Intermolecular oxidative animation of olefins with amines catalyzed by the Pd(II)/NPMoV/O2 System

Article abstract of DOI:10.1021/ol902052z

A novel and efficient lntermolecular aerobic oxidative amination of electron-deficient olefins with secondary aromatic amines has been successfully achieved by a Pd(ll)/NPMoV/HQ-catalyzed reaction under dioxygen.

Full text of DOI:10.1021/ol902052z

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5058-5061
Intermolecular Oxidative Amination of
Olefins with Amines Catalyzed by the
Pd(II)/NPMoV/O2 System
Yasushi Obora,* Yosuke Shimizu, and Yasutaka Ishii*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials
and Bioengineering, High Technology Research Center, and ORDIST, Kansai
UniVersity, Suita, Osaka 564-8680, Japan
obora@kansai-u.ac.jp; ishii@ipcku.kansai-u.ac.jp
Received September 4, 2009
ABSTRACT
A novel and efficient intermolecular aerobic oxidative amination of electron-deficient olefins with secondary aromatic amines has been successfully
achieved by a Pd(II)/NPMoV/HQ-catalyzed reaction under dioxygen.
Transition metal-catalyzed amination is an important meth-
odology for synthesizing various nitrogen-containing com-
pounds.1 In particular, Pd(II)-catalyzed oxidative amination
of olefins by using dioxygen, which is referred to as the aza-
Wacker reaction, has been the topic of intensive
investigation.1f,2 Currently, the Pd(II)-catalyzed aza-Wacker-
type reactions have been utilized to process nitrogen-
containing heterocycles like pyrroles and quinolines.3 Al-
though recent significant developments on the aza-Wacker
process have been performed by Stahl and other groups, the
existing process generally calls for nonbasic nitrogen nu-
cleophiles such as carboxamides, carbamates, and sulfonea-
mides.4 In contrast, the oxidative amination of olefins with
simple amines as substrate is relatively less explored5 and
generally limited to the intramolecular reaction,6 owing to
deactivation of the Pd catalyst by strong coordination of
(4) For example: (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am.
Chem. Soc. 2003, 125, 12996. (b) Brice, J. L.; Harang, J. E.; Timokhin,
V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868. (c)
Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888. (d)
Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251. (e) Lee, J. M.;
Ahn, D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.; Chang, S. J. Am.
Chem. Soc. 2006, 128, 12954. (f) Liu, G.; Stahl, S. S. J. Am. Chem. Soc.
2006, 128, 7179. (g) Rogers, M. M.; Kotov, V.; Chatwichien, J.; Stahl,
S. S. Org. Lett. 2007, 9, 4331. (h) Mun˜iz, K.; Ho¨velmann, C. H.; Streuff,
J. J. Am. Chem. Soc. 2008, 130, 763. (i) Hosokawa, T.; Takano, M.; Kuroki,
Y.; Murahashi, S.-i. Tetrahedron Lett. 1992, 33, 6643. (j) Ragaini, F.; Longo,
T.; Cenini, S. J. Mol. Catal. A 1996, 110, L171. (k) Bar, G. L. J.; Lloyd-
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2005, 127, 7308,
and references cited therein.
(5) (a) Bozell, J. J.; Hegedus, L. S. J. Org. Chem. 1981, 46, 2561. (b)
Hegedus, L. S.; Akermark, B.; Zetterberg, K.; Olsson, L. F. J. Am. Chem.
Soc. 1984, 106, 7122. (c) Beller, M.; Eichberger, M.; Trauthwein, H. Angew.
Chem., Int. Ed. 1997, 36, 2225. (d) Tillack, A.; Trauthwein, H.; Hartung,
C. G.; Eichberger, M.; Pitter, S.; Jansen, A.; Beller, M. Monatsh. Chem.
2000, 131, 1327. (e) Wang, J.-R.; Yang, C.-T.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2007, 48, 5449, and references cited therein.
(1) For reviews, see: (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98,
675. (b) Brunet, J. J.; Neibecker, D. In Catalytic Heterofunctionalization;
Togni, A., Gru¨tzmacher, H., Eds.; Wiley-VCH: New York, 2001; pp
91-141. (c) Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C. G.; Seayad,
J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002, 1579. (d) Hong,
S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. (e) Hartwig, J. F. Pure
Appl. Chem. 2004, 76, 507. (f) Kotov, V.; Scarborough, C. C.; Stahl, S. S.
Inorg. Chem. 2007, 46, 1910, and references cited therein.
(6) For intramolecular oxidative anmination reactions with simple
amines, see: (a) van Benthem, R. A. T. M.; Hiemstra, H.; Longarela, G. R.;
Speckamp, W. N. Tetrahedron Lett. 1994, 35, 9281. (b) Ro¨nn, M.; Ba¨ckvall,
J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749. (c) Larock, R. C.;
Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61,
3584. (d) Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002,
41, 164. (e) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2003, 42, 2892.
(2) For reviews, see: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. ReV. 2007, 107, 5318. (b) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400
.
(3) For example: (a) Zhang, Z.; Zhang, J.; Tan, J.; Wang, Z. J. Org.
Chem. 2008, 73, 5180. (b) Zhang, Z.; Tna, J.; Wang, Z. Org. Lett. 2008,
10, 173. (c) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
10.1021/ol902052z CCC: $40.75
Published on Web 10/02/2009
 2009 American Chemical Society

amines. Therefore, the investigation of the novel efficient
catalytic system for the intermolecular aza-Wacker reaction
with amines as a substrate is highly desirable.
Table 1. Oxidative Amination of Diphenylamine (1a) with
Ethyl Acrylate (2a) Catalyzed by the Pd(II)/NPMoV/HQ
Systema
On the other hand, we found that molybdovanadophos-
phoric acid (HPMoV) served as a good reoxidant of Pd(0)
to Pd(II).7,8 Thus, the Pd(II)/HPMoV/O2 system showed an
efficient catalyst for an oxidative coupling reaction of
benzenes with olefins (direct Mizoroki-Heck-type reaction)
and a reaction of acrylate and vinyl carboxylates, through
direct aromatic or alkenyl C-H bond activations.7 The same
catalyst system was also effective for carboxylation of arenes
with CO and O2.8
yield/%b
Alternatively, molybdovanadophosphate (NPMoV), which
is partly replaced with an ammonium cation of the acidic
complex, HPMoV, has also been utilized as an efficient
reoxidation system for the Pd(II)-catalyzed oxidation of
alkenes.9 We reported that the Pd(II)/NPMoV/O2 or Pd(II)/
NPMoV/HQ/O2 (HQ:hydroquinone) system showed the
effective catalytic activity for reactions of acetoxylation and
acetalization of olefins under mild conditions.9 The Pd(II)/
NPMoV/O2 catalyst system could be extended to the Waker-
type oxidation and a carbomethoxylation of olefins.10,11
entry
Pd-catalyst
solvent
3a
4a
<1
1
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
Pd(OAc)2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DME
PhCN
MeCN
t-BuOH
90 (84)
18
86
35
14
24
10
7
14
56
62
66
34
59
54
2c
3e
4f
n.d.d
<1
<1
<1
<1
n.d.d
<1
<1
<1
<1
8
5g
6h
7i
8
9
Pd(acac)2
PdCl2
10
11
12
13
14
15
In this letter, our attention has been focused on the aza-
Wacker-type reaction of amines with olefins and we found
that the Pd(II)/NPMoV/HQ/O2 system realized an efficient
catalytic activity to the intermolecular aza-Wacker reaction
of secondary amines with electron-deficient olefins to give
oxidative amination products in good yields (eq 1). In
addition, we would like to show an unusual formation of
1-amino-2,4-dicarboxylate-substituted 1,3-dienes by using the
present catalyst system.
Pd(OCOCF3)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
28
26
8
a Conditions: 1a (2 mmol) was allowed to react with 2a (6 mmol)
in the presence of Pd-catalyst (5 mol %) combined with (NH4)5-
H4PMo6V6O40·23H2O (NPMoV) (1 mol %) and hydroquinone (20 mol %)
in DMF (2 mL) under O2 (1 atm) at 60 °C for 6 h. b GC yields based on
1a used. The number in parentheses shows the isolated yield. c The reaction
was performed with 1a (2 mmol) and 2a (2 mmol). d Not detected by GC.
e Reaction was performed at 80 °C. f Reaction was performed in the absence
of NPMoV. g Reaction was performed in the absence of hydroquinone.
h Reaction was performed under air (1 atm). i Reaction was performed under
Ar (1 atm).
ethyl-3-(diphenylamino)propenoate (3a) was produced in
90% yield (Table 1, entry 1).12
We first chose the reaction of diphenylamine (1a) with
ethyl acrylate (2a) as a model reaction and the results under
various reaction conditions are summarized in Table 1. When
1a (2 mmol) was allowed to react with 2a (6 mmol) in
the presence of PdCl2(PhCN)2 (0.1 mmol, 5 mol %),
(NH4)5H4PMo6V6O40·23H2O (NPMoV) (0.02 mmol, 1 mol
%), and hydroquinone (HQ) (0.4 mmol, 20 mol %) in DMF
(2 mL) under atmospheric oxygen (1 atm) at 60 °C for 6 h
This reaction was successfully performed by using 3 equiv
of 2a to 1a, while the yield of 3a was decreased to 18%
when an equimolar reaction was carried out (entry 2). The
optimized reaction temperature was 60 °C, but the reaction
at an elevated temperature (80 °C) under these reaction
conditions gave almost the similar result (entry 3). Removal
of either NPMoV or hydroquinone from the catalytic system
resulted in sluggish reactions (entries 4 and 5). Needless to
say, no reaction occurred in the absence of Pd(II) catalyst.
The reaction under air or argon resulted in low yields of 3a,
owing to difficulty of regenerating Pd(II) from the reduced
(7) (a) Yokota, T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc.
2003, 125, 1476. (b) Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004,
69, 1221. (c) Yamada, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70,
5471. (d) Yamada, T.; Sakakura, A.; Sakaguchi, S.; Obora, Y.; Ishii, Y.
New J. Chem. 2008, 32, 738
.
(12) Typical experimental procedure for the oxidative amination
(entry 1, Table 1): A mixture of 1a (338 mg, 2 mmol) and 2a (600 mg, 6
mmol) was allowed to react in the presence of PdCl2(PhCN)2 (38 mg, 0.1
mmol, 5 mol %), (NH4)5H4PMo6V6O40·23H2O (NPMoV) (35 mg, 0.02
mmol, 1 mol %), and hydroquinone (HQ) (44 mg, 0.4 mmol, 20 mol %) in
DMF (2 mL) under atmospheric oxygen (1 atm) at 60 °C for 6 h in a 30
mL round-bottomed flask. The conversions and yields of products were
estimated from peak areas based on an internal standard using GC and the
product 3a was obtained in 90% yield along with a trace amount of 4a.
The product 3a was isolated by column chromatography (230-400 mesh
silica gel, n-hexane/ethyl acetate ) 9/1) in 84% yield (224 mg).
(8) (a) Ohashi, S.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2005, 486.
(b) Yamada, S.; Sakaguchi, S.; Ishii, Y. J. Mol. Catal. A: Chem. 2007,
262, 48. (c) Yamada, S.; Ohashi, S.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J.
Mol. Catal. A: Chem. 2008, 282, 22
.
(9) (a) Yokota, T.; Sakaguchi, S.; Ishii, Y. J. Jpn. Pet. Inst. 2003, 46,
15. (b) Yokota, T.; Fujibayashi, S.; Nishiyama, Y.; Sakaguchi, S.; Ishii, Y.
J. Mol. Catal. A: Chem. 1996, 114, 113.
(10) Yokota, T.; Sakakura, A.; Tani, M.; Sakaguchi, S.; Ishii, Y.
Teterahedron Lett. 2002, 43, 8887
(11) Yokota, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2002, 67, 5005
.
.
Org. Lett., Vol. 11, No. 21, 2009
5059

Table 2. Oxidative Amination of Amines (2) and Electron-Deficient Olefins (2) Catalyzed by the Pd(II)/NPMoV/HQ Systema,d
a Conditions: 1 (2 mmol) was allowed to react with 2 (6 mmol) in the presence of PdCl2(PhCN)2 (5 mol %) combined with NPMoV (1 mol %) and
hydroquinone (20 mol %) in DMF (2 mL) at 60 °C for 6 h. b Isolated yields based on 1 used. c GC analysis of the reaction mixture showed a negligible
amount of 4 (<1%) was obtained under these reaction conditions. d Reaction time was 24 h.
Pd(0) during the reaction (entries 6 and 7). Pd(OAc)2 and
Pd(acac)2, which showed high catalytic activity in previously
reported Pd(II)/HPMoV/O27,8 or Pd(II)/NPMoV/O29-11 cata-
lytic system, only showed lower catalytic activity for the
present oxidative amination reaction (entries 8 and 9).
However, the use of PdCl2 and Pd(OCOCF3)2 under these
reaction conditions gave a moderate yield of 3a (entries 10
and 11). Among the solvents examined, DMF was found to
be the best solvent and 3a was obtained in high selectivity
and yield, while the reactions in DME, PhCN, MeCN, and
t-BuOH under these reaction conditions afforded 3a in fair
to moderate yields (34-66%) along with 1-amino-2,4-
dicarboxylate-substituted 1,3-dienes, (2E,4E)-diethyl-4-
((diphenylamino)methylene)pent-2-enedioate (4a), in 8-28%
yields (entries 12-15). In this reaction, the choice of the
solvent and the ratio of 1a to 2a affected markedly the
selectivity of 3a and 4a. Thus, we tried the optimization of
the reaction conditions for the formation of 4a and found
that the use of an excess (5 equiv) of 1a toward 2a in PhCN
resulted in 4a in maximum yield (57%) with 83% selectivity
(eq 2). The best choice of solvent to obtain the highest yield
of 4a was PhCN.
olefins, such as methyl acrylate (2b), methyl vinyl ketone
(2c), acrylonitrile (2d), and styrene (2e), was found to
progress smoothly to give the corresponding products
(3b-e) in good yields (entries 1-4). In addition the
reaction was tolerated with secondary aromatic amines
such as 3-methyldiphenylamine (1b), 3-methoxydipheny-
lamine (1c), 3-chlorodiphenylamine (1d), and n-butylphe-
nylamine (1e) to afford the corresponding aza-Wacker
product (3f-i), exclusively, in good yields (entries 5-8).
As for the amine substrates in the present reaction,
secondary amines having a phenyl group can also be
utilized as a substrate. Unfortunately, the reaction with
aromatic primary amines like aniline was sluggish to
afford low yield (<10%) of the oxidative amination
product along with a mixture of several unidentified
compounds.
It was considered that compound 4a would be formed from
a successive reaction of the resulting 3a with 2a. Hence, the
reaction of 3a with 2a under similar reaction conditions was
carried out (eq 3). As expected, 4a was obtained in 43%
yield.
Under the optimized reaction conditions, the reaction of
various olefins with amines was examined (Table 2). As a
result, the reaction with 1a with various electron-deficient
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Org. Lett., Vol. 11, No. 21, 2009

Furthermore, the reaction of 2a with primary aliphatic
amines such as hexylamine and secondary aliphatic amines
like dibutylamine resulted in only conjugated addition
(Michael addition) products13 in place of the formation of
the desired oxidative amination products.
(HQ), which then dehydrogenated to BQ with dioxygen by
NPMoV, as we previously reported.9
Considering the formation of 4a under these reaction
conditions, it is assumed that the formation of a zwitterionic
structure D as a resonance form of 3a would serve as a
carbon nucleophile. Subsequently, the aminopalladation
proceeds through nucleophilic attack of D to the Pd(II)-olefin
complex A leading to the intermediate E, followed by
ꢀ-hydride elimination leading to 4a as a product with the
formation of Pd(0) (Scheme 3).
Although a detailed reaction mechanism remains to be
further elucidated, a plausible path is shown in Scheme 1.
Scheme 1. A Plausible Pathway of the Aza-Wacker Process
Scheme 3
.
A Plausible Reaction Pathway for the Formation of
4a from 3a
The reaction is thought to be initiated by the coordination
of the olefin (2) to Pd(II), forming a Pd(II)-olefin complex
(A). Then, A is subjected to intermolecular nucleophilic
attack of amine (1), leading to aminopalladation adducts B.
The intermediate B is likely to undergo ꢀ-hydride elimination
leading to 3 and LnPdH(II) intermediate (C), which subse-
quently resulted in Pd(0).
In conclusion, we found an efficient catalyst system for
an intermolecular aza-Wacker reaction of olefins and second-
ary aromatic amines by employing a Pd(II)/NPMoV/HQ/O2
system that affords oxidative amination products in good
yields. In addition, by tuning the reaction solvent and the
substrate ratio, we could obtain 1-amino-2,4-dicarboxylate-
substituted 1,3-dienes as a major adduct.
The reoxidation step of Pd(0) to Pd(II) is outlined in
Scheme 2. Here, benzoquinone (BQ) serves as a good
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, “High-
Tech Research Center” Project for Private Universities:
matching fund subsidy from the Ministry of Education,
Culture, Sports, Science and Technology, 2005-2009, and
Shionogi Award (Y.O.) in Synthetic Organic Chemistry,
2007 Japan.
Scheme 2. A Mechanism of Regeneration of Pd(II) from Pd(0)
under the Influence of NPMoV, Hydroquinone (HQ), and O2
oxidizing agent of the reduced palladium(0) in the reaction
cycle to disproportionate to palladium(II) and hydroquinone
Supporting Information Available: Experimental pro-
cedures and characterization data for the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For examples of the conjugate addition of amines with electron-
deficient olefins, see: (a) Khan, A. T.; Parvin, T.; Gazi, S.; Choudhury,
L. H. Tetrahedron Lett. 2007, 48, 3805. (b) Xu, L. W.; Li, L.; Xia, C.-G.
HelV. Chim. Acta 2004, 87, 1522, and references cited therein.
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