Palladium-catalyzed aerobic oxidative hydroamination of vinylarenes using anilines: A wacker-type amination pathway

Article abstract of DOI:10.1021/acs.orglett.7b02532

A palladium-catalyzed intermolecular hydroamination of vinylarene derivatives using anilines has been developed for the first time under aerobic conditions, where the regioselective formation of N-arylketimines is accomplished. The current aerobic oxidative hydroamination pathway of anilines is distinct from that of palladiumcatalyzed hydroamination reactions that proceed to give sec-arylethylamine and arylethylamine derivatives, identifying a longstanding missing reaction pathway, Wacker-type amination, to N-arylketimines using anilines. The ready availability of both starting materials, vinylarenes and anilines, offers an attractive and facile synthetic route to N-arylketimines in good to excellent yields.

Full text of DOI:10.1021/acs.orglett.7b02532

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Aerobic Oxidative Hydroamination of
Vinylarenes Using Anilines: A Wacker-Type Amination Pathway
Eunsun Song, Hun Young Kim, and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic
of Korea
S
* Supporting Information
ABSTRACT: A palladium-catalyzed intermolecular hydroamination of
vinylarene derivatives using anilines has been developed for the first
time under aerobic conditions, where the regioselective formation of N-
arylketimines is accomplished. The current aerobic oxidative hydro-
amination pathway of anilines is distinct from that of palladium-
catalyzed hydroamination reactions that proceed to give sec-arylethyl-
amine and arylethylamine derivatives, identifying a longstanding
missing reaction pathway, Wacker-type amination, to N-arylketimines using anilines. The ready availability of both starting
materials, vinylarenes and anilines, offers an attractive and facile synthetic route to N-arylketimines in good to excellent yields.
presence of an acid cocatalyst (Scheme 1, path A).3 In contrast,
mine derivatives continue to be a major source of
Ainnovation in the chemical sciences as they serve as the base-catalyzed Markovnikov hydroaminations of anilines to
vinylarenes were observed by the groups of Hultzsch4 and
basic scaffolds for the preparation of fine chemicals,
pharmaceuticals, and natural products. One of the most direct
Doye,5 demonstrating the possibility of complementary
regiodivergent hydroamination of anilines (Scheme 1, path
B). Nevertheless, the catalytic hydroamination of styrenes with
anilines via oxidative addition remains an unsolved problem.
Previously, the laboratory of Brunet in 1993 first reported the
rhodium-catalyzed oxidative hydroamination of styrene using
lithium anilide to give a 2:1 mixture of phenylketimine and sec-
phenylethylamine.6 Complementary to Brunet’s work, the
group of Beller in 2000 postulated the intermediacy of an
anti-Markovnikov product from the rhodium-catalyzed oxida-
tive hydroamination of styrenes using anilines (Scheme 1, path
D),7 where the formation of quinolines was observed in 13−
48% yields. In 2003, the group of Stahl reported the palladium-
catalyzed aerobic oxidative hydroamination of vinylarenes using
amines with a relatively acidic N−H group in the presence of
base. However, Stahl’s oxidative hydroamination chemistry
failed to work for aniline (Scheme 1, path C).8 As a result, there
exists a significant knowledge gap in the oxidative hydro-
amination of alkenes using less “nucleophilic” anilines, the only
missing reaction pathway in the general realm of hydro-
amination of alkenes with anilines. Herein, we for the first time
report a regioselective, simple, and general method for the
synthesis of N-arylketimines from vinylarenes via a palladium-
catalyzed aerobic oxidative hydroamination using anilines. The
developed catalyst system represents a formal Wacker process,9
an oxidation of the alkenes, where the hydrolysis of the
ketimines leads to the Wacker oxidation products.
synthetic methods to amine derivatives is the intermolecular
addition of amines to unsaturated C−C multiple bonds, also
known as hydroamination.1 However, the development of
hydroamination catalysts that defy the repulsive forces between
π-electrons of C−C unsaturated bonds and lone-pair electrons
of the amine nitrogen has met with significant challenges in the
catalyst control over regioselectivity between Markovnikov and
anti-Markovnikov products.2 In general, the hydroamination of
alkenes is more problematic than alkynes because of their lower
reactivity and electron density. Thus, the intermolecular
addition reactions between aniline and unactivated alkenes
such as styrene are the hallmark of catalyst-controlled divergent
hydroamination strategies (Scheme 1).
The pioneering work of Hartwig disclosed the palladium-
catalyzed hydroamination of vinylarenes with anilines where the
anti-Markovnikov products were exclusively obtained in the
Scheme 1. Divergent Hydroamination Pathways of
Vinylarenes Using Anilines
Our initial studies began by attempting the intermolecular
reaction between styrene 1a and aniline 2a under different
Received: August 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
palladium salts, solvents, and reaction temperatures, where we
observed the formation of phenylketimine 3a and acetophe-
none 4a, a hydrolyzed form of 3a, as the only identifiable
products in <5% yields at 100 °C.10 With no apparent solvent
effect in the oxidative hydroamination reaction, we opted for a
neat reaction under aerobic conditions to re-evaluate the
palladium salts (Table 1). Among palladium salts we screened
60−78% (entries 12−14). Thus, the aerobic oxidative hydro-
amination of aniline 2a using 20 equiv of styrene 1a in the
presence of 5 mol % of Pd(OAc)2, 100 mol % of pyridine, and
20 mg/mmol of 3 Å MS at 90−100 °C was adopted as the
optimal conditions (entries 13 and 15).13 Further control
experiments of the reaction confirmed the optimal amount of
Pd(OAc)2 (entry 16), the importance of 3 Å MS, not 4 Å MS,
(entry 16),14 the dual action between Pd(OAc)2 and
dioxygen,15 and the absence of Wacker oxidation product, 4a,
in the absence of aniline 2a (entry 17).
With the optimized reaction conditions in hand, the scope of
the Pd-catalyzed aerobic oxidative hydroamination was
investigated using various vinylarenes and anilines (Scheme
2). The examination of vinylarenes with different electronic
Table 1. Selected Optimization Conditions of Pd(II)-
Catalyzed Aerobic Oxidative Hydroamination of Styrene
a
Using Aniline
Scheme 2. Scope of Pd(II)-Catalyzed Aerobic Oxidative
Hydroamination*
b
additive
(mol %)
yield of 3a/4a
entry
Pd (mol %)
PdCl2 (10)
base
(%)
1
2
3
4
5
6
7
0/0
0/0
Pd(dppf)Cl2 (10)
Pd(PPh3)2Cl2 (10)
Pd2(dba)3 (10)
Pd(TFA)2 (10)
Pd(OAc)2 (10)
2/0
13/2
0/0
32/6
13/7
Pd(OAc)2(PPh3)2
(10)
8
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
pyr (30)
pyr (60)
40/7
9
28/22
30/27
10
pyr
(100)
11
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
3 Å MS
3 Å MS
3 Å MS
3 Å MS
3 Å MS
3 Å MS
3 Å MS
pyr
47/4
58/2
67/1
72/6
67/3
47/3
0/0
(100)
12c
13d
pyr
(100)
pyr
(100)
14e
pyr
(100)
15d f Pd(OAc)2 (5)
pyr
(100)
,
16d
17g
Pd(OAc)2 (3)
Pd(OAc)2 (5)
pyr
(100)
pyr
(100)
*
a
Yields of 3/4 are shown. Use of 5 equiv of 2-vinylnaphthalene.
a
Reaction conditions: 1a (6.0 mmol), 2a (0.6 mmol), Pd catalyst (mol
%), base (mol %), powdered molecular sieves (20 mg/mmol), neat
b
1
properties indicated no significant influence of the electronic
nature of vinylarenes, although the presence of an electron-
donating methoxy group facilitated the hydrolysis of phenyl-
ketimines 3c to acetophenone derivative 4c. The use of 2-
vinylnaphthalene 1f under our optimized conditions only led to
the formation of 3f in 20% yield. However, the reduced amount
of 1f from 20 equiv to 5 equiv provided ketimine 3f in an
improved yield of 54%. Next, we examined various aniline
derivatives with different electronic and steric properties. While
the presence of aryl chloride did not affect the current Pd-
catalyzed reaction (3b), aryl bromide was not tolerated in the
oxidative hydroamination conditions, providing a complex
mixture with only 18% yield of 4-bromophenylketimine 3g.
Anilines with different electronic properties also provided the
desired phenylketimines (3h−j) in good yields. The steric
effect of anilines was minimal (3k,l), but the use of 2,6-
dimethylaniline gave the corresponding ketimine 3m in about
30% yield. Among the tested aniline derivatives, the use of 2-
methylaniline proved to be suitable for further substrate
under O2 balloon at 100 °C. Yield was determined by H NMR
relative to internal standard, 1,3,5-trimethoxybenzene. Reaction for 48
c
d
e
h. Reaction using 20 equiv of 1a. Reaction using 40 equiv of 1a.
f
g
Reaction at 90 °C. Reaction without 2a.
(entries 1−7), the use of Pd(OAc)2 led to the formation of 3a/
4a in a combined yield of 38% (entry 6). Speculating an
inadvertent acid formation during the reaction that resulted in
the formation of a hydrolyzed product 4a from 3a, we
examined the role of base.11 The addition of pyridine to the
reaction mixture provided slightly improved yields of 3a/4a to
47− 57% yields (entries 8−10); however, the formation of the
hydrolyzed product 4a could not be prevented with the use of
pyridine. Next, we employed 3 Å molecular sieves to sequester
water, a byproduct of dioxygen reduction.12 Gratifyingly, the
formation of 4a was significantly reduced to less than 5% while
the reaction yields were maintained at 51% (entry 11). Further
optimization studies using the increased amount of styrene 1a
and the reduced amount of Pd(OAc)2 led to yields of 3a/4a to
B
DOI: 10.1021/acs.orglett.7b02532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
screening. Indeed, 2-methylaniline smoothly underwent the
intermolecular aerobic oxidative hydroamination with various
vinylarenes to give the desired phenylketimine derivatives in
excellent yields.
While the detailed reaction mechanism for the Wacker-type
amination is yet to be studied,16 it is reasonable to speculate the
involvement of the Markovnikov addition of aniline to Pd(II)−
styrene complexes followed by a sequential dioxygen-mediated
regeneration of active Pd(II) catalysts (Scheme 3). As such, the
palladium catalyst with the first order reaction from the initial
rate experiments (see the Supporting Information). However,
the reaction after about 70% conversion appeared to be almost
zero order with respect to Pd(OAc)2. This scenario might be
interpreted for the presence of alternative reaction pathways:
(1) the possibility of hydroamination activity of the palladium
hydride, E, to give sec-phenylethylamines3 or (2) the reduction
activity of E to reduce styrene to ethylbenzene derivatives.7b
A
close inspection of the reaction mixtures did not yield any sec-
phenylethylamine product, and only on one occasion with the
use of 4-fluorostyrene did we observe the formation of a
reduced form, 1-ethyl-4-fluorobenzene, in <5%. Alternatively,
the zero-order reaction rate at the later stage could be
considered as the ineffective catalyst regeneration, Pd(II) from
Pd(0) (Scheme 3, F to A). The formation of Pd(0) black was
visible after the reaction, and the presence of ketimine products
could competitively compete with aniline to coordinate to the
metal center. Thus, the kinetic data as well as the experimental
findings support the depletion of active Pd(II) catalyst for the
observed kinetic profile. Furthermore, the kinetic isotope effect
of 1.6 (kH/kD) using aniline-d7 suggests the active involvement
of aniline in the catalyst-turnover processes.23 Previously, in the
hydroamination of vinylarenes using anilines, Hartwig proposed
the migratory insertion of vinylarene into a palladium hydride
to give catalytic intermediates that reacted in the presence of
excess aniline.24 In his studies, the presence of both
phenylketimine byproduct and palladium hydride intermediate
was observed in an almost identical ratio to the palladium
catalyst used. The reason why palladium hydride intermediate
E did not initiate a typical hydroamination pathway of
vinylarenes is not clear at this time. However, the high
concentration of ligands such as styrene, pyridine, and
phenylketimine should improve the short lifetime of the
palladium hydride intermediate E, limiting the reaction with
aniline to give sec-phenylethylamines.25
Scheme 3. Plausible Catalytic Cycle for the Pd-Catalyzed
Aerobic Oxidative Hydroamination Using Anilines
In summary, we have identified a novel aerobic oxidative
hydroamination pathway of vinylarenes using anilines to mimic
the Wacker-type amination process. The current oxidative
hydroamination pathway is substantially different from the
status quo of the hydroamination pathways of alkenes, where
the formations of phenylethylamines and sec-phenylethylamines
are achieved under metal and base catalysis. Defying the known
hydroamination pathways of anilines is perhaps due to the
higher concentration of vinylarenes that increased the Pd−
styrene complexation in combination with a coordinatively
non-innocent pyridine additive and 3 Å MS. Using structurally
unaltered anilines, the palladium-catalyzed aerobic oxidative
hydroamination of vinylarenes has been achieved for the first
time. While more detailed mechanistic studies are needed, the
current palladium catalyst system might be modulated for the
complementary Wacker-type amination to anti-Markovnikov
enamine products.26 Additional studies to understand the
mechanistic details and to extend the substrate scope to other
amines are currently underway, and our results will be reported
in due course.
Pd−styrene complex A undergoes a ligand exchange with
aniline to give the complex B. A subsequent action of pyridine
helps the removal of acetic acid to give the Pd−anilide complex
C.17 A migratory insertion, controlled by a sterically congested
palladium complex, occurs to give Pd−alkyl complexes D/D′
that undergo a hydride elimination to give the enamine and the
palladium hydride E. The enamine product isomerizes to
ketimine,18 and the palladium hydride species E oxidatively
regenerates the active catalyst A.19 The proposed catalytic cycle
is supported by our key experimental observations: (1) the high
concentration of styrene positively influences the reaction
conversion; thus, the high ratio between styrene and Pd catalyst
is preferred;20 (2) the control experiment without aniline did
not provide the Wacker oxidation product, acetophenone 4a,
illustrating the involvement of aniline in the catalytic cycle; (3)
the presence of pyridine improves the catalytic activity, thus
pyridine may serve as both ligand and base;21 and (4) the 3 Å
MS primarily absorbs water to prevent the phenylketimine 3a
from hydrolyzing to acetophenone; thus, the 3 Å MS does not
significantly influence the reaction rate.22
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02532.
To investigate our mechanistic proposal in Scheme 3, we
have performed the kinetic studies, where we found the
C
DOI: 10.1021/acs.orglett.7b02532
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures and characterization data for all
Letter
(12) The optimal amount of 3 Å molecular sieves appears to be about
20 mg for 1 mmol of styrene where the phenylketimine product 2a
was obtained in 70% yield (8 mg/mmol; 52% and 32 mg/mmol;
68%).
new compounds (PDF)
AUTHOR INFORMATION
(13) The optimized reaction conditions are run in neat without
solvent; however, the presence of toluene or o-xylene in the same
amount as styrene (i.e., 20 equiv) did not influence the reaction
outcome (neat, 70%; in toluene, 68%; in o-xylene, 62%).
(14) Upon use of 4 Å MS, the phenylketimine product 2a was
obtained in 18% yield. While the precise reason for the low catalytic
activity in the presence of 4 Å MS is not clear, the sequestration of
palladium catalysts is possible through the absorption of palladium
species to the surface of 4 Å MS. For the formation of 4 Å MS-
supported Pd(II) catalysts, see: Dey, R.; Sreedhar, B.; Ranu, B. C.
Tetrahedron 2010, 66, 2301−2305.
(15) The use of alternative oxidants such as oxone, p-benzoquinone,
and PhI(OAc)2 was not successful under argon atmosphere.
(16) An aqueous workup of the reaction provided the desired
acetophenone products without loss of yields, thus providing the
formal Wacker oxidation products.
■
Corresponding Author
*E-mail: kyungsoooh@cau.ac.kr.
ORCID
Kyungsoo Oh: 0000-0002-4566-6573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grants funded by the Korean
government (MSIP) (NRF-2015R1A5A1008958 and NRF-
2015R1C1A2A01053504).
(17) The possibility of H-bonding between Pd-bound aniline and
acetate as a driving force to form the complex C from B was
eliminated from our kinetic isotope effect experiments, where we
found no isotope effect at the beginning of the reaction.
(18) Phenylketimine should be the thermodynamic product based on
the ketimine−enamine tautomerization as found in the keto−enol
tautomerization.
(19) Popp, B. V.; Stahl, S. S. Chem. - Eur. J. 2009, 15, 2915−2922.
(20) The ratio between vinylarene and Pd(OAc)2 under our
optimized conditions is 400:1, except for 2-vinylnaphthalene (100:1).
(21) The presence of pyridine additive helps the stability of
palladium catalyst, making them less susceptible to decomposition to
palladium(0) black. For the effect of pyridine in the intramolecular
aerobic oxidative amination, see: Ye, X.; Liu, G.; Popp, B. V.; Stahl, S.
S. J. Org. Chem. 2011, 76, 1031−1044.
(22) We did not observe the rate acceleration and the increase in the
catalyst stability in the presence of 3 Å MS. The use of 3 Å MS without
pyridine additive led to 27% yield of phenylketimine 2a. For the
beneficial effect of 3 Å MS in terms of catalyst stability and rate
enhancement, see: Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org.
Chem. 2006, 71, 1861−1868.
(23) The KIE of 1.6 might be relevant to the different kinetic orders
in substrates. For a discussion on either first or saturation dependence
on [substrate] in the aerobic oxidative amination of styrene, see:
Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46,
1910−1923.
(24) Nettekoven, U.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
1166−1167.
(25) The insertion of dioxygen into a palladium(II) hydride followed
by reductive water removal cannot be ruled out. For the first
crystallographic evidence for such a process, see: Denney, M. C.;
Smythe, N. A.; Cetto, K. L.; Kemp, R. A.; Goldberg, K. I. J. Am. Chem.
Soc. 2006, 128, 2508−2509.
(26) Because aliphatic alkenes are inert under our optimized
conditions, the steric requirement of Pd−anilide complex C to Pd−
alkyl complexes D/D′ using bulky alkene ligands is currently assessed
in order to induce the anti-Markovnikov reaction pathway.
REFERENCES
■
(1) For general reviews, see: (a) Taube, R. In Applied Homogeneous
Catalysis, 1st ed.; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH:
Weinheim, 1996; Vol. 1, pp 507−526. (b) Muller, T. E.; Beller, M. In
̈
Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998; Vol. 2, pp 316−330. (c) Brunet, J. J.;
Neibecker, D. In Catalytic Heterofunctionalization from Hydroamination
to Hydrozirconation; Togni, A., Grutzmacher, H., Eds.; Wiley-VCH:
Weinheim, 2001; pp 91−141.
(2) For reviews, see: (a) Muller, T. E.; Beller, M. Chem. Rev. 1998,
̈
̈
98, 675−704. (b) Nobis, M.; Drießen-Holscher, B. Angew. Chem., Int.
̈
Ed. 2001, 40, 3983−3985. (c) Seayad, J.; Tillack, A.; Hartung, C. G.;
Beller, M. Adv. Synth. Catal. 2002, 344, 795−813. (d) Roesky, P. W.;
Muller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708−2710. (e) Hong,
̈
S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673−686. (f) Hultzsch, K. C.
Adv. Synth. Catal. 2005, 347, 367−391. (g) Muller, T. E.; Hultzsch, K.
̈
C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795−3892.
(h) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem.
Rev. 2015, 115, 2596−2697. (i) Margrey, K. A.; Nicewicz, D. Acc.
Chem. Res. 2016, 49, 1997−2006. (j) Patel, M.; Saunthwal, R. K.;
Verma, A. K. Acc. Chem. Res. 2017, 50, 240−254.
(3) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546−
9547.
(4) Horrillo-Martínez, P.; Hultzsch, K. C.; Gil, A.; Branchadell, V.
Eur. J. Org. Chem. 2007, 2007, 3311−3325.
(5) Jaspers, D.; Doye, S. Synlett 2011, 1444−1448.
(6) Brunet, J.-J.; Neibecker, D.; Philippot, K. Tetrahedron Lett. 1993,
34, 3877−3880.
(7) (a) Beller, M.; Thiel, O. R.; Trauthwein, H.; Hartung, C. G.
Chem. - Eur. J. 2000, 6, 2513−2522 For the Rh(I)-catalyzed anti-
Markovnikov products using secondary amines, see:. (b) Beller, M.;
Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed. Engl. 1997, 36,
2225−2227.
(8) (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc.
2003, 125, 12996−12997. (b) Timokhin, V. I.; Stahl, S. S. J. Am. Chem.
Soc. 2005, 127, 17888−17893 For a review of the Pd-catalyzed
oxidation reactions, see:. (c) Stahl, S. S. Angew. Chem., Int. Ed. 2004,
43, 3400−3420.
(9) For a review, see: Keith, J. A.; Henry, P. M. Angew. Chem., Int. Ed.
2009, 48, 9038−9049.
(10) For the initial evaluations of key experimental parameters, see
the Supporting Information.
(11) The use of other pyridine derivatives provided the formation of
phenylketimine product 2a in about 30% yields; however the
employment of stronger bases such as Et3N, K2CO3, and KOH
significantly reduced the observed yields to about 5%. For example, the
employment of lithium anilide resulted in 8% yield of phenylketimine
2a.
D
DOI: 10.1021/acs.orglett.7b02532
Org. Lett. XXXX, XXX, XXX−XXX