Synthesis of α-peroxyesters via organocatalyzed O-H insertion of hydroperoxides and aryl diazoesters

Article abstract of DOI:10.1021/ol502494h

(Chemical Equation Presented) The synthesis of α-aryl peroxyesters, an unprecedented class of organic peroxide, via hydrogen-bond donor catalyzed O-H insertions of hydroperoxides and α-aryl diazoesters is reported. The method is applicable to a diverse set of substrates and the corresponding α-peroxyesters are typically isolated in high yield. Both thermogravimetric analysis and reactions with traditional peroxide reducing agents demonstrate the stability of α-peroxyesters.

Full text of DOI:10.1021/ol502494h

Letter
pubs.acs.org/OrgLett
Synthesis of α‑Peroxyesters via Organocatalyzed O−H Insertion of
Hydroperoxides and Aryl Diazoesters
Thomas J. Fisher and Anita E. Mattson*
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United
States
*
S Supporting Information
ABSTRACT: The synthesis of α-aryl peroxyesters, an unprecedented class of organic peroxide, via hydrogen-bond donor
catalyzed O−H insertions of hydroperoxides and α-aryl diazoesters is reported. The method is applicable to a diverse set of
substrates and the corresponding α-peroxyesters are typically isolated in high yield. Both thermogravimetric analysis and
reactions with traditional peroxide reducing agents demonstrate the stability of α-peroxyesters.
7
eroxide-containing organic molecules are ubiquitous
reduced (alcohol) product. Still others have invoked peroxidic
1
8
P
among a plethora of bioactive natural products and
intermediates in radical oxidations of α-iodocarbonyls. A
substructure search reveals few reports of compounds bearing
a peroxide functional group at the α-position of an α-arylester,
such as 2. This finding inspired us to pursue the synthesis of
2
9
other biologically relevant species (Figure 1). Naturally
10
this class of peroxide.
Organocatalytic methods that offer analogous or orthogonal
reactivity patterns to transition-metal-catalyzed processes are
currently of great interest to the synthetic community. One
important approach involves developing these processes via
1
1
enhanced hydrogen-bond-donor (HBD) organocatalysis.
Recently, we have published the HBD-catalyzed S−H and
O−H insertion of thiols and carboxylic acids with aryl
12
diazoesters, taking advantage of our enhanced HBD catalyst
3a. As part of our ongoing investigation into organocatalytic
reactions with diazo compounds, we questioned whether
hydroperoxides could be competent insertion partners given
their similar nucleophilicity and acidity to thiols. To our
13
knowledge, with one exception, hydroperoxides have not
been shown to undergo either thermal or transition metal-
catalyzed O−H insertions with diazo compounds. The latter is
potentially precluded given the known reactivity of hydro-
peroxides with transition metals typically utilized (i.e., Cu(I),
Cu(II), and Rh(II)) for X−H insertion reactions. Herein, we
report the HBD-catalyzed O−H insertion of hydroperoxides
with aryl diazoesters.
Figure 1. Biologically important peroxides.
occurring and synthetic peroxides are used as, or are being
investigated for, treatments against several diseases such as
14
3
4
malaria and various cancers. While several methods for the
5
installation of the peroxide functional group do exist, many of
these methods are limited in substrate scope or reactivity
6
Our investigations began with the reaction of aryl-diazoester
pattern. Given the potential of organic peroxides as bioactive
1a and tert-butyl hydroperoxide (TBHP) in the presence of 10
compounds, new methods for their synthesis are necessary to
exploit their prospective utility fully. One class of unexplored
peroxides is α-aryl α-peroxyesters. While some examples of α-
hydroperoxyamides have been reported as intermediates in, for
example, the oxidation of chiral amide enolates with O , these
mol % of catalyst 3a (Table 1). We initially screened several
common solvents and found toluene to be the optimal solvent,
providing 33% of the desired product at a concentration of 0.5
3
2
compounds were reported to be unstable to chromatography
and readily decomposed, thereby providing access to only the
Received: August 23, 2014
Published: September 29, 2014
©
2014 American Chemical Society
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Letter
Table 1. Optimization of O−H Insertion Reaction
a
b
c
entry
3 (mol %)
solvent
temp (°C)
TBHP (equiv)
time
4 h
yield (%)
1
2
3
4
5
6
7
8
9
3a (10)
3a (10)
3a (10)
3a (10)
3a (10)
3a (5)
Et O
2
rt
rt
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
0.5
0.5
0.5
0.5
20
21
solvent
MTBE
DCE
5 h
10 min
24 h
rt
17
MeCN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
nd
rt
20 min
20 min
30 min
24 h
33
rt
35
catalyst loading
3a (2.5)
3a (0)
rt
50
rt
trace
80
3a (2.5)
3a (2.5)
3a (0)
rt
3 h
TBHP equiv/temp
catalyst structure
1
1
1
1
0
1
2
3
40
40
40
40
10 min
24 h
83
12
3b (2.5)
3c (2.5)
24 h
trace
76
0.5
6 h
a
b
c
1
Reactions performed with 0.1 mmol of 1a. Catalyst loading relative to 1a. Yields determined by H NMR analysis and based upon limiting
reagent.
a
M at 23 °C. Reducing the catalyst loading to 5 and 2.5 mol %
provided 35% and 50% of the desired product, respectively,
albeit with a concurrent increase in reaction time. A key
discovery was the requirement for excess diazo compound in
the reaction to obtain optimal yields of product. When 0.5
equiv of TBHP was used, an increase in yield from 50% to 80%
Scheme 1. Substrate Scope of O−H Insertions
15
was observed (entry 9). At this point, we found that
increasing the temperature to 40 °C provided the same yield
but with much shorter reaction times (10 min vs 3 h, entry 10).
Under our optimized conditions, no product formation was
16
detected when catalyst was omitted from the reaction; after
4 h, only 12% of product could be observed (entry 11). Other
2
urea catalysts (3b and 3c) provided lower yields with longer
reaction times, or failed to react (entries 12 and 13).
With optimized conditions in hand, we set out to explore the
scope of the newly discovered reaction. Peroxide 2a was formed
in 71% isolated yield under the standard conditions. In addition
to TBHP, cumene hydroperoxide efficiently undergoes the
insertion reaction (2b). Changing the OR linkage of the ester
had little effect; ethyl or tert-butyl esters were both well
tolerated (2c and 2d). However, the optimized conditions
provided lower yields than desired for aryl-diazoesters bearing a
less activating (i.e., electron donating, vide infra) group at the 4-
position of the aryl ring, and increasing the catalyst loading to 5
mol % was required. For example, 4-OAc- and 4-Me-substituted
aryl diazoesters afforded moderate yields of the desired product
(
2f and 2g). Substitution at the 2-position of the aryl side chain
was tolerated well (2h). Other aryl side chains such as N-Boc-
protected indole (2i) and 2-thiophene (2j) also underwent the
O−H insertion reaction. Highly deactivated substrates (e.g., Ar
=
4-CF C H ) failed to provide the desired product even at
3 6 4
a
b
elevated temperatures and with prolonged reaction times.
To alleviate concerns surrounding the potential instability of
the products, the stability of this new class of peroxide was
Isolated yields based upon hydroperoxide. Five mol % 3a.
c
1
Determined by H NMR analysis.
5
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Organic Letters
Letter
investigated using thermogravimetric analysis (TGA) as well as
by interrogation with a variety of chemical agents known to
destroy dialkyl peroxides. TGA revealed that peroxide 2a
undergoes slow decomposition at temperatures between
Scheme 3. Possible Catalytic Cycle for O−H Insertion
17
approximately 90−160 °C (Figure 2). Reaction of 2a with
Figure 2. TGA analysis of peroxide 2a.
various reducing agents also reveals the stability of the
Scheme 4. Reaction of 2-Pyridyl Diazoester
1
8
peroxides. PPh failed to reduce the peroxide bond at rt,
3
while heating for 20 h at 60 °C in THF converted 50% of the
starting material to α-ketoester 4; reaction with NaBH gave
4
rise to a complex mixture of products, requiring 8 h to consume
the starting material (Scheme 2, eqs 1 and 2). Reaction with
Et N cleanly afforded 4 in quantitative yield whereas O−O
3
scission with Fe(II) provided a mixture of 4 and alcohol 5
19
(
Scheme 2, eqs 3 and 4).
quantitative recovery of the starting material was observed by
H NMR spectroscopic analysis. Furthermore, a second
Scheme 2. Reduction of the O−O Bond
1
experiment found that 2a was not observed when Et N was
3
added to the standard conditions. No product was formed, and
the starting material was recovered quantitatively. These
findings are in alignment with the proposed deprotonation of
the acidified hydroperoxide by the aryl diazoester. They are also
consistent with the observation that less electron rich (i.e., less
basic) aryl diazoesters are outperformed by their more electron
rich counterparts in terms of overall yield of the desired
product.
To conclude, a new class of peroxide has been synthesized
via a novel organocatalytic O−H insertion of hydroperoxides
21
with aryl diazoesters. The products are stable under typical
storage and handling conditions and pave the way for
continued exploration of other natural and synthetic frame-
works and their bioactivity analysis.
1
2
ASSOCIATED CONTENT
Supporting Information
Drawing upon observations from related work, a possible
catalytic cycle is shown in Scheme 3. Initial complexation and
acidification of the hydroperoxide with 3a is followed by
deprotonation of the hydroperoxide by aryl diazoester 1.
■
*
S
Experimental procedures, spectra, and characterization for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Insertion of the peroxy anion via either an S 1- or S 2-like
attack affords the product and N gas while releasing the
N
N
2
catalyst. Interestingly, recent computational work has shown a
AUTHOR INFORMATION
Corresponding Author
■
*
remarkable increase in acidity of X−H protons upon interaction
20
with hydrogen-bond-donor organocatalysts.
E-mail: mattson@chemistry.ohio-state.edu.
Notes
In support of the above mechanism, an aryl diazoester
bearing a basic side chain (2-pyridyl) was subjected to the
reaction conditions (Scheme 4). No product was formed, and
The authors declare no competing financial interest.
5
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Letter
(
c) Schiaffo, C. E.; Rottman, M.; Wittlin, S.; Dussault, P. H. ACS Med.
ACKNOWLEDGMENTS
■
Chem. Lett. 2011, 2, 316−319. Et N: (d) Reference 10.
3
Support for this research has been provided by the OSU
Department of Chemistry and Biochemistry.
1
(19) Yields determined by H NMR spectroscopy.
(20) (a) Xue, X.-S.; Yang, C.; Li, C.; Cheng, J.-P. J. Org. Chem. 2014,
7
9, 1166−1173. (b) Yang, C.; Xue, Z.-S.; Li, X.; Cheng, J.-P. J. Org.
Chem. 2014, 79, 4340−4351.
21) Safety note: While no problems were encountered surrounding
the stability of the peroxides or diazo compounds throughout the
course of this work, as always, proper attention must be paid to the
potential for rapid, exothermic decompositions of organic peroxides or
diazo compounds. For references pertaining to safe handling of
peroxides, see: (a) Medard, L. A. Accidental Explosions: Types of
Explosive Substances; Ellis Horwood Limited: Chichester, 1989; Vol. 2;.
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