substrates possess significant Baeyer
(angle) strain, calculated to be 17.6 kcal mol−1 in the liquid
state.19 Double ipso-addition at the ring junction alleviates this
strain through rehybridization at the carbons, from sp2 to sp3,
providing an energetic driving force for this reaction. The ipso
reactivity is in turn driven by oxygen ortho to the carbon
reacting. It is worth noting that heating the adducts does not
lead to the formation of related phenolic products.
The effects of equivalents of phthaloyl peroxide (2),
temperature, and solvent on the outcome of the reaction
were examined in an effort to optimize the reaction (Table 1).
While the use of slightly greater than 1 equiv of phthaloyl
peroxide led to the isolation of unreacted starting material
(variant 1), increasing the peroxide to 3 equiv (variant 2) did
not positively affect the yields. Notably, no overoxidized
products were identified in these reactions, even in the presence
of multiple equivalents of peroxide. Running the reaction at 0
°C resulted in incomplete conversion of starting material
(variant 3). Reaction above ambient temperature (variant 4)
did not improve the outcome and for operational simplicity
heating was not used. Analogous to the hydroxylation reaction,
we found the fluorinated alcohol solvents (commercial grade)
trifluoroethanol (TFE) and hexafluoro-2-propanol (HFIP)
were superior for arenes, including those possessing electron-
withdrawing substituents.20 For electron-rich substrates,
trifluorotoluene (TFT, commercial grade) proved optimal
(see the Supporting Information).
B
DOI: 10.1021/acs.orglett.5b02008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. Phthaloyl peroxide mediated dearomatization. Isolated yields are indicated below each entry for both isomers with the major isomer shown
(yields following silica gel flash chromatography). See the Supporting Information for experimental details and diastereomeric selectivity. Ts: p-
toluenesulfonyl.
bromodihydrobenzofuran reacted to provide 27 in a yield
comparable to that for the (bromomethylene)dioxy product 11.
Indan, lacking oxygen direction, provides the phenolic
product.16a
The major diastereomers generated possess the aryl ring of
the phthalate projecting away from the methylenedioxy bridge.
For most products of the oxidation reaction, the major and
minor isomers can be separated by silica gel column
chromatography, if desired, and isolated in pure form. Warming
either of the pure diastereomers in HFIP leads to the formation
of the same starting mixture of isomers.
The broad array of functional groups tolerated by the
dearomative reaction provided an opportunity to investigate the
mechanism of the transformation through the determination of
linear free energy relationships (Figure 4). A comparison of the
rates of reaction between the parent compound, 1,3-
benzodioxole, and substituted derivatives were obtained
through direct competition reactions using a 5-fold excess of
each arene relative to phthaloyl peroxide. Comparison of the
ratio of adducts formed was achieved from crude reaction NMR
analysis; kX/kH was determined for each competition reaction.
Figure 4. Linear free energy diagram using σp values. Ratios were
determined by NMR integration.
20
+
(EAS) which correlate strongly with σp . Linear regression
analysis provides a correlation (ρ) of the linear free energy
diagram and provides insight into the reaction mechanism. A ρ
value of −2.94 suggests the reaction is mildly influenced by the
+
Hammett plots were constructed using σp or σp . The reaction
fits σp values (R2 = 0.95) more closely than σp (R2 = 0.91), a
+
divergence from electrophilic aromatic substitution reactions
C
DOI: 10.1021/acs.orglett.5b02008
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
stabilization of polar intermediates but is not predicted to be
ionic as EAS reactions possess larger negative ρ values.21 It is
important to note that diradicals, differing from radicals, do
possess polarity.
The diradical-based intermediates present in the rate-
determining step are analogous to what was found computa-
tionally for the phthaloyl peroxide mediated arene hydrox-
ylation reaction.16a A mechanistic pathway that is in agreement
is depicted in Figure 5. Carbon−oxygen bond formation yields
as Steve Sorey, Angela Spangenberg, and Dr. Ben Shoulders for
NMR assistance.
REFERENCES
■
(1) (a) Mason, H. S.; Fowlks, W.; Peterson, J. J. Am. Chem. Soc. 1955,
77, 2914. (b) Hayaishi, O.; Katagiri, M.; Rothberg, S. J. Am. Chem. Soc.
1955, 77, 5450. (c) Gibson, D. T.; Koch, J. R.; Kallio, R. E.
Biochemistry 1968, 7, 2653.
(2) Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. Rev.
1996, 96, 2841−2887.
(3) (a) Solomon, E. I.; Brunold, T. C.; Davis, M. I.; Kemsley, J. N.;
Lee, S. K.; Lehnert, N.; Neese, F.; Skulan, A. J.; Yang, Y. S.; Zhou, J.
Chem. Rev. 2000, 100, 235. (b) Neidig, M. L.; Solomon, E. I. Chem.
Commun. 2005, 5843.
(4) (a) Gibson, D. T.; Koch, J. R.; Schuld, C. L.; Kallio, R. E.
Biochemistry 1968, 7, 3795. (b) Hudlicky, T.; Gonzalez, D.; Gibson, D.
T. Aldrichimica Acta 1999, 32, 35.
(5) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104,
1383.
(6) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50,
4068.
(7) (a) Yang, Q. L.; Njardarson, J. T.; Draghici, C.; Li, F. Angew.
Chem., Int. Ed. 2013, 52, 8648. (b) Yang, Q.; Draghici, C.; Njardarson,
J. T.; Li, F.; Smith, B. R.; Das, P. Org. Biomol. Chem. 2014, 12, 330.
(8) Feng, Z. G.; Bai, W. J.; Pettus, T. R. R. Angew. Chem., Int. Ed.
2015, 54, 1864.
Figure 5. Proposed mechanism of dearomatization reaction.
(9) Xu, X. F.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2013,
52, 12664.
(10) Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Nat. Chem. Biol. 2012,
a cyclohexadienyl radical 28. The carboxyl radical adds into the
ester carbonyl generating radical 29. Combination of the two
radicals forms the lactonic orthoester 3a.
9, 21.
(11) Huigens, R. W., III; Morrison, K. C.; Hicklin, R. W.; Flood, T.
A., Jr.; Richter, M. F.; Hergenrother, P. J. Nat. Chem. 2013, 5, 195.
(12) Grenning, A. J.; Boyce, J. H.; Porco, J. A. J. Am. Chem. Soc. 2014,
136, 11799.
(13) Russell, K. E. J. Am. Chem. Soc. 1955, 77, 4814.
(14) (a) Greene, F. D. J. Am. Chem. Soc. 1956, 78, 2246. (b) Greene,
F. D. J. Am. Chem. Soc. 1956, 78, 2250. (c) Greene, F. D.; Rees, W. W.
J. Am. Chem. Soc. 1958, 80, 3432. (d) Greene, F. D. J. Am. Chem. Soc.
1959, 81, 1503. (e) Greene, F. D.; Rees, W. W. J. Am. Chem. Soc. 1960,
82, 890. (f) Greene, F. D.; Rees, W. W. J. Am. Chem. Soc. 1960, 82,
893.
A new dearomatative oxidation reaction has been developed
using phthaloyl peroxide. High levels of chemoselectivity allow
the reaction to be run with predictability with benzodioxole and
dihydrobenzofuran derivatives reacting on the arene in
preference to other functional groups. Additionally, the reaction
is convientiently run in commercial grade solvents and, in most
cases, at ambient temperature. The determination of linear free
energy correlations fitting to σp with a ρ value of −2.93
supports previously proposed diradical intermediates. With an
absence of overoxidation of the resulting 1,3-cyclohexadiene the
reaction provides a key advancement in the development of
synthetic methods that can achieve aromatic dihydroxylation
reactions in a manner similar to Nature’s dioxygenases.
(15) Yuan, C. X.; Axelrod, A.; Varela, M.; Danysh, L.; Siegel, D.
Tetrahedron Lett. 2011, 52, 2540.
(16) (a) Yuan, C. X.; Liang, Y.; Hernandez, T.; Berriochoa, A.; Houk,
K. N.; Siegel, D. Nature 2013, 499, 192. (b) Yuan, C. X.; Eliasen, A.
M.; Camelio, A. M.; Siegel, D. Nat. Protoc. 2014, 9, 2624. (c) Eliasen,
A. M.; Thedford, R. P.; Claussen, K. R.; Yuan, C. X.; Siegel, D. Org.
Lett. 2014, 16, 3628. (d) Camelio, A. M.; Liang, Y.; Eliasen, A. M.;
Johnson, T. C.; Yuan, C.; Schuppe, A. W.; Houk, K. N.; Siegel, D. J.
Org. Chem. 2015, 80, 8084.
(17) Groves, J. T. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 3569.
(18) Benson, S. W.; Buss, J. H. J. Chem. Phys. 1958, 29, 546.
(19) Cohen, N. J. Phys. Chem. Ref. Data 1996, 25, 1411.
(20) Begue, J. P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 18.
(21) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02008.
Experimental procedures, characterization data, and
spectral reproductions for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: drsiegel@ucsd.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Welch Foundation
(F-1694) and the University of California, San Diego. We
thank, from UT Austin, Professor Eric Ansyln for helpful
discussions, Dr. Vince Lynch for X-ray diffraction data, as well
D
DOI: 10.1021/acs.orglett.5b02008
Org. Lett. XXXX, XXX, XXX−XXX