Manganese(II)/Picolinic Acid Catalyst System for Epoxidation of Olefins

Article abstract of DOI:10.1021/acs.orglett.6b00518

An in situ generated catalyst system based on Mn(CF₃SO₃)₂, picolinic acid, and peracetic acid converts an extensive scope of olefins to their epoxides at 0 °C in <5 min, with remarkable oxidant efficiency and no evidence of radical behavior. Competition experiments indicate an electrophilic active oxidant, proposed to be a high-valent Mn = O species. Ligand exploration suggests a general ligand sphere motif contributes to effective oxidation. The method is underscored by its simplicity and use of inexpensive reagents to quickly access high value-added products.

Full text of DOI:10.1021/acs.orglett.6b00518

Letter
pubs.acs.org/OrgLett
Manganese(II)/Picolinic Acid Catalyst System for Epoxidation of
Olefins
Ross A. Moretti, J. Du Bois, and T. Daniel P. Stack*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: An in situ generated catalyst system based on Mn(CF3SO3)2, picolinic acid, and peracetic acid converts an
extensive scope of olefins to their epoxides at 0 °C in <5 min, with remarkable oxidant efficiency and no evidence of radical
behavior. Competition experiments indicate an electrophilic active oxidant, proposed to be a high-valent Mn = O species. Ligand
exploration suggests a general ligand sphere motif contributes to effective oxidation. The method is underscored by its simplicity
and use of inexpensive reagents to quickly access high value-added products.
poxides are a widely used class of compounds, valued as
intermediates to a range of chemical functionality.1 The
atures using 1.1 equiv of a base-modified commercial PAA
solution (PAAM; see the Supporting Information). We selected
the conditions of 0.4 mol % of Mn(CF3SO3)2 and 2 mol % of
2-PyCO2H at 0 °C over 5 min, with slow addition of PAAM
(Table 1, entry 1), to be our general working conditions due to
their broad applicability and ease of execution. Lower alkene
E
selective production of epoxides from abundant olefin starting
materials has therefore received much attention over the past
several decades. Transition metal catalysts have been key to the
development of many of these methodologies, yet a general
method for epoxidation of alkenes of diverse steric and
electronic profiles does not exist. Established catalysts in the
field, such as methyltrioxorhenium2 and metal−salen com-
plexes,3 are limited in scope and not broadly useful for
substrates more electron-deficient than a terminal olefin.
Recent advances have derived inspiration from oxidative
metalloenzymes,4 pursuing Fe- and Mn-based catalysts that
use environmentally benign terminal oxidants, such as H2O2
and peracetic acid (PAA).5 This class of catalysts is more
powerful than its predecessors, but poor selectivity and ligand
oxidation6 are observed as undesired consequences. Elaborate
ligand scaffolds7 have been designed to modulate reactivity, but
such synthetically laborious modifications may limit their
widespread use. We report herein a general epoxidation catalyst
system, capable of transforming alkenes of varied geometric and
electronic natures to their epoxides with good selectivity and
high oxidant efficiency. Furthermore, the transformation is
achieved using the simple, inexpensive reagents Mn(CF3SO3)2,
picolinic acid (2-PyCO2H), and PAA, making it a readily
accessible choice for epoxidation.
Table 1. Epoxidation of 1-Octene with Mn/2-PyCO2H
a
Catalyst System
Mn
(mol %)
[alkene]
(M)
temp
(°C)
conv
(%)
yield (selectivity)
(%)
b
c
1
2
3
4
5
6
0.4
0.45
0.1
0
0
98
95
93
96
90
<5
83 (85)
80 (84)
80 (86)
85 (89)
82 (91)
trace
0.4
b
d
e
0.1
0.45
0.45
0.45
0.45
0
0.4
−40
−78
0
0.4
none
a
Conversion and yield determined by GC relative to dodecane
internal standard. Results are an average of three trials: conversion
2%, yield 1%. Selectivity = (yield/conversion) × 100. PAAM
=
b
10:3:13 (v/v/v) 32% PAA/10% KOH (aq)/AcOH. MeCN, 5 min.
c
d
e
MeCN, 10 min. MeCN, 20 min. 1:1 EtCN/iPrCN (v/v), 30 min.
Epoxidation was first investigated using 1-octene as a model
substrate. Optimization of reaction conditions achieved
complete conversion within minutes at subambient temper-
Received: February 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00518
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Letter
a
Table 2. Scope of Epoxidation with Mn/2-PyCO2H Catalyst System
a
0.4 mol % of Mn(CF3SO3)2, 2 mol % of 2-PyCO2H, 100 μmol of substrate in MeCN (0.45 M), 1.1 equiv of PAAM, 0 °C, 5 min. Conversion and
1
yield determined by GC and H NMR relative to an internal standard (see the Supporting Information). Results are an average of three trials:
conversion 2%, yield 1%. cis-Epoxide produced selectively. Isolated yield. 4.0 equiv of PAAM, 10 min. 4% trans-epoxide observed as
byproduct; competing ester cleavage also observed. 14% phenylacetaldehyde observed as byproduct. 5% 3-nitrophenylacetaldehyde observed as
byproduct. With 1 equiv BF3·MeCN in 1:1 EtCN/iPrCN (v/v), −78 °C, 30 min. 1.5 equiv of PAAM.
b
c
d
e
f
g
h
i
concentrations and catalyst loadings (Table 1, entries 2 and 3),
as well as alternative Mn(II) salts (e.g., MnCl2, Mn(OAc)2),
can be equally effective. Surprisingly, epoxidation is attainable at
temperatures as low as −78 °C8 (Table 1, entries 4 and 5), and
selectivity increases with decreasing temperature. The indicated
1:5 ratio of Mn(II) salt to 2-PyCO2H is rationalized using the
binding equilibria for Mn(II) and 2-PyCO2H.9 For the
concentrations of species in this study, a 1:5 ratio maximizes
formation of the bis-ligated species in solution (see the
Supporting Information), a ligand sphere comparable to many
known Mn and Fe oxidation catalysts.5
The selected conditions were applied to an array of olefin
substrates (Table 2 and Table S1). Aliphatic alkenes (Table 2,
entries 1−3) are converted successfully to their epoxides with
retention of the geometry at the olefin. Such stereoretention
suggests either (a) concerted O atom transfer from the metal-
based oxidant or (b) a stepwise mechanism sufficiently fast to
outcompete C−C bond rotation in a radical/cationic
intermediate.5g,10 Additionally, C−Br homolysis is not observed
in the reaction of an aliphatic halide (Table 2, entry 4), nor is
Baeyer−Villiger oxidation competitive in an unsaturated ketone
(Table 2, entry 5). The system is also amenable to the
epoxidation of challenging electron-deficient alkenes (Table 2,
entries 6 and 7). Even the extremely electron-poor diethyl
maleate (Table 2, entry 8), reasonable epoxidation of which is
only achieved via the exceptionally electrophilic oxidant
HOF,11 undergoes limited epoxidation with this methodology.
Arenes of various functionalities (Table 2, entries 9−13) are
compatible as well. The epoxidations of 2- and 4-vinylpyridine
(Table 2, entries 11 and 12) are particularly noteworthy, as the
ligating nitrogen atoms do not inhibit catalysis and undesired
oxidation to the pyridine N-oxides is not observed. Trans-
formations of sensitive substrates such as allyl halides (Table 2,
entries 14 and 15) and phenyldimethylvinylsilane (Table 2,
entry 16) highlight the surprising mildness of this powerful
oxidant system. Finally, epoxidation of an unsaturated N-
hydroxysuccinimide (NHS) ester (Table 2, entry 17) provides
not only a bifunctional product but also a route to epoxy
amides through subsequent displacement of the activated
ester12 with amines; typically, amides (e.g., Table S1, entry 13)
are not directly compatible with metal-based oxidants due to α-
C−H oxidation.13 Other incompatible functional groups
include ethers and phenols (Table S1, entries 14 and 15),
which are both oxidized nonspecifically, and alcohols (Table S1,
entry 16), which are competitively oxidized to carbonyls.
With minor modifications, the methodology is extendable to
basic N-containing, oxidatively unstable substrates (Table 2,
entries 18 and 19). By protecting these functionalities as their
BF3 adducts14 and conducting reactions at −78 °C, good yields
of the epoxides are obtained. Furthermore, use of BF3·MeCN
as an in situ BF3 source provides the epoxides directly, without
the need for a second step to cleave the N−BF3 adducts (see
the Supporting Information). In the absence of BF3 protection,
oxidative decomposition of these alkenes is observed.
Importantly, the methodology can be efficiently scaled to
rapidly produce gram quantities of epoxides. For example, the
B
DOI: 10.1021/acs.orglett.6b00518
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epoxidation of butyl methacrylate (Scheme 1), carried out on a
∼2 g scale, furnished the epoxide in 87% isolated yield. Thus,
Table 3. Comparison of Mn/2-PyCO2H to Mn/phen and
Mn/bipy for Epoxidation of 1-Octene
a
ligand
conv (%)
yield (selectivity) (%)
Scheme 1. Gram-scale Synthesis of Butyl 2-Methyl-2-
oxiranecarboxylate
1
2
3
2-PyCO2H
phen
98
54
61
83 (85)
35 (66)
43 (70)
bipy
a
0.4 mol % of Mn(CF3SO3)2, 2 mol % of ligand, 100 μmol of 1-octene
in MeCN (0.45 M), 1.1 equiv of PAAM, 0 °C, 5 min; PAAM added at a
rate of ∼5 μL every 10 s. Conversion and yield determined by GC
relative to dodecane internal standard. Results are an average of three
trials: conversion 2%, yield 1%.
this protocol also enables synthesis of preparatively useful
amounts of epoxides within 5 min in a manner analogous to the
small-scale reactions.
received commercial PAA,5c resin-synthesized PAA,5d,e will
yield different results with each system (see the Supporting
Information for further discussion).
Intra- and intermolecular competition experiments (Scheme
2) were carried out to interrogate the nature of the active
oxidant. Geranyl acetate provided an intramolecular competi-
tion (Scheme 2A), as it contains two alkene moieties with
similar steric properties but differentiated electronic properties.
When subjected to the standard reaction conditions with 1.0
equiv PAAM, a mixture of the 2,3- and 6,7-epoxides, as well as
the diepoxide, was obtained in a 1:10:4 ratio, preferring
oxidation of the more electron-rich alkene. Conducting the
same competition at −78 °C further differentiated the alkenes,
yielding a 1:12:3 ratio of products. Similar results were obtained
in the intermolecular competition between electron-rich 2,4,4-
trimethyl-2-pentene and electron-deficient butyl methacrylate
(Scheme 2B). Under standard conditions, the relative reactivity
was ca. 5:1 in favor of 2,4,4-trimethyl-2-pentene. Lowering the
temperature to −78 °C increased the relative reactivity to 12:1,
suggesting this methodology may extend to selective
epoxidation of molecules with electronically dissimilar alkenes.
The preference for epoxidation of the more electron-rich olefin
in these experiments indicates an electrophilic active oxidant,
consistent with a high-valent Mn = O species.15
The Mn/2-PyCO2H system was compared with related in
situ generated oxidation systems Mn/phen and Mn/bipy.5e
Under this study’s standard conditions, Mn/2-PyCO2H
dramatically outperforms both Mn/phen and Mn/bipy in the
epoxidation of 1-octene, yielding the epoxide in 15−20%
greater selectivity (Table 3). Similar results were obtained with
comparably electron-rich and electron-poor alkenes (Table S2).
It is important to note that the nature of the peracetic acid used
to generate the active oxidant is critical, and we therefore chose
to compare systems using our PAAM solution. Conditions used
in other studies with respect to the peracetic acid, e.g., as-
We hypothesize that the outstanding oxidant efficiency of
this system is attributable to both the durability of 2-PyCO2H6b
and the coordination environment at Mn. Exploration of
related ligands (Table 4 and Table S3) suggests this
phenomenon is common across a wider family of “picolinic
acid-like” ligands; comparable reactivity is observed with 2-
pyrimidinecarboxylic acid (Table 4, entry 2), 1-isoquinoline-
carboxylic acid (Table 4, entry 3), and 1-methyl-2-imidazole-
carboxylic acid (Table 4, entry 4). Ligands not incorporating
similar features (Table 4, entries 5−7) do not generate
competent catalysts. Further inspection of these ineffective
cases illustrates that all aspects of the 2-PyCO2H binding motif
are required for catalysis: an aromatic nitrogen donor, a
carboxylate16 donor, and a connectivity capable of forming a
five-membered chelate. Of particular interest is the incorpo-
ration of an anionic ligand to the coordination sphere, a known
paradigm for stabilization of reactive, high-valent metal−oxo
complexes.17
We have reported an effective oxidant system for olefin
epoxidation based on Mn(CF3SO3)2, 2-PyCO2H, and PAA.
This method is highlighted by the following characteristics: its
ease of use as an in situ generated oxidant system; the
simplicity, accessibility, and economy of its components; and its
ability to produce preparatively useful quantities of a broad
range of epoxides within minutes. The Mn/2-PyCO2H system
reported here is further distinguished from related systems5d,g,i
by its superior oxidant efficiency. This report provides a
complement to the work of Browne et al.,5i which
demonstrated dihydroxylation of electron-deficient olefins
using a similar catalyst system. Though their system also
shows some epoxidation reactivityoften concomitant with
Scheme 2. Competition Experiments with Mn/2-PyCO2H Catalyst System
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Table 4. Binding Motif of 2-PyCO2H and Expansion of 1-
Octene Epoxidation to Related Ligands
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AUTHOR INFORMATION
■
Corresponding Author
(16) 2-PyCO2H2+ has pKa’s of 1.0 and 5.4: Harris, D. C. Quantitative
Chemical Analysis, 7th ed.; WH Freeman & Co.: New York, 2006. In
the buffered conditions employed in this study, the carboxylate anion
should be the major species in solution.
*E-mail: stack@stanford.edu.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Tim Brown (Zare lab, Stanford University) for
assistance with HRMS data collection.
D
DOI: 10.1021/acs.orglett.6b00518
Org. Lett. XXXX, XXX, XXX−XXX