2,3-dichloro-5,6-dicyano-1,4-benzoquinone-catalyzed teactions employing MnO2 as a stoichiometric oxidant

Article abstract of DOI:10.1021/ol102078v

Several oxidative reactions can be effected with MnO₂ in the presence of substoichiometric quantities of DDQ. These transformations include oxidative cyclization, deprotection, and dehydrogenation reactions. The use of MnO₂ as a terminal oxidant for DDQ-mediated reactions is attractive based on economical and environmental factors.

Full text of DOI:10.1021/ol102078v

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4686-4689
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-
Catalyzed Reactions Employing MnO2 as
a Stoichiometric Oxidant
Lei Liu and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh,
PennsylVania 15260, United States
florean@pitt.edu
Received August 31, 2010
ABSTRACT
Several oxidative reactions can be effected with MnO2 in the presence of substoichiometric quantities of DDQ. These transformations include
oxidative cyclization, deprotection, and dehydrogenation reactions. The use of MnO2 as a terminal oxidant for DDQ-mediated reactions is
attractive based on economical and environmental factors.
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) is a highly
effective oxidant for a number of chemical transformations
Scheme 1. DDQ as a Catalytic Oxidant
including protecting group removal, aromatization, acetal
formation, and biaryl construction.1 DDQ is moderately
expensive, however, with a cost of $526/mol according to
the 2009-2010 Aldrich catalog.2 In addition to concerns
about cost, DDQ also poses modest toxicity concerns, with
an LD50 of 82 mg/kg,3 and the potential for HCN liberation
upon exposure to H2O. These issues, coupled with the
potential purification difficulties associated with utilizing
stoichiometric amounts of an organic oxidant, have led to
the search for economical and environmentally benign
oxidants that regenerate DDQ from its reduced hydroquinone
form (Scheme 1). HNO3 is a suitable oxidant for this
purpose,4 though its strong acidity is often not compatible
with functionalized organic compounds and necessitates that
the reoxidation be conducted as an independent step.
Chandrasekhar and co-workers reported5 that DDQ could
(1) Buckle, D. R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, UK, 1995; Vol. 3, p
1699.
(2) All price quotes are based on 100 g bottles of reagent grade
material.
(4) Newman, M. S.; Khanna, V. K. Org. Prep. Proced. Int. 1985, 17,
422.
(3) Rat LD50 values can be found on MSDS sheets.
10.1021/ol102078v  2010 American Chemical Society
Published on Web 09/23/2010

be used as a catalytic oxidant with FeCl3 serving as the
stoichiometric oxidant. This system is economically and
ecologically attractive, with FeCl3 costing only $41/mol, and
having an LD50 of 450 mg/kg, though the Lewis acidity of
FeCl3 again makes it incompatible with many functional
groups. Sharma and co-workers showed6 that Mn(OAc)3 is
also an effective agent for DDQ regeneration that does not
exhibit strong Lewis acidity. However, Mn(OAc)3·2H2O is
actually more expensive than DDQ at a price of $647/mol.
The cost factor is compounded by the fact that Mn(OAc)3 is
a single electron oxidant, making 2 equiv necessary to
regenerate DDQ.7
the acylium ion that forms when the enol acetate group reacts
with the oxocarbenium ion. Cognizant of the long-term
toxicity of lead, we explored other metal oxides as terminal
oxidants. Exposing 1 to 15 mol % DDQ and MnO2 in
CH3NO2 provided 2 in 79% yield. While the reaction time
was long (48 h) this result was quite gratifying in consid-
eration of the low cost of MnO2 ($28/mol) and its negligible
toxicity (LD50 ) 3478 mg/kg). The products of these
reactions were quite easy to isolate, with the excess metal-
containing reagents and byproduct being removed with a
simple filtration over silica gel. In general oxidative cycliza-
tions are slower in CH3NO2 than in less polar solvents, such
as 1,2-dichloroethane. However, the regeneration of DDQ
was clearly faster in CH3NO2, making it the solvent of choice
for this process. No conversion of 1 to 2 was observed when
PbO2 or MnO212 was used in the absence of DDQ, confirm-
ing that the reactions were mediated by DDQ and that the metal
oxides function to oxidize the hydroquinone. Additional evi-
dence in support of DDQ regeneration was provided by
observing the formation of DDQ upon subjecting 2,3-dichloro-
5,6-dicyanohydroquinone13 to MnO2 in CH3NO2.14
The successful demonstration of MnO2-mediated DDQ
turnover for our oxidative cyclization protocol led us to
examine the generality of the protocol. A representative
group of these reactions is shown in Table 1. Allylic ethers,
benzylic ethers, and vinyl oxazolidinones serve as substrates
for the protocol. While we did not study a broad range of
nucleophiles, we observed that alcohols are tolerated by the
reaction conditions in addition to electron-rich alkenes.
Quaternary centers can be formed in the process, and
sterically hindered ethers can be used as substrates. In general
the yields of the reactions were within approximately 10%
of the yields for the corresponding reactions that employ 2.0
equiv of DDQ. The rates of these reactions roughly correlate
to the corresponding stoichiometric reactions, though the long
reaction times that are observed for even the most reactive
substrates show that hydroquinone oxidation is the rate-
limiting step. The only significant problem was encountered
when slowly reacting substrate 19 (entry 9) was examined.
This problem can be attributed to the change in solvent,
because these cyclizations proceed more slowly in CH3NO2
than DCE, and to the low reaction rates that result from
employing a substoichiometric amount of oxidant.
In accord with our efforts8 and those of other groups9 to
use DDQ as a reagent for oxidative carbon-carbon bond
forming reactions and our interest in developing catalytic
oxidative transformations,10 we have initiated an effort to
identify an inexpensive, nonacidic, and environmentally
benign reagent that can be used as a terminal oxidant in the
presence of substoichiometric DDQ loadings. Following the
observation that the use of FeCl3 as a terminal oxidant for
DDQ-catalyzed carbon-hydrogen bond functionalization
reactions induced substrate decomposition, we directed our
initial screen for terminal oxidants toward metal oxides that
are known to effect phenol oxidations. This search led us to
11
explore PbO2 ($117/mol, LD50 ) 220 mg/kg). Exposing
prenyl ether 1 to DDQ (20 mol %) and PbO2 in CH3NO2
provided tetrahydropyrone 2 in 75% yield after 48 h (Scheme
2). Incorporating 2,6-dichloropyridine made this reaction and
Scheme 2
.
PbO2 and MnO2 as Terminal Oxidants for a
DDQ-Mediated Oxidation
subsequent transformations proceed more efficiently because
it can act as a nonoxidizable base and because it quenches
(5) Chandrasekhar, S.; Sumithra, G.; Yadav, J. S. Tetrahedron Lett. 1996,
37, 1645.
We examined the applicability of using MnO2 as a terminal
oxidant to other commonly employed DDQ-mediated trans-
formations to explore the generality of the process. A number
of these reactions are shown in Scheme 3. PMB ether
cleavage can be effected, as seen in the conversion of 20 to
21. Water deactivates MnO2, so MeOH was used as the
nucleophile in this transformation. Oxidizing hydroxyl-
(6) Sharma, G. V. M.; Lavanya, B.; Mahalingam, A. K.; Krisha, P. R.
Tetrahedron Lett. 2000, 41, 10323.
(7) For a review of Mn(OAc)3 chemistry, see: Snider, B. B. Chem. ReV.
1996, 96, 339.
(8) (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008,
47, 4184. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48,
4567. (c) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152. (d) Jung,
H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830. (e) Liu, L.; Floreancig,
P. E. Angew. Chem., Int. Ed. 2010, 49, 3069. (f) Cui, Y.; Tu, W.; Floreancig,
P. E. Tetrahedron 2010, 66, 4867. (g) Liu, L.; Floreancig, P. E. Angew.
Chem., Int. Ed. 2010, 49, 5894.
(10) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E. Org. Lett. 2001, 3,
4123.
(9) (a) Ying, B.-P.; Trogden, B. G.; Kohlman, D. T.; Liang, S. X.; Xu,
Y.-C. Org. Lett. 2004, 6, 1523. (b) Zhang, Y.; Li, C.-J. Angew. Chem., Int.
Ed. 2006, 45, 1949. (c) Li, Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.;
Pan, S. Org. Lett. 2008, 10, 803. (d) Cheng, D.; Bao, W. J. Org. Chem.
2008, 73, 6881. (e) Tsang, A. S.-K.; Todd, M. H. Tetrahedron Lett. 2009,
50, 1199. (f) Yu, B.; Jiang, T.; Li, J.; Su, Y.; Pan, X.; She, X. Org. Lett.
2009, 11, 3442. (g) Benfatti, F.; Capdevila, M. G.; Zoli, L.; Benedetto, E.;
Cozzi, P. G. Chem. Commun. 2009, 5919. (h) He, Z.; Lin, X.; Zhu, Y.;
Wang, Y. Heterocycles 2010, 81, 965. (i) Guo, C.; Song, J.; Luo, S.-W.;
Gong, L.-Z. Angew. Chem., Int. Ed. 2010, 49, 5558.
(11) Cook, C. D.; English, E. S.; Wilson, B. J. J. Org. Chem. 1958, 23,
755.
(12) For an example of a manganese-catalyzed ether oxidation, see:
Kamijo, S.; Amaoka, Y.; Inoue, M. Chem. Asian J. 2010, 5, 486.
(13) van Haeringen, C. J.; West, J. S.; Davis, F. J.; Gilbert, A.; Hadley,
P.; Pearson, S.; Wheldon, A. E.; Henbest, R. G. C. Photochem. Photobiol.
1998, 67, 407.
(14) We thank an anonymous reviewer for suggesting this experi-
ment.
Org. Lett., Vol. 12, No. 20, 2010
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Table 1. DDQ-Catalyzed Oxidative Cyclization Reactionsa
Scheme 3. MnO2-Mediated DDQ-Catalyzed Reactions
be quite beneficial for economical syntheses of these
important structures.18 The protocol can be utilized for Li’s
cross dehydrogenative coupling19 between acetophenone (28)
and isochroman 29 to form alkylation product 30. While the
yield for the reaction was modest, the transformation
illustrated the capability of forming carbon-carbon bonds
from readily available precursors by using an inexpensive
oxidant. Attempts to conduct a biaryl formation of 31 through
Rathore’s variant20 of the Scholl reaction were unsuccessful,
most likely indicating that the MeSO3H that is necessary for
the coupling deactivates MnO2.
The ability to conduct large-scale transformations with
minimal DDQ loading would be a major benefit of this
protocol. We confirmed the capacity to apply the procedure
to large-scale reactions by converting 24 to 25 on a 4.1 g
(31.5 mmol) scale. The reaction proceeded in comparable
yield (94%) to the smaller scale reaction (96%) and reached
completion more rapidly (16 h compared to 24 h). The rate
enhancement can be attributed to the reaction being con-
ducted at approximately 3 M as opposed to the 0.1 M
concentration that was used in the smaller scale transforma-
tions.
a Representative procedure: DDQ was added in three equal portions
over the course of the reaction (0.15 equiv total) to a suspension of the
substrate, 2,6-dichloropyridine (2 equiv), and activated MnO2 (6 equiv) in
CH3NO2 (0.1 M). The reaction was stirred at room temperature for the
indicated period of time. b Yields refer to isolated, purified products.
c Reaction required 0.2 equiv of DDQ.
containing PMB ether 22 in the absence of MeOH provided
PMP acetal 23. Dehydrogenation reactions are quite effective,
with dihydronaphthalene (24) being converted to naphthalene
(25) in 96% yield. This process can also be applied to the
conversion of oxazolines to oxazoles, as seen in the conver-
sion of 26 to 27.15 This method of oxazole preparation is an
improvement over a previously reported variant16 in which
specially prepared high surface area MnO2 (25 equiv) is used
for oxazoline oxidation in the absence of DDQ,17 and should
We have shown that a number of oxidations can be
effected by using catalytic DDQ with MnO2 serving as an
inexpensive and environmentally benign terminal oxidant.
These transformations include oxidative cyclizations, ether
(16) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.; Anzai, M.;
Ando, A.; Shioiri, T. Synlett 1998, 35.
(17) We did not observe oxazoline oxidation using activated reagent
grade MnO2 in the absence of DDQ.
(18) Jin, Z. Nat. Prod. Rep. 2006, 23, 464.
(19) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242. For a
review of cross dehydrogenative coupling reactions, see: Li, C.-J. Acc. Chem.
Res. 2009, 42, 335.
(15) For recently reported oxidative approaches to oxazole synthesis,
see: (a) Graham, T. H. Org. Lett. 2010, 12, 3614. (b) Phillips, A. J.; Uto,
Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165.
(20) Zhai, L.; Shukla, R.; Rathore, R. Org. Lett. 2009, 11, 3474.
4688
Org. Lett., Vol. 12, No. 20, 2010

cleavages, dehydrogenations, and cross-dehydrogenative cou-
plings. The processes, while significantly slower than the
corresponding stoichiometric reactions, are comparable with
respect to yield and the resulting products are easier to purify.
The protocol is incompatible with very slow oxidations and
with the presence of water or strong acid. The range of
successful transformations reported herein and the capacity to
conduct reactions on a large scale, however, suggest that this
process should be useful for most DDQ-mediated oxidations,
and the cost advantages and minimal toxicity benefits could
prove to be very valuable for multigram syntheses.
Acknowledgment. We thank the National Institutes of
Health, Institute of General Medicine (GM062924), for
generous support of this work. We thank Professor Yoshito
Kishi (Harvard University) for suggesting the use of polar
solvents to improve oxidant turnover.
Supporting Information Available: Experimental details
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL102078V
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