Palladium-catalysed anti-Markovnikov selective oxidative amination

Article abstract of DOI:10.1038/nchem.2904

In recent years, the synthesis of amines and other nitrogen-containing motifs has been a major area of research in organic chemistry because they are widely represented in biologically active molecules. Current strategies rely on a multistep approach and require one reactant to be activated prior to the carbon-nitrogen bond formation. This leads to a reaction inefficiency and functional group intolerance. As such, a general approach to the synthesis of nitrogen-containing compounds from readily available and benign starting materials is highly desirable. Here we present a palladium-catalysed oxidative amination reaction in which the addition of the nitrogen occurs at the less-substituted carbon of a double bond, in what is known as anti-Markovnikov selectivity. Alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide through trans-aminopalladation. Subsequently, olefin isomerization occurs to afford the thermodynamically favoured products. Both the scope of the transformation and mechanistic investigations are reported.

Full text of DOI:10.1038/nchem.2904

ARTICLES
PUBLISHED ONLINE: 1 JANUARY 2018 | DOI: 10.1038/NCHEM.2904
Palladium-catalysed anti-Markovnikov selective
oxidative amination
Daniel G. Kohler, Samuel N. Gockel, Jennifer L. Kennemur, Peter J. Waller and Kami L. Hull
*
In recent years, the synthesis of amines and other nitrogen-containing motifs has been a major area of research in organic
chemistry because they are widely represented in biologically active molecules. Current strategies rely on a multistep
approach and require one reactant to be activated prior to the carbon–nitrogen bond formation. This leads to a reaction
inefficiency and functional group intolerance. As such, a general approach to the synthesis of nitrogen-containing
compounds from readily available and benign starting materials is highly desirable. Here we present a palladium-catalysed
oxidative amination reaction in which the addition of the nitrogen occurs at the less-substituted carbon of a double bond,
in what is known as anti-Markovnikov selectivity. Alkenes are shown to react with imides in the presence of a palladate
catalyst to generate the terminal imide through trans-aminopalladation. Subsequently, olefin isomerization occurs to afford
the thermodynamically favoured products. Both the scope of the transformation and mechanistic investigations
are reported.
lkene amination reactions, including hydro- and oxidative (Fig. 1e)7,30. During the trans-aminopalladation step, a relatively
amination, are atom-economical approaches to the synthesis large nucleophile would be kinetically biased to approach the
A
of ubiquitous C–N bonds1–7. Oxidative amination, also alkene to form the less hindered C–N bond and would lead to
known as the aza-Wacker oxidation, differs from hydroamination the desired anti-Markovnikov product28,29,31–33. Although trans-
reactions in that it retains the degree of unsaturation in the aminopalladations with cationic palladium catalysts are known to
product, allowing for further elaboration of this functionality3–7
.
afford the Markovnikov constitutional isomer34,35, we hypothesized
As terminal amines are prevalent in pharmaceuticals, especially that the electronic differentiation between the double-bond carbons,
distal to polar functionalities8, the development of an anti- which leads to Markovnikov’s rule, would be minimized with a less
Markovnikov-selective aza-Wacker oxidation of unactivated alkenes electrophilic anionic palladate catalyst and lead to a more sterically
would represent a significant advance. Such a process would consti- biased transformation28. The successful development of an anti-
tute a novel approach to the remote anti-Markovnikov amination of Markovnikov selective aminopalladation of simple alkenes would
organic molecules, and represent a powerful disconnection in have implications that reach far beyond the aza-Wacker reaction,
organic synthesis. Additionally, when performed aerobically, this as aminopalladation is the regioselectivity-determining step in
transformation would couple two easily accessible starting materials many olefin difunctionalization reactions34,35. Thus, the principles
and would generate only an equivalent of H2O as waste.
we have learned from the studies reported herein could find
The primary challenge in generating the anti-Markovnikov future applications in other anti-Markovnikov aminofunctionaliza-
product is biasing the aminometallation step to afford the branched tions of simple alkenes, and thus enable single-step access to a wide
[M]–C (where [M] is the metal catalyst) and terminal N–C bonds. class of products36,37
.
Owing to both steric repulsion and the inherent electronic bias of
nucleophile addition to alkenes, known as Markovnikov’s rule, Results and discussion
this selectivity is not generally favoured for an intermolecular ami- Reaction discovery and optimization. Our initial investigation
nometallation6,7. However, several strategies have been successfully focused on developing an anti-Markovnikov selective oxidative
employed to reverse this inherent selectivity. One approach uses amination of homoallyl benzene (1a). As seen in Table 1 and
activated alkenes that can form π-benzyl or [M]-enolate intermedi- further elaborated in Supplementary Section B, employing known
ates (Fig. 1a)9–16. A second approach utilizes an allylic C–H acti- oxidative amination conditions affords the expected Markovnikov
vation followed by nucleophilic attack at the terminal carbon on isomer exclusively in 88% yield (Table 1, entry 11)4. However, in
the resulting π-allyl (Fig. 1b)17–20. Alternatively, proximal Lewis the presence of 10 mol% Pd(OAc)2, the addition of either
basic groups can direct functionalization of the alkene to afford 40 mol% Bu4NCl (Table 1, entry 2) or 20 mol% Bu4NOAc
the favoured metallacycle (Fig. 1c)21–27. Finally, in stoichiometric (Table 1, entry 6) reverses the regioselectivity to favour the anti-
investigations, the combination of a palladate complex and sterically Markovnikov products in 95% (3:1 anti-Markovnikov:Markovnikov
hindered amine nucleophiles promoted a trans-aminopalladation to (a-M:M)) and 59% (1.3:1 a-M:M) total yields, respectively. The in
functionalize the terminal carbon and produce the anti- situ generation of a palladate complex is supported by the
Markovnikov constitutional isomer (Fig. 1d)28,29. However, con- independent synthesis and crystallographic characterization of
ditions that afford the anti-Markovnikov aza-Wacker product with [PdCl4][Bu4N]2 (Supplementary Section I). The significant increase
simple aliphatic alkenes have not been reported in catalytic in reactivity of the Bu4N+ salts relative to Li+ (Table 1, entry 3) or
amination reactions.
Cs+ (Table 1, entry 4) can be attributed to the increased solubility
We envisioned utilizing a palladate catalyst that could promote a of the resulting palladate complexes under the reaction conditions.
selective trans-nucleopalladation by saturating the coordination Accordingly, no product was observed when Na2PdCl4 or K2PdCl4
sites with excess halide, as has been seen in the Wacker oxidation was used directly, with or without added acetate sources. Known
Department of Chemistry, University of Illinois, Urbana-Champaign, 600 S. Mathews, Urbana, Illinois 61801, USA. e-mail: kamihull@illinois.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2904
ARTICLES
a
+ H+
[M]
X
+ [M]
+ HNR2
X
X
NR2
– [M]
X
NR2
or
– [M]–H
– H+
X
X
Ts
N
b
c
R
R
L
+ [Pd]
– H+
+ HNTsCO2Me
R
OMe
– H+
H
[Pd]
L
O
+ [M]
+ H+
– [M]
or
L
+ HNR2
[M]
– H+
NR2
– [M]–H
R2N
d
e
iPr2HN
Cl
Cl
Pd
+ HNiPr2
Cl
Cl
Cl
Pd
Pd
Cl
N
H
+ [palladate]
+ HNR2
[Pd]
NR2
R
NR2
R
– H+
– [Pd]–H
R
H
Figure 1 | Current strategies for the anti-Markovnikov oxidative amination of simple alkenes. a, Use of activated alkenes gives rise to stabilized alkyl–Pd
intermediates, which provide a basis for anti-Markovnikov selectivity. b, Allylic C–H bond activation can afford a π-allyl intermediate, which can be
intercepted by a nucleophile to afford allylic amines. c, A tethered directing group can direct functionalization at the terminal position through the formation
of a more-stable metallacyclic intermediate. d,e, Use of a palladate species can kinetically favour anti-Markovnikov functionalization of simple aliphatic
alkenes, with sterically encumbered nucleophiles in stoichiometric studies (d), and catalytically in the present work (e). L, nitrogen or oxygen; [M], metal
catalyst; R, alkyl chain; Ts, tosyl group (CH3C6H4SO2); X, carbon, nitrogen or oxygen.
aza-Wacker conditions typically form the enimide, in which the
These studies suggest that proximal electron-withdrawing groups
double bond remains unmoved and the nitrogen replaces one of improve the selectivity for the anti-Markovnikov isomer. Given this
the hydrogen atoms as the exclusive product; however, using the observation, we became interested in investigating homoallylic alco-
palladate catalyst, mixtures of olefin isomers were observed with hols as substrates. The alcohol would presumably increase the
the (E)-styrenyl isomer (2a) as the major product4,5. When both regioselectivity by acting as an electron-withdrawing group and
additives were present, the regioselectivity improved to afford an would, through formation of the ketone, favour a single isomeric
86% combined yield (4:1 a-M:M), with a 62% yield of 2a (Table 1, product34,38–42. Moreover, the reaction would afford the thermodyn-
entry 8). Further optimization led to the conditions employed in amic γ-aminoketone product—a common motif and intermediate
Table 1, entry 9, which afforded 2a in 60% in situ and 57% in biologically active molecules and their synthetic precursors8.
isolated yield as a single isomer; the combined yield of all the Excitingly, when homoallylic alcohol 1m is combined with phthali-
isomers was 75% (8:1 a-M:M) (Table 1, entry 9).
mide (NPhth) in the presence of 5 mol% Pd(OAc)2 and 20 mol%
Bu4NCl, a 77% yield of the γ-aminoketone 2m is observed. The
Reaction generality. With the optimized conditions identified, we regioselectivity is also significantly enhanced in favour of the anti-
investigated the anti-Markovnikov amination of other olefinic Markovnikov product in a 14:1 ratio. This aerobic oxidation reaction
substrates. Substitution on the aryl group of homoallylbenzene can be conducted at ambient pressures, whereas high pressure is a
showed a minimal effect on yield and regioselectivity (2a–2e). common requirement for other aza-Wacker processes5. The reaction
The functionalization of allylbenzene (1f) afforded 2f with a is also readily scalable and provides 2m in 75% yield on a 0.5 mmol
significantly higher selectivity (47:1) and moderate yield (47%). scale and 77% yield on a 5.0 mmol scale. Given the presence of the
Particularly, electron-poor p-CF3-allylbenzene (1j) gave 2j in a electron-withdrawing oxygen atom, Bu4NOAc is no longer required
much higher selectivity (57:1 a-M:M) than the electron-rich p- to achieve excellent levels of selectivity in most cases. Importantly,
MeO-allylbenzene (1g), which formed 2g in only a 6:1 a-M:M the thermodynamically driven isomerization process exclusively
selectivity. Overall, the selectivity is generally lower for the generated the ketone product; that is, no enimide or allyl imide
homologated products (2a–2e) compared with the allyl benzenes products were observed.
(2f–2j), with greater quantities of Markovnikov and double-bond
Under the modified conditions identified for these alcohol-con-
isomers observed. Increasingly distal functionality, such as a taining substrates, both electron-withdrawing and -donating groups
phenyl ring three methylene units away (1k), affords the primary were tolerated well. It was found that substituting the aryl ring with
amine derivative 2k in modest yield and good selectivity (23%, 8:1 electron-withdrawing substituents (1q–1u) generally gave higher
a-M:M). However, when substrates lack an inductively yields and regioselectivities of 2q–2u compared with unsubstituted
withdrawing aryl ring (1l), reactivity and regioselectivity are poor.
or electron-rich substrates (2m–2p); for example, 2t, with a p-CF3
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2904
Table 1 | Optimization of oxidative amination reaction on 1a.
ARTICLES
in the reaction for these substrates. Similarly, inductively withdraw-
ing imides and amides at the allylic or homoallylic position pro-
moted the anti-Markovnikov selective oxidative amination. These
substrates, which lack the thermodynamic sink of a styrene or car-
bonyl, afford the enimide 2ad and enamide 2ae with the allylic sub-
strate and the allyl imide 2af with the homoallylic substrate.
Importantly, the resulting terminal phthalimides are easily depro-
tected. 2a has been shown to react with NH2NH2 to afford 2a′ in
85% yield (Table 2)45. Additionally, under similar conditions we
were able to remove the phthalimide from 2s to afford cyclic
imine 6s in 78% yield (Table 2).
Ph
NPhth
Ph
1.1 equiv. phthalimide
NPhth
2a
2a'
NPhth
10 mol% [Pd]
Ph
X mol% additive
2a''
Ph
DMA, O2, 80 °C, 24 h
NPhth
NPhth
1a
Ph
Ph
2a'''
2a''''
Next, we sought to explore the scope of the reaction. Other cyclic
acidic amine nucleophiles, including succinimide, saccharine and
4-nitrophthalimide were all effective under the reaction conditions,
affording 3m–5m in good to very good yields.
Entry Additive (mol%) Total yield (%)* Yield 2a (%)* a-M/M*
1
None
Bu4NCl (40)
LiCl (40)
20
95
32
13
80
59
15
<1
68
18
2
24
26
0
0.06
3.0
1.4
0.2
2.3
1.3
<0.01
4.0
2
3
4
5
6
7
8†
CsCl (40)
Bu4NI (40)
Bu4NOAc (20)
NaOAc (20)
Bu4NCl (20),
Bu4NOAc (10)
Bu4NCl (25),
Bu4NOAc (15)
Bu4NCl (30),
Bu4NOAc (20)
None
Mechanistic investigations. The significant selectivity difference
between this transformation and that of other oxidative amination
reactions4,5 led us to probe whether this reaction goes through an
aminopalladation mechanism or if it goes through π-allyl Pd
intermediates formed via an allylic C–H activation event, as has
been demonstrated in related reactions.
To gain mechanistic insight into the nature of the catalytic cycle,
we performed kinetic analyses on the optimized reaction conditions
for homoallyl benzene. The concentrations of additives were kept
constant relative to the palladium(II) acetate for all the investi-
gations, as certain concentrations are required to form the active
catalyst (Fig. 2a). Additional Bu4NOAc was found to have an inhibi-
tory effect on the rate. Interestingly, the results indicate that the reac-
86
62
9†
75
24
88
60
21
0
8.0
130
NA
10†
11‡
*In situ yield determined by gas chromatographic analysis and comparison with an internal standard.
†5 mol% Pd(OAc)2. ‡Literature conditions for oxidative amination used: Pd(OAc)2 (5 mol%), PhCN
(1 M), 1a (6 equiv.), 60 °C, 1 atm O2. NPhth, phthalimide.
substituent, was formed in 72% yield and 19:1 a-M:M selectivity, tion is zero order in nucleophile, first order in olefin and 1.4 order in
whereas 2n, with a p-MeO substituent, was afforded in 56% yield [Pd]. The non-integer order in [Pd] is probably because of an equi-
and 14:1 a-M:M selectivity. Steric hindrance on the aryl ring has a librium between monomeric and dimeric palladate complexes, as
deleterious effect on the yield, but results in an increase in the both are competent catalysts for the reaction at low concentrations
regioselectivity of the reaction. For example, the o-tolyl (2o) and and generate less-active complexes at high concentrations. A similar
mesityl (2p) products were obtained with improved selectivities effect was reported previously by Henry and co-workers46. The
(20:1 and 18:1 a-M:M, respectively) as compared with 2m (14:1 addition of Bu4NOAc first shifts the equilibrium towards the
a-M:M), in albeit lower isolated yields (64% for 2o and 31% for dimeric species and thus reduces the concentration of active [Pd]
2p). Overall, the reaction offers very good functional group toler- catalysts47. To support this conclusion, we determined the order
ance. For example, ethers (2b, 2g and 2n), chlorides (2d, 2i and in catalyst in the absence of additional Bu4NOAc and found an
2s), trifluoromethyl groups (2e, 2t and 2u) and heterocycles (2v order of 1.1 (Fig. 2b). The oxidative aminations of homoallylic
and 2w) were all tolerated well. Additionally, a triflate (2r), an alcohols have similar orders in reagents (Supplementary Section
α,β-unsaturated ketone (2x) and a silyl ether (2ab) were unaffected C): zero order in phthalimide, first order in homoallyl alcohol
under the reaction conditions. Substrates with free primary alcohols and first order in [Pd]. The order in [Pd] suggests that a monomeric
did not afford any of the desired products, as the primary alcohol palladate complex is the active catalysts for the homoallylic alcohol
oxidizes under the reaction conditions.
system in which Bu4NOAc is not added to the reaction. These order
In the case of alkyl substitution α to the alcohol, we observed a experiments are consistent with either coordination of the olefin or
high yield, but significantly diminished anti-Markovnikov selectiv- allylic C–H activation as the turnover-limiting step.
ity under the conditions optimized for the α-aryl alcohols. This is
As the optimized conditions are related to Jeffery’s conditions for
probably because of the diminished inductive effect of alkyl substi- the Heck reaction, which under similar conditions are thought to
tuents relative to aryl groups. As with the simple alkenes, the involve Pd nanoparticles, we sought to determine if the catalyst
addition of Bu4NOAc (5 mol%) restored the regioselectivity. It was homogeneous or heterogeneous48. When the reaction is run in
was observed that the size of the aliphatic group had an impact the presence of Hg(0), the product is still generated, albeit in lower
on regioselectivity—larger substituents afforded a more-selective yield (12–14%). However, an induction period is observed for the
transformation (2y–2ab).
Heck reaction, and no induction period was observed in our oxi-
The increase in regioselectivity observed with substrates bearing dative amination reaction48,49. These studies suggest that the Pd(II)
a homoallylic alcohol suggest that it may be acting as a directing catalytic intermediate is homogeneous, although Pd(0) species may
group during the aminopalladation step21–27. Although this was be stabilized as transient nanoparticles prior to oxidation by O2.
not observed in related reactions, it has been proposed in the
The requirement for the olefin to bear an electron-withdrawing
Wacker oxidation of β-substituted homoallylic alcohols43, but not group was investigated by performing a Hammett study. A ρ
unsubstituted homoallylic alcohols or ethers44. When 1ac was value of 0.878 was observed for a series of homoallylbenzene deriva-
subjected to the optimized reaction conditions, 2ac was afforded tives, which indicates that electron-withdrawing groups increase the
in 58% yield as a 3.6:1 mixture of Z/E isomers and 9:1 mixture of rate of the oxidative amination reaction. This is consistent with
2ac to all other constitutional and stereoisomers. These experiments either the aminopalladation or C–H activation mechanism. In the
indicate that the coordination of the alcohol to the catalyst is not first, reducing the electrostatic repulsion between the olefin and
necessary for an anti-Markovnikov selective transformation, electron-rich anionic palladate complex would accelerate the rate
although we cannot eliminate the possibility that it is participating of the ligand exchange. A similar effect was reported by Hanley
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Table 2 | Anti-Markovnikov oxidative amination of simple alkenes and homoallylic alcohols.
5 mol% Pd(OAc)2
20–25 mol% Bu4NCl
0–15 mol% Bu4NOAc
O
O
R
N
+
n
HN
R
DMA, 5 Å MS, 1 atm O2, 80 °C, 24 h
1a–1ab
n
O
O
2a–2ab, 3m–5m
NPhth
NPhth
NPhth
NPhth
NPhth
NPhth
2a*
57%
11:1 a-M:M
2b*
54%
10:1 a-M:M
2c*
51%
14:1 a-M:M
2d*
67%
27:1 a-M:M
2e*
56%
8:1 a-M:M
O
Cl
F3C
NPhth
NPhth
NPhth
NPhth
2f†
47%
47:1 a-M:M
2g†
58%
6:1 a-M:M
2h†
68%
37:1 a-M:M
2i†
50%
24:1 a-M:M
2j†
41%
57:1 a-M:M
O
Cl
F3C
O
O
O
NPhth
NPhth
NPhth
2m‡
NPhth
NPhth
NPhth
2n‡
56%
14:1 a-M:M
2o‡
64%
2l¶
2k*
23%
8:1 a-M:M
24%
75%
O
1:1.4 a-M:M
14:1 a-M:M
20:1 a-M:M
O
O
O
O
O
NPhth
NPhth
NPhth
NPhth
2p‡
31%
18:1 a-M:M
2q‡
76%
> 20:1 a-M:M
F3C
2r‡
2s‡
2t‡
72%
19:1 a-M:M
Cl
OAc
OTf
49%
79%
10:1 a-M:M
16:1 a-M:M
O
O
O
O
F3C
NPhth
O
NPhth
NPhth
NPhth
O
S
NPhth
2y§
66%
9:1 a-M:M
2u‡
2v‡
69%
2w‡
2x‡
CF3
O
56%
78%
53%
>20:1 a-M:M
14:1 a-M:M
>20:1 a-M:M
>20:1 a-M:M
O
O
O
O
NPhth
NPhth
NPhth
TBSO
NPhth
N
NPhth
5
2z§
71%
2aa§
72%
>20:1 a-M:M
2ab§
72%
10:1 a-M:M
2ac‡
2ad‡
83%
>20:1 a-M:M
O
58% 3.6:1 Z:E
9:1 a-M:M
13:1 a-M:M
NO2
O
O
O
O
O
O
O
O
S
NPhth
O
N
N
N
N
N
NPhth
O
O
O
2ae‡
2af‡
84% 4:1 Z:E
>20:1 a-M:M
3m‡
4m‡
78%
19:1 a-M:M
5m‡
O
62%
60%
63%
>20:1 a-M:M
14:1 a-M:M
> 20:1 a-M:M
O
O
N
NH3Cl
NH2NH2·H2O (3 equiv.)
Ref. 45
NPhth
N
MeOH, 60 °C, 6 h
78% yield
85% yield
O
Cl
Cl
2a
6a
2s
6s
Bottom line: removal of the terminal phthalimide, in this work affording the cyclic imine (right). *Bu4NOAc (15 mol%), Bu4NCl (25 mol%). †Pd(OAc)2 (10 mol%), Bu4NOAc (10 mol%), Bu4NCl (40 mol%).
‡Bu4NCl (20 mol%). §Bu4NOAc (5 mol%), Bu4NCl (20 mol%). ||Bu4NCl (15 mol%). ¶Bu4NCl (25 mol%).
and Hartwig in computationally comparing the ΔΔG≠ for styrene formation occurs after the rate-determining step (Fig. 3a). To eliminate
derivatives that undergo ligand exchange with a neutral Pd(II) one of the two possible mechanisms, we isotopically labelled the sub-
complex, for which m-MeO-styrene was predicted to have a lower strate at the allylic position. Substrate 1a-d2 subjected to the reaction
barrier than p-Me-styrene50. Alternatively, electron-withdrawing conditionsallowed usto distinguish between the two mechanisticpath-
groups would stabilize the anionic charge build-up and therefore ways. If the reaction proceeded through the aminopalladation pathway,
accelerate the rate of C–H allylic activation through deprotonation. it is expected that 2a-d2 would be the primary product of the reaction,
The order in reagents and Hammett investigations demonstrate in which one of the deuterium atoms migrates to C3. Additionally, as
that the alkene and the catalyst are both involved during the rate-deter- no C–H bond cleavage would occur until after the turnover-limiting
mining step, but do not allow us to distinguish between aminopallada- step, no kinetic isotope effect is expected. Alternatively, if the reaction
tion or C–H activation, as this would be consistent with the turnover- proceeded through an allylic C–H activation pathway, 2a-d1 would be
limiting step being either olefin coordination for the aminopalladation formed, with only a single deuterium atom in the product, as the
mechanism6,7 or allylic C–H activation17–19 in which C–N bond second would have been deprotonated during the C–H activation
4
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ARTICLES
0.60–1.2 equiv. phthalimide
a
l
4.0–7.0 mol% Pd(OAc)2 or Bu4N2PdC 4
0–50 mol% Bu4NCl
NPhth
NPhth
0–50 mol% Bu4NOAc
+
+
DMA, O2, 80 °C, 24 h
NPhth
1a
2a
2a'
2a"
0.20–2.0 equiv.
[a-M] = [2a] + [2a'] + [2a"]
0.9
y = 0.6652x–0.043
R2 = 0.12236
0.8
0.21
y = 0.0001x1.0633
R2 = 0.96177
y = 0.0014x1.4493
R2 = 0.99951
0.6
0.4
0.2
0.0
0.6
0.3
0.0
0.14
0.07
0.00
0
500
1,000
0
20
40
60
80
0
500
1,000
1,500
[1a] (mM)
[Pd] (mM)
[PhthNH] (mM)
2.0
1.5
1.0
0.5
0.0
2.0
1.5
1.0
0.5
0.0
1a: 1.0 order
[Pd]: 1.45 order
Phthalimide: –0.04 order
Bu4NCl: saturation kinetics
Bu4NOAc: complex kinetics
0
200
400
600
0
200
400
600
Bu4NCI (mM)
[Bu4NOAc] (mM)
b
c
1.0 equiv. phthalimide
5.0 mol% Pd(OAc)2
25 mol% Bu4NCl
1.0 equiv. phthalimide
4.0–7.0 mol% Pd(OAc)2
20–35 mol% Bu4NCl
NPhth
15 mol% Bu4NOAc
NPhth
X
DMA, O2, 80 °C, 24 h
a-M
DMA, O2, 80 °C, 24 h
X
1a
2.0 equiv.
1a–5a
2.0 equiv.
a-M(X)
0.8
0.8
y = 0.0059x1.1258
R2 = 0.99627
0.6
0.4
0.2
0.0
0.0
0.0
0.5
σ
1.0
–0.5
y = 0.878x – 0.0932
R2 = 0.67444
0
20
40
60
80
–0.8
[Pd] (mM)
Figure 2 | Mechanistic investigation of the anti-Markovnikov oxidative amination through reagent order determination and Hammett plot analysis.
a, Determination of the order in all reagents for the anti-Markovnikov selective oxidative amination of 1a shows first-order kinetics for the alkene, non-integer
1.4 order for the catalyst and zero order for the nucleophile. b, Determination in the order of [Pd] when no Bu4NOAc is added, which indicates first order in
the catalyst with a lower acetate equivalence and implicates palladium oligomerization. c, A Hammett investigation for the effect of electronics on the aryl
ring on the rate of the oxidative amination reaction demonstrates the rate enhancement of electron-withdrawing groups, even several bonds removed from
the reactive alkene. Error bars represent the standard deviation of the measured values across three independent runs. DMA, N,N-dimethyl acetamide.
step. Further, if allylic C–H activation is the turnover-limiting step, a phthalimide and 13% α to the phenyl ring (Supplementary Section E).
primary kinetic isotope effect would be observed. 1a-d2 subjected As shown in Fig. 3d, the major isomer is, indeed, consistent with
to the reaction conditions afforded 2a-d2 selectively and a kH/kD a reaction that occurs through trans-aminopalladation followed by
of 1.0 was observed, consistent with a reaction that occurs β-hydride elimination. The minor isomer, in which the deuterium
through aminopalladation and not C–H activation (Fig. 3b).
has migrated, may be the result of an initial trans-aminopalladation/
Next, we sought to distinguish between the cis- and trans-amino- β-deuteride elimination to afford the cis-diastereomer and subsequent
palladation pathways. As the stereochemical outcome of this trans- isomerization to the trans-product by Pd–D insertion, β-H elimination.
formation cannot be determined by examining the stereochemistry A kinetic isotope effect could also account for some of the preference
of the products after the olefin isomerization has occurred, we toward hydride elimination if a cis-aminopalladation occurred;
chose to investigate styrene as a substrate because it cannot undergo however, if this was the case, the cis-diastereomer (Z-2ag-d1)
an olefin isomerization and can only afford the enimide product would be the expected product.
(Fig. 3c). (Z)-β-deuterostyrene (1ag-d1) subjected to the standard
Combining the mechanistic information garnered from the
reaction conditions afforded 2ag-d1, with 79% deuterium α to the kinetic data and the isotope labelling studies, the catalytic cycle
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2904
ARTICLES
Mechanism 1: aminopalladation
a
b
30%
Ph
90%
1.1 equiv. phthalimide
5 mol% Pd(OAc)2
25 mol% Bu4NCl
Ph
D
+ HNPhth
D
NPhth
[Pd]
D
D
Ph
D
– H+
C2
D
– H+
15 mol% Bu4NOAc
NPhth
D
C2
+ Cat.
– [Pd]
PhthN
C1
C3
Ph
2a-d2
DMA, 1 atm O2, 80 °C, 24 h
[Pd]
Ph
D
D
D
D
44%
2a-d2
kH/kD = 1.01 0.03
1a-d2
95%
95%
Ph
1a-d2
+ HNPhth
NPhth
Ph
D
– D+
[Pd]
– H+
D
2a-d1
– [Pd]
Mechanism 2: C–H activation
Mechanism 1a: cis-aminopalladation
c
d
NPhth
NPhth
H
[Pd]
H
13%
Ph
1.1 equiv. phthalimide
5 mol% Pd(OAc)2
20 mol% Bu4NCl
H
Ph
D
D
2ag-d0
+ Cat. [Pd]
+ HNPhth
NPhth
79%
Ph
D
DMA, 1 atm O2, 80 °C, 24 h
D
D
98%
1ag-d1
1ag-d1
H
[Pd]
H
NPhth
2ag-d1
D
Ph
D
NPhth
Ph
2ag-d1
Mechanism 1b: trans-aminopalladation
Figure 3 | Deuterium labelling studies as probes to distinguish between multiple mechanistic pathways. a, Potential C–H activation and aminopalladation
mechanisms. b, Isotopic labelling experiments to test the two possible mechanisms show full deuterium retention and no kinetic isotope effect as evidence
for aminopalladation and against C–H activation. c, Possible outcomes for cis- and trans-aminopalladation pathways. d, Isotopic labelling study to probe the
mechanism of aminopalladation shows a predominately deuterium retention at the terminal carbon and thereby indicates an anti-aminopalladation pathway
(Supplementary Fig. 32). Cat., catalyst.
2NBu4+
Ph
X
X
X
X
X
X
1a
Ligand exchange
(turnover-limiting step)
Pd
Pd
Oxidation
H2O2
or H2O
O2 or H2O2
2HX
– 2NBu4X
+ 2NBu4X
Bu4NX
[Pd]
X
X
2–
Pd
X
[Pd(0)]
Ph
X
+
2NBu4
Bu4NNPhth
HOAc
Bu4NOAc
HNPhth
X = Cl or OAc
HX
Reductive
elimination
Trans-aminopalladation
HOAc
H
[Pd]
[Pd(II)]
PhthN
Ph
X
[Pd]
H
PhthN
β-Hydride elimination
PhthN
Ph
Ph
2a
Olefin isomerization and
dissociation from metal
Figure 4 | A catalytic cycle proposal based on the mechanistic studies undertaken. The order in reagents implicates the involvement of the alkene and
catalyst at or before the rate-determining step and excludes the involvement of the phthalimide. This suggests that alkene binding through associative ligand
dissociation is the rate-determining step, and that nucleophilic attack on the bound olefin is fast relative to this. The requirement of some catalytic quantity of
acetate suggests its involvement in this process, and its function as a catalytic base is proposed, to generate a nucleophilic anionic phthalimide. Subsequent
β-hydride elimination and olefin isomerization generates the most stable olefin isomer, and the resultant Pd–H is then oxidized aerobically to regenerate
the palladate.
shown in Figure 4 is proposed. Either the Pd(0) or the Pd(II) palla- coordination. Outer-sphere nucleophilic attack by the phthalimide
date complex is the catalyst resting state, with the loss of an anionic and olefin isomerization of the Pd(0) all occur between the turn-
ligand required either during or prior to the turnover-limiting olefin over-limiting step and the catalyst resting state, as supported by
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2904
ARTICLES
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Conclusion
In conclusion, we have demonstrated a palladate catalyst that
promotes an anti-Markovnikov selective aza-Wacker oxidation.
Additionally, under the reaction conditions, olefin isomerization
occurs to translocate the unit of unsaturation to the most thermo-
dynamically favoured position in the molecule. Further, we have
demonstrated that this reaction occurs through a trans-aminopalla-
dation mechanism with rate-determining olefin coordination. This
report represents a major advance in oxidative amination technol-
ogy, and constitutes a unique approach to conceptualize the
remote amination disconnections in organic synthesis. Our
current efforts seek to develop an in-depth mechanistic under-
standing of the regioselectivity-determining step, as well as to
explore the intermediacy and capture of alkylpalladium species for
the development of alkene difunctionalization reactions.
Data availability. Synthetic procedures, NMR spectra and
characterization for all the new compounds, kinetic plots,
deuterium labelling data and X-ray diffraction data are available
within this article and its Supplementary Information. X-ray
structural data for the bis(tetrabutylammonium) tetrachloropalladate
[Pd] have also been deposited with the Cambridge Crystallographic
Data Centre under CCDC no. 1548343 and are available from
CCDC in cif format. Data are also available from the corresponding
author on request.
28. Äkermark, B. et al. Palladium-promoted addition of amines to isolated double
bonds. J. Organomet. Chem. 72, 127–138 (1974).
Received 7 May 2017; accepted 30 October 2017;
published online 1 January 2018
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30. Keith, J. A. & Henry, P. M. The mechanism of the Wacker reaction: a tale of two
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32. Ogura, T., Kamimura, R., Shiga, A. & Hosokawa, T. Reversal of regioselectivity in
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The authors thank the University of Illinois and the National Institutes for Health
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Author contributions
D.G.K. and K.L.H. conceived and designed the experiments and wrote the manuscript.
D.G.K. and P.J.W. discovered the reaction. D.G.K., J.L.K. and S.N.G. performed
the experiments.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. Correspondence and
requests for materials should be addressed to K.L.H.
49. Reetz, M. T. & Westermann, E. Phosphane-free palladium-catalyzed coupling
reactions: the decisive role of Pd nanoparticles. Angew. Chem. Int. Ed. 39,
165–168 (2000).
Competing financial interests
The authors declare no competing financial interests.
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