Aerobic Linear Allylic C-H Amination: Overcoming Benzoquinone Inhibition

Article abstract of DOI:10.1021/jacs.5b11294

An efficient aerobic linear allylic C-H amination reaction is reported under palladium(II)/bis-sulfoxide/Br?nsted base catalysis. The reaction operates under preparative, operationally simple conditions (1 equiv of olefin, 1 atm O₂ or air) with

Full text of DOI:10.1021/jacs.5b11294

Subscriber access provided by GAZI UNIV
Article
Aerobic Linear Allylic C-H Amination: Overcoming Benzoquinone Inhibition
Christopher C. Pattillo, Iulia I Strambeanu, Pilar Calleja, Nicolaas
A. Vermeulen, Tomokazu Mizuno, and M. Christina White
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Jan 2016
Downloaded from http://pubs.acs.org on January 5, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Aerobic Linear Allylic C−H Amination: Overcoming Benzoquinone
Inhibition
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡
‡
∇
⊥
Christopher C. Pattillo , Iulia I. Strambeanu , Pilar Calleja , Nicolaas A. Vermeulen , Tomokazu
Mizuno§, and M. Christina White‡,*
‡Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois, 61801, United States
KEYWORDS Amination, C-H oxidation, Palladium, Sulfoxide, Oxygen, Benzoquinone, Air, Cobalt, Vanadium
ABSTRACT: An efficient aerobic linear allylic C—H amination reaction (LAA) is reported under Pd(II)/bis-sulfoxide/Brønsted
base catalysis. The reaction operates under preparative, operationally simple conditions (1 equiv. olefin, 1 atm. O2 or air), with
reduced Pd(II)/bis-sulfoxide catalyst loadings while providing higher turnovers and product yields than systems employing
stoichiometric benzoquinone (BQ) as the terminal oxidant. Palladium(II)/benzoquinone π-acidic interactions have been invoked in
various catalytic processes and are often considered beneficial in promoting reductive functionalizations. When such electrophilic
activation for functionalization is not needed, however, benzoquinone at high concentrations may compete with crucial ligand (bis-
sulfoxide) binding and inhibit catalysis. Kinetic studies reveal an inverse relationship between the reaction rate and the
concentration of BQ, suggesting that benzoquinone is acting as a ligand for Pd(II) which results in an inhibitory effect on catalysis.
INTRODUCTION
Nature routinely uses molecular oxygen (O2) as
a
Scheme 1. BQ Ligand Effects in Intermolecular Allylic C-H
Amination.
stoichiometric oxidant for metalloenzyme catalyzed C—H
bond oxidations.1 In the context of chemical synthesis, the
economic and environmental advantages of using O2 for these
purposes are clear: O2 is an abundant, highly atom-efficient
oxidant per weight that generates no toxic byproducts.2 Less
evident, however, is the potential for employing this oxidant in
a manner that would increase the catalytic efficiency of
oxidation reactions.
Since an early report that benzoquinone (BQ) is capable of
acting as an effective stoichiometric oxidant for Pd-catalyzed
olefin oxidations, BQ has become the most common terminal
oxidant for palladium-catalyzed oxidations proceeding via
Pd(II)/Pd(0) redox cycles.3,4 We and others have demonstrated
that at BQ may fill a dual role in palladium-catalyzed C—H
oxidation reactions by acting as both an oxidant and a π-acidic
ligand to promote reductive eliminations at the metal.5 Allylic
C—H oxidations that benefit from this effect operate under the
principle of serial ligand catalysis, wherein distinct ligands
promote specific steps along a catalytic cycle (Scheme 1A).5c
Under these conditions, the reversibly coordinating bis-
sulfoxide ligand coordinates to Pd(II) to promote a C—H
cleavage step and generate
a
reactive π-allylPd(II)
intermediate. Benzoquinone may then coordinate to this
electrophilic intermediate via an η2-π complex and act as a π-
acidic ligand to promote reductive eliminations at the metal
center.5 We hypothesized that when activation of the
electrophilic metal center is not required for functionalization,
these BQ-Pd(II)Ln interactions may prove detrimental in
systems using weakly coordinating ligands. By competing
with the essential bis-sulfoxide binding event at the metal, BQ
binding at high concentrations may lead to an inhibitory effect
on catalysis.
employing a cobalt-mediated redox-relay catalytic cycle that
uses molecular oxygen as the terminal oxidant under mild (1
atm., 45oC) and preparatively useful conditions (1 equiv.
olefin, 1.5 equiv. nitrogen nucleophile). This improved system
enables the reaction to proceed with catalytic quantities of
benzoquinone, thus reducing the potential for inhibitory
Herein, we describe the development of an efficient
intermolecular linear allylic C—H amination reaction
ACS Paragon Plus Environment

Journal of the American Chemical Society
binding of BQ to the Pd(II)-catalyst. As a result, this system
Page 2 of 9
Table 1. Reaction Optimization.
1
2
3
4
5
6
7
8
affords higher or comparable yields while operating at lower
catalyst loadings than those previously developed using super-
stoichiometric BQ as the terminal oxidant. The aerobic linear
allylic amination reaction even remains operational at reduced
oxygen concentrations found in air. Kinetic experiments
substantiate the hypothesis of an inhibitory BQ effect at high
concentrations and indicate that the improved efficiency of the
aerobic system results from the low concentration of
benzoquinone present in the reaction mixture.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
DESIGN PRINCIPLES
Palladium(II)/bis-sulfoxide catalysis has emerged as a
general platform for allylic C—H oxidations, aminations,
dehydrogenations, halogenations, and alkylations of α-
olefins.6,7 Common to all of these C—H functionalization
reactions is the use of 10 mol% Pd bis-sulfoxide catalyst and
stoichiometric quinone oxidants such as BQ. Additionally, the
majority of these reactions exploit benzoquinone as a π-acidic
ligand, often in combination with Lewis or Brønsted acid co-
catalysts, to activate the electrophilic π-allylPd intermediate
towards functionalization.5,6h,7a
Given the ubiquity of nitrogen functionality in bioactive
compounds, its selective and general introduction represents a
particularly powerful synthetic strategy.8 We disclosed a
catalytic Brønsted base activation mode for the intermolecular
linear allylic C—H amination (LAA) reaction that proceeds
via activation of the nitrogen nucleophile.7b Importantly, this
reaction is no longer dependent on the π-acidic effect of
benzoquinone for functionalization. Under these conditions,
we noted a slight increase in reaction yield when a bulky
quinone- having diminished ability to coordinate to Pd- was
employed as a terminal oxidant.7b With these considerations in
mind, we chose the LAA reaction as a platform to evaluate the
hypothesis that replacing benzoquinone with O2 as
a
stoichiometric oxidant can improve the catalytic efficiency of
Pd(II)-catalyzed oxidations with catalysts employing weakly
coordinating ligands.
Scheme 2. Proposed Mechanism for Aerobic Linear Allylic
Amination (LAA) With Redox-Relay Catalysis
nucleophile), high Pd catalyst loadings (e.g. 10-20 mol%), and
elevated pressures (e.g. 6-10 atm. O2 or air).12,13 Significant
amounts of double bond isomerization in both the starting
materials and products (up to 50%) necessitate the use of large
excesses of olefin and limit applications in fine chemical
synthesis.12-14
We considered two possible strategies for engaging
molecular oxygen as the terminal oxidant for the linear allylic
amination reaction (LAA) under preparatively useful
conditions. While oxidatively stable ligands which promote
direct oxidation of Pd(0) with molecular oxygen have been
developed, these ligands have not yet demonstrated the same
generality in C—H oxidation processes as compared to the
bis-sulfoxide ligand class.2a,4,15 A more general approach,
compatible with the continued use of bis-sulfoxides, would be
through the use of redox-active co-catalysts that act as electron
transfer reagents to relay electrons from Pd(0) to O2 at rates
that compete with Pd(0) precipitation (Scheme 2). An early
example of this is seen in the Pd(II)-catalyzed Wacker
oxidation of ethylene to acetaldehyde that uses catalytic
Cu(II)Cl2 to shuttle electrons from Pd(0) to O2.16
While
a
variety of important palladium-catalyzed
oxidations of alcohols and olefins have been developed using
O2 as a stoichiometric oxidant, analogous C—H oxidation
processes are scarce.4,9-14 Palladium (II)-catalyzed C—H
oxidation reactions often proceed with no formal ligands [e.g.
Pd(OAc)2] or weakly coordinating, oxidatively stable ligands
such as bis-sulfoxide.10 For allylic C—H acetoxylations and
aminations under such conditions, the slow electron transfer
directly between Pd(0) and O2 relative to the rapid formation
of palladium black via precipitation of palladium metal is
thought to result in deleterious olefin isomerization processes
and contribute to the requirement for high catalyst loadings.11-
14
While aerobic Pd(II)-catalyzed linear allylic C—H
aminations have been reported, their utility is limited by
requirements such as excess alkene (e.g. 3-7 equiv. relative to
Unfortunately, unligated metal salts generally have
a
deleterious effect on Pd(II)/bis-sulfoxide catalysis, possibly by
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
sequestering the bis-sulfoxide ligand that binds weakly and binding to Pd, we observed comparable yields to the aerobic
1
2
3
4
5
6
7
8
reversibly to Pd(II). Alternatively, a variety of base metal
complexes with covalent, non-exchangeable ligands are
known to catalyze the oxidation of dihydroquinones to the
corresponding quinones with O2.17,18 In a notable series of
seminal publications, Bäckvall and co-workers demonstrated
that this form of redox-relay catalysis enabled catalytic
quantities of benzoquinone to be effective at regenerating
Pd(II)(OAc)2 catalysts for the 1,4-diacetoxylation of dienes,
acetoxylation of cyclohexene, and oxidation of terminal
olefins to methyl ketones.19 Mechanistic studies of processes
proceeding via serial ligand catalysis have demonstrated that
high concentrations of BQ are required to effectively interact
with the Pd(II) species to promote π-allyl Pd(II)
functionalizations.5c,f,g Collectively, this led us to hypothesize
that in the context of an aerobic redox-relay catalytic cycle,
the low concentration of BQ present would diminish its ability
to effectively compete with the bis-sulfoxide ligand for Pd(II)
but would remain an efficient electron carrier for Pd(0)/ Pd(II)
reoxidation.
conditions (Table 1, entry 4 vs. entry 16).
REACTION SCOPE
We began our investigations into the scope and
reproducibility of the aerobic linear allylic C—H amination
(LAA) with a variety of unactivated α-olefins, the most
challenging substrates for amination (Table 2). Both the
Co(salophen) 2 and VO(acac)2 3 redox co-catalyst systems
were evaluated under fragment-coupling stoichiometries of
olefin (1 equiv. terminal olefin and 1.5 or 2 equiv. nitrogen
nucleophile). It is significant to note that these preparative
conditions contrast those of previously reported aerobic allylic
C—H amination methods (vida supra).12,13
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Aliphatic Substrates.
REACTION DEVELOPMENT
An efficient aerobic LAA process (1 equiv. olefin, reduced
Pd catalyst loadings, 1 atm. O2) was first evaluated with a
series of established redox-active co-catalysts. At reduced
catalyst loading (5 mol%), a substantial diminishment in yield
is observed under standard LAA conditions using
stoichiometric BQ as the oxidant (Table 1, entries 1 versus 2).
In contrast, the combination of Co(salophen) (2.5
mol%)/dihydroquinone (10 mol%) under a balloon of O2 (1
atm.) allowed for the Pd/bis-sulfoxide 1 catalyst loading to be
cut in half (10 mol% to 5 mol%) and the nitrogen nucleophile
loadings reduced (2 equiv. to 1.5 equiv.) with no diminishment
in selectivity while maintaining a good yield (entries 3 and 4
versus 1). We were also encouraged by the observation that,
under these optimized conditions, no significant decrease in
yield was observed after reducing the reaction time to 24 hours
(79% versus 78% yield, entry 4). A series of other base metal
co-catalysts were evaluated, however none were found to be
more efficient than Co(salophen) 2 (entries 5-8). Interestingly,
VO(acac)2 3/DHBQ in THF solvent appeared to be equally
effective as a redox co-catalyst system to Co(salophen)
2/DHBQ, albeit at higher loadings of nitrogen nucleophile (1.5
equiv. versus 2 equiv., entries 9 and 10). Although never
explored in aerobic Pd(II)-catalyzed reactions, VO(acac)2 3
had been reported to catalyze the aerobic oxidation of
hydroquinones to quinones at ambient temperatures and
pressures of O2.18 We were initially encouraged by the
observation that the vanadium co-catalyst loading could be
reduced to 1 mol% with no diminishment in yield, suggesting
it is an efficient electron-transfer agent (entry 10). Additional
vanadium catalysts were also evaluated (entries 11-13), and
under these conditions only VOSO4 was comparable to
VO(acac)2 3, affording a 65% yield of the desired product
(entry 13). Omission of the redox co-catalyst under these
aerobic conditions resulted in significantly diminished yields,
confirming its central role in Pd(II)/bis-sulfoxide 1 catalyst
regeneration (entry 14). The Pd(OAc)2/4,5-diazafluorene-9-
one (DAF) system known to enable linear allylic
acetoxylations using O2 as the terminal oxidant provided only
trace quantities of aminated product under these conditions
(entry 15).15 Notably, when using stoichiometric amounts of
bulky 2,5-dimethyl benzoquinone (2,5-DMBQ) as a terminal
oxidant, where methyl groups shield both olefin faces from
When comparing the Co(salophen) 2 and VO(acac)2 3
redox co-catalysts over a range of substrates at reduced Pd/bis-
sulfoxide 1 catalyst loadings (5 mol%), we found both
furnished products generally in excellent regio- and
stereoselectivities (>20:1 linear:branched and >20:1 E:Z). The
system employing cobalt uniformly furnished allylic
amination products with higher turnover numbers (TON) and
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
product yields comparable to or exceeding those using BQ.7
cobalt co-catalyst. Analogous Co(salen) complexes are known
to catalyze ring opening reactions of terminal epoxides with
water.20 Additional attempts to use the VO(acac)2 system with
1
2
3
4
5
6
7
For example, substrates with branching oxygen, carbon, or
nitrogen functionality in the homoallylic or bis-homoallylic
positions (Table 2, entries 5-8) proceed on average with 17%
higher isolated yields and average TON of 14.6 versus average
TON of 5.7 when compared to the Pd/bis-sulfoxide
1/Cr(salen) catalyzed system using BQ as a stoichiometric
Table 3. Aromatic substrates.
oxidant.7a Additionally, for substrates where
a direct
comparison can be made with previously reported aerobic
LAAs, the same trend in yields and turnover numbers is
observed (entries 3 and 4).12 We also note that higher yielding
substrates can be run for 24 hours without a significant
decrease in yield (entries 3 and 7). The mass balance for these
reactions is generally high, with unbranched substrates (e.g.
entries 1-3) furnishing predominantly linear E-allylic amine
(L:B = 20:1, 11:1, and 15:1 respectively) and small quantities
of isomerized recovered starting material (entries 1 and 3, 11%
and 4% respectively). Branched substrates (e.g. entry 7) give
isomerically pure products and small amounts of recovered
starting material as a mixture of isomerized (ca. 9%) and
isomerically pure terminal olefin (ca. 10%) (see supporting
information, Table 2, entry 7).
Unfortunately, the VO(acac)2 3 system proved to be less
robust, generally providing linear allylic amine products in
diminished yields and with significantly lower reproducibility
between experiments than the cobalt system (see Table 2 entry
2 standard deviation and supporting information). Although in
several cases yields for the vanadium system were comparable
(entries 4, 7, and 8; Scheme 4) or even exceeded (entry 3)
those of the cobalt system, no clear trend emerged for
predicting these observed differences in reaction efficiency
(see supporting information).
We next investigated the reactivity of the new aerobic
LAA system for a variety of activated allylarene substrates
(Table 3). Under these conditions, both electron poor and
electron rich aromatic rings are well tolerated, furnishing
products as one olefin isomer in good to excellent yields
(entries 1-3). Additionally, efficient reactivity is observed for
highly functionalized, electron rich aromatic systems (entries 4
and 5). Tolerance for medicinally relevant heterocyclic
aromatic functionality is demonstrated in the aerobic LAA of
an indole heterocycle (entry 6). In some cases, reactions may
be run for 24 hours without a significant decrease in yield
(entries 4 and 5). We were also pleased to find that often the
Pd catalyst loading could be further reduced to 2.5 mol%
while still maintaining useful yields of aminated product
(entries 1-5). In general, under these aerobic conditions, the
yields and TONs are significantly higher than those of the
benzoquinone system (entries 4 and 5). When comparing these
results with a previous aerobic system, we again observe
higher catalyst turnover numbers and product yields (entry
1).12
It was previously demonstrated that substrates containing
sensitive terminal epoxides and unprotected alcohols may be
aminated with the base promoted LAA reaction in useful
yields.7b A potential limitation of this aerobic linear allylic
amination system, which employs a Lewis-acidic redox co-
catalyst, is poor tolerance of highly Lewis basic functionality.
Under our optimized aerobic LAA conditions employing the
Co(salophen) 2 co-catalyst, we obtained a lower (ca. 30%)
yield for a terminal epoxide substrate (Table 3, entry 7). We
attribute this diminished reactivity to deleterious side reactions
of the terminal epoxide in the presence of the Lewis acidic
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a similar terminal epoxide substrate led to no significant
improvement in yield. We next looked to conditions
employing the sterically hindered quinone oxidant 2,5-DMBQ,
which had shown equal efficiency to the aerobic conditions at
reduced palladium loadings (Table 1, entry 16), and found that
C—H amination proceeded in 68% yield after 24 hours (entry
7). This constitutes a nearly 15% increase in yield relative to
stoichiometric benzoquinone conditions run with twice the
palladium loading and longer reaction times (72h).7b This
result illustrates the complementarity of a bulky, readily
available quinone to our aerobic conditions, allowing for
efficient amination of substrates containing Lewis-acid
sensitive functionality.
Reactivity with Reduced O2 Concentrations
We next sought to assess the efficiency of the aerobic LAA
conditions under reduced concentrations of O2 considered
beneficial for application of such aerobic chemistry in the
synthesis of fine chemicals (Table 4).21 The aerobic LAA
reaction was evaluated under identical conditions of
temperature, pressure and catalyst loadings (45oC, 1 atm., 5-
2.5 mol%), now at the significantly reduced O2 concentrations
found in air.
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
The aerobic LAA run with air furnished aliphatic and
Scheme 3. Reactivity of Functionally Diverse Substrates.
1
2
3
4
5
6
7
8
aromatic aminated products with the same isomeric purities
while maintaining synthetically useful yields at 1 equiv. of
substrate and low catalyst loadings. Yields of aminated
products were generally diminished relative to those of the
analogous system using O2. Decreasing the catalyst loadings
from 5 mol% to 2.5 mol% with aromatic substrates in some
cases still allowed for a useful reaction to proceed (entries 5-
7).
These
findings
demonstrate
that
the
DHBQ/Co(salophen)/O2 redox-relay is able to remain
operative even under reduced concentrations of molecular
oxygen. Whereas focused reaction optimization to develop an
aerobic LAA using air is an important future goal, it is
significant to note that for the majority of substrates run under
air, aminated products were generated in comparable yields
with higher TONs relative to the LAA using stoichiometric
BQ oxidant. 7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Allylic C-H Amination Using Air
LAA was applied to protected estrone derivative 23, the linear
allylic amination product 24 was furnished in good yield
(64%).7b Based on previous results demonstrating the limited
compatibility of Lewis basic functionality under our aerobic
LAA conditions, we evaluated 25 under conditions employing
2,5-DMBQ (1 equiv.) as the stoichiometric oxidant.
Gratifyingly, these conditions afforded the allylic amine
product 26 in 50% yield using only 5 mol% of palladium
catalyst.7b These results demonstrate the applicability of these
aerobic LAA conditions to afford useful yields of
functionalized complex molecules, as well as the increase in
reaction efficiency possible under conditions that limit
detrimental Pd-quinone interactions.
Scheme 4. Streamlined Synthesis of a Deoxynegamycin
Analog.
Late Stage C—H Amination and Streamlining
Late stage C—H oxidation is a powerful approach for the
streamlining and diversification of complex natural products
and compounds of medicinal interest.22 With optimal
conditions in hand, we sought to evaluate the performance of
functionally and topologically complex substrates under our
aerobic LAA reaction (Scheme 3). A glucose-derived substrate
21, bearing an abundance of oxygenated functionality,
furnished the corresponding allylic amine 22 in 76% yield as a
single diastereomer, after only 24 hours.
Given the improved synthetic efficiency of the aerobic
linear allylic amination with respect to both catalyst loadings
and product yields, we sought to re-evaluate the LAA in the
context of synthetic streamlining. The linear allylic C—H
Estrone derivatives were evaluated in both their
protected 23 and unprotected forms 25. When the aerobic
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
amination reaction has been previously used in the context of a
catalytic cycles largely based on kinetic studies.24 In the
1
2
3
4
5
6
7
8
streamlined synthesis of 28, a rigidified analog of the
antibiotic deoxynegamycin (Scheme 4).7a This C—H to C—N
bond-forming route eliminated five steps, all of which were
functional group manipulations, and proceeded with higher
overall yield as compared to the previous route based on
allylic C—O substitution.7a,23 When applying the new aerobic
amination conditions to the key C—H amination step of the
previous synthesis, we were delighted to find that these
optimized conditions afforded a nearly 30% increase in yield
of aminated intermediate 27 under either Co 2 or V 3 co-
catalysis with 5 mol% of Pd/bis-sulfoxide catalyst 1 (Scheme
4). The increased efficiency of this key C—N bond-forming
step now affords a 35% overall yield of deoxynegamycin
analog 28, a nearly three-fold increase in yield as compared to
the C—O to C—N route.23
Pd(OAc)2-catalyzed diacetoxylation of 1,3-dienes using MnO2
as the stoichiometric oxidant, a linear dependence of reaction
rate on benzoquinone concentration supported the hypothesis
that BQ acts as a π-acidic ligand for Pd(II) to promote
functionalization.5a In order to more definitively demonstrate
the inhibitory effect of BQ, we measured the rate of reaction
under the aerobic LAA conditions- a scenario where an
appreciable accumulation of dihydroquinone is unlikely- in the
presence of increasing amounts of BQ. Reaction rates were
measured at 5 mol% Pd(II)/bis-sulfoxide 1 while varying the
BQ concentration between 0.066 and 0.66 M (10-100 mol%
relative to substrate). These experiments were performed in
triplicate between 4-150 minutes of initiating the reaction
(Figures S3 – S8, supporting information). A plot of the
inverse of the reaction rate at various concentrations of BQ is
shown in Figure 1. The LAA reaction rate shows a clear
inverse dependence on BQ: a 10-fold increase in [BQ] results
in a nearly 9-fold decrease in reaction rate.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
THE BENZOQUINONE EFFECT
We have demonstrated that the linear allylic amination
(LAA) reaction run under aerobic conditions and conditions
using bulky quinone terminal oxidants (2,5-DMBQ) lead to
both improved product yields and catalyst turnover relative to
the previous system relying on stoichiometric benzoquinone as
the terminal oxidant. We hypothesized that the mechanistic
basis for these differences is that at high concentrations, BQ
acts as an inhibitory ligand for this Pd(II)/bis-sulfoxide
catalysis (Table 5A). As a preliminary evaluation of this, we
increased the concentration of BQ under the aerobic reaction
conditions and measured the effect on overall yields.
Strikingly, under both Co(salophen) 2 and VO(acac)2 3 co-
catalysis, a significant diminishment in yield was observed
(Table 5B, entries 1-3 and 4-6, respectively).
Figure 1. Inverse Relationship Between Rate and BQ
Concentration.
Although stable palladium (0) benzoquinone complexes
are known, palladium (II) benzoquinone complexes are
fleeting and have been proposed as intermediates within
Table 5. Effect of Elevated BQ on Reaction Yields.
Collectively, this data indicates that BQ has an inhibitory
effect on the linear allylic amination (LAA) at high
concentrations. While this is consistent with the hypothesis
that interactions of BQ with the Pd(II)/bis-sulfoxide catalyst
are detrimental to reaction efficiency, future mechanistic
studies will be directed at elucidating the precise mechanism
for BQ inhibition.
CONCLUSIONS
We have demonstrated that using an O2/Co/catalytic
dihydroquinone redox relay in combination with our Pd/bis-
sulfoxide catalysis enables aerobic linear allylic aminations
(LAA) of terminal olefins to proceed at reduced palladium
catalyst loadings and higher reaction efficiency than the
previous system relying on stoichiometric BQ. Kinetic
experiments show for the first time an inhibitory effect of BQ
on Pd(II) oxidative catalysis. Collectively this data implies
that for reactions relying on Pd(II) catalysts with weakly
coordinating ligands (e.g. bis-sulfoxide) to promote key steps
in the catalytic cycle (e.g. C—H cleavage), interactions of BQ
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
when present in high concentrations with the Pd(II) catalyst
⊥
Department of Chemistry, Northwestern University, 2145
1
2
3
4
may be detrimental to reaction efficiency. For such systems,
adopting a system which uses molecular oxygen as a
stoichiometric oxidant offers not only practical environmental
benefits but may also lead to enhanced catalytic efficiency.
Sheridan Road, Evanston IL, USA.
§Graduate School of Engineering, Nagoya University, Furo-
cho, Chikusa, Nagoya 464-8603, Japan.
5
6
EXPERIMENTAL PROCEDURE
Funding Sources
General procedure for the linear allylic amination: To an
oven dried 10 mL round bottom flask containing a PTFE-
covered stir bar was added: tetra n-butyl ammonium acetate in
7
8
9
Financial support was provided by the NIH/NIGMS (2R01
GM 076153B) and ARRA supplemental funding.
a
glove box, followed by carbamate nucleophile,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACKNOWLEDGMENTS
dihydroquinone, metal co-catalyst and catalyst 1. Due to the
hygroscopic nature of TBAA, the reaction flask was not
opened until all solids were ready to be transferred into the
flask. The terminal olefin (pre-weighed in a ½ dram vial) was
transferred to the reaction flask using the corresponding
solvent (1M). The flask was then attached to a cold-water
condenser, previously purged briefly with oxygen, and
equipped with an O2 balloon. The flask was secured with a
Teflon adaptor, sealed with Teflon tape, and the reaction was
allowed to stir at 400 rpm in a 45°C oil bath for 24-72 hours or
until completed by TLC. Upon completion, a workup with an
aqueous solution of 5% K2CO3 may be used to remove
remaining nucleophile and water-soluble impurities.
(Generally this workup leads to higher purity of isolated
products). Alternatively, the reaction may diluted with
dichloromethane and flushed through a 3-5 cm silica gel plug
with an 80% ethyl acetate/20% hexanes mixture to separate
the product from metal catalysts. If no work-up is necessary,
the reaction mixture may also be directly loaded onto a silica
gel column using dichloromethane or toluene. Purification of
the products is done using flash column chromatography - in
general, with a gradient of 10-30% EtOAc/hexanes. We have
also found that 10-30% acetone/hexanes or 10-50%
ether/pentane gradients are effective solvent systems for
purification.
We thank Sigma Aldrich for a generous gift of Pd/bis-
sulfoxide catalyst (1) (product number 684821), Johnson
Matthey for a generous gift of Pd(OAc)2, Anitox for a
generous gift to explore α-olefin oxidations, Mr. Jeffrey D.
Sayler for help with substrate synthesis and initial studies for
Table 3 and Ms. Jennifer R. Griffin and Mr. Stephen E.
Ammann for checking the experimental procedure in Table 2,
entry 2.
REFERENCES
(1) (a) Berkessel, A.; Diversity-Based Approaches to
Selective Biomimetic Oxidation Catalysis. In
Advances in Inorganic Chemistry; van Eldik, R.,
Reedijk, J., Eds.; Elsevier, 2006; vol. 58, pp 1-28. (b)
Ortiz de Montellano, P.R. Chem. Rev. 2010, 110, 932.
(2) (a) Stahl, S.S. Angew. Chem. Int. Ed. 2004, 43, 3400.
(b) Piera, J.; Bäckvall, J.E. Angew. Chem. Int. Ed.
2008, 47, 3506. (c) Cavani, F.; Teles, J.H. Chem. Sus.
Chem. 2009, 2, 508.
(3) Moiseev, I.I.; Vargaftik, M.N.; Syrkin, Y.K. Dokl.
Akad. Naak. SSSR. 1960, 133, 377.
(4) Popp, B. V.; Stahl, S. S. Palladium-Catalyzed
Oxidation Reactions: Comparison of Benzoquinone
and Molecular Oxygen as Stoichiometric Oxidants. In
Topics in Organometallic Chemistry; Meyer, F.,
Limberg, C., Eds.; Springer: New York, 2007; vol.
22, pp 149-189.
For reactions run under air, the same general procedure
outlined above was employed, the only change being a balloon
of air was used. While the reaction condenser may be left
opened to air, we have noted rapid and continual loss of the
very volatile TBME solvent under this scenario and
recommend the use of an air balloon.
(5) (a) Bäckvall, J.E.; Byström, S.E.; Nordberg, R.E. J.
Org. Chem. 1984, 49, 4619. (b) Castaño, A.M.;
Bäckvall, J.E. J. Am. Chem. Soc. 1995, 117, 560. (c)
Chen, M.S.; Prabagaran, N.; Labenz, N.A.; White,
M.C. J. Am. Chem. Soc. 2005, 127, 6970. (d) Bar,
G.L.J.; Lloyd-Jones, G.C.; Booker-Milburn, K.I. J.
Am. Chem. Soc. 2005, 127, 7308. (e) Chen, X.; Li,
J.J.; Hao, X.S.; Goodhue, C.E.; Yu, J.Q. J. Am. Chem.
Soc. 2006, 128, 78. (f) Fraunhoffer, K.J.; Prabagaran,
N.; Sirois, L.E.; White, M.C. J. Am. Chem. Soc. 2006,
128, 9032. (g) Covell, D.J.; White, M.C. Angew.
Chem. Int. Ed. 2008, 47, 6448. (h) Hull, K.L.;
Sanford, S.S. J. Am. Chem. Soc. 2009, 131, 9651. (i)
Osberger, T.J.; White. M.C. J. Am. Chem. Soc. 2014,
136, 11176.
(6) (a) Chen, M.S.; White, M.C. J. Am. Chem. Soc. 2004,
126, 1346. (b) Fraunhoffer, K.J.; White, M.C. J. Am.
Chem. Soc. 2007, 129, 7274. (c) Young, A.J.; White,
M.C. J. Am. Chem. Soc. 2008, 130, 14090. (d) Lin, S.;
Song, C.X.; Cai, G.X.; Wang, W.H.; Shi, Z.J. J. Am.
Chem. Soc. 2008, 130, 1290. (e) Rice, G.T.; White,
M.C. J. Am. Chem. Soc. 2009, 131, 11707. (f) Nahra,
F.; Liron, F.; Prestat, G.; Mealli, C.; Messaoudi, A.;
Poli, G. Chem. Eur. J. 2009, 15, 11078. (g) Stang,
E.M.; White, M.C. J. Am. Chem. Soc. 2011, 133,
ASSOCIATED CONTENT
Supporting
Information.
Experimental
procedures,
1
characterization data, and copies of H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*
mcwhite7@illinois.edu
Author Contributions
All authors have given approval to the final version of the
manuscript.
Present Addresses
∇
Institute of Chemical Research of Catalonia (ICIQ), Av.
Països Catalans 16, 43007 Tarragona, Spain.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
14892. (h) Braun, M.G.; Doyle, A.G. J. Am. Chem. 1959, 71, 176. (b) Henry, P.M.; Keith, J.A. Angew.
1
Soc. 2013, 135, 12901.
Chem. Int. Ed. 2009, 48, 9038.
2
3
4
5
6
7
8
9
(7) (a) Reed, S.A. White, M.C. J. Am. Chem. Soc. 2008,
130, 3316. (b) Reed, S.A.; Mazotti, A.R.; White, M.C.
J. Am. Chem. Soc. 2009, 131, 11701.
(8) (a) Collet, F.; Dodd, R.H.; Dauban, P. Chem.
Commun. 2009, 5061, and references therein. (b)
Jeffrey, J.L.; Sarpong, R. Chem. Sci. 2013, 4, 4092,
and references therein. (c) Paradine, S.M.; Griffin,
J.R.; Zhao, J.; Petronico, A.L.; Miller, S.M.; White,
M.C. Nature Chem. 2015, 7, 987.
(17) (a) Németh, S.; Szeverény, Z.; Simándi, L.I.
Inorganica Chimica Acta, 1980, 44, 107. (b) Rio,
M.F.; Pujol, D.; Charreton, C.B.; Fauvet, M.P.;
Gaudemer, A. J. Chem. Soc. Perkin Trans. 1 1984,
1971.
(18) (a) Tatsuno, Y.; Tatsuda, M.; Otsuka, S. J. Chem.
Soc.,Chem. Commun. 1982, 1100. (b) Hwang, D.R.;
Chu, C.Y.; Wang, S.K.; Uang, B.J. Synlett. 1999, 1,
77.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) For examples of aerobic olefin oxidation, see: (a)
Larock, R.C.; Hightower, T.R.; Hasvold, L.A.;
Peterson, K.P. J. Org. Chem. 1996, 61, 3584. (b)
Brice, J.L.; Harang, J.E.; Timokhin, V.I.; Anastasi,
N.R.; Stahl, S.S. J. Am. Chem. Soc. 2005, 127, 2868.
For examples of aerobic alcohol oxidation, see: (c)
Jensen, D.R.; Pugsley, J.S.; Sigman, M.S. J. Am.
Chem. Soc. 2001, 123, 7475. (d) Ferreira, E.M.;
Stoltz, B.M. J. Am. Chem. Soc. 2001, 123, 7725. For
examples of aerobic C-H oxidation, see (e) Zhang,
Y.H.; Yu, J.Q. J. Am. Chem. Soc. 2009, 131, 14654
and references 8,9,10 and 15.
(10) (a) Sigman, M.S.; Schultz, M.J. Org. Biomol. Chem.
2004, 2, 2551. (b) Gladysz, J.A.; Bedford, R.B.;
Fujita, M.; Gabbaï, F.P.; Goldber, K.I.; Holland, P.L.;
Kiplinger, J.L.; Krische, M.J.; Louie, J.; Lu, C.C.;
Norton, J.R.; Petrukhina, M.A.; Ren, T.; Stahl, S.S.;
Tilley, D.T.; Webster, C.E.; White, M.C.; Whiteker,
G.T. Organometallics, 2014, 33, 1505.
(11) Mitsudone, T.; Umetani, T.; Nosaka, N.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem.
Int. Ed. 2006, 45, 481
(12) Liu, G.; Yin, G.; Wu, L. Angew. Chem. Int. Ed. 2008,
47, 4733.
(13) Shimizu, Y.; Obora, Y.; Ishii, Y. Org. Lett. 2010, 12,
1372.
(14) Yin, G.; Wu, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132,
11978.
(19) (a) Bäckvall, J.E.; Awasthi, A.K.; Renko, Z.D. J. Am.
Chem. Soc. 1987, 109, 4750. (b) Bäckvall, J.E.;
Hopkins, R.B.; Grennberg, H.; Mader, M.M.;
Awasthi, A.K. J. Am. Chem. Soc. 1990, 112, 5160.
(20) Schaus, S.E.; Brandes, B.D.; Larrow, J.F.; Tokunaga,
M.; Hansen, K.B.; Gould, A.E.; Furrow, M.E.;
Jacobsen, E.N. J. Am. Chem. Soc. 2002, 124, 1307.
(21) (a) Witt, A.; Teodorovic, P.; Linderberg, M.;
Johansson, P.; Minidis, A. Org. Process Res. Dev.
2013, 17, 672. (b) Osterberg, P.M.; Niemeier, J.K.;
Welch, C.J.; Hawkins, J.M.; Martinelli, J.R.; Johnson,
T.E.; Root, T.W.; Stahl, S.S. Org. Process Res. Dev.
2014, 19, 1537.
(22) (a) Fraunhoffer, K.J.; Bachovchin, D.A.; White, M.C.
Org. Lett. 2005, 7, 223. (b) Chen, M.S.; White, M.C.
Science, 2007, 318, 783 (c) Stang, E.M.; White, M.C.
Nature Chem. 2009, 1, 547. (d) Kim, J.; Ashenhurst,
J.A.; Movassaghi, M. Science, 2009, 324, 238. (e)
Chen, K.; Baran, P.S. Nature, 2009, 459, 824. (f)
Chen, M.S.; White, M.C. Science, 2010, 327, 566. (g)
Malik, H.A.; Taylor, B.L.; Kerrigan, J.R.; Grob, J.E.;
Houk, K.N.; Dubois, J.N.; Hamman, L.G.; Patterson,
A.W. Chem. Sci. 2014, 5, 2352. (h) He, J.; Hamann,
L.G.; Davies, H.M.L.; Beckwith, R.E.J. Nat.
Commun. 2015, 6, 5943.
(23) Raju, B.; Anandan, S.; Gu, S.; Herradura, P.;
O’Dowd, H.; Kim, B.; Gomez, M.; Hackbarth, C.;
Wu, C.; Wang, W.; Yuan, Z.; White, R.; Trias, J.;
Patel, D. V. Bioorg. Med. Chem. Lett. 2004, 14, 3103.
(24) For spectroscopic evidence of π-allylPd(II)/BQ
complexes see: Bäckvall, J.E.; Gogoll, A. Tetrahedron
Lett. 1988, 29, 2243.
(15) Campbell, A.N.; White, P.B.; Guzei, I.A.; Stahl, S.S.
J. Am. Chem. Soc. 2010, 132, 15116.
(16) (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.;
Sieber, R.; Ruttinger, R.; Kojer, H. Angew. Chem.
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
Insert Table of Contents artwork here
1
2
3
4
5
6
7
8
9
OTBS
2
OPMB
1 equiv.
O
O
S
S
Ph
Pd(OAc)2
Ph
1 (5 mol%)
OTBS
NCO Me
2
Ts
Co(II) salophen 2 (2.5 mol%)
DHBQ (10 mol%)
45°C
OPMB
1 olefin isomer
+
O
O2 (1 atm.): 75%
air (1 atm.): 59%
BQ, 10% Pd: 65%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TsHN
1.5 equiv.
OMe
ACS Paragon Plus Environment