Maleimide-assisted anti-Markovnikov Wacker-type oxidation of vinylarenes using molecular oxygen as a terminal oxidant

Article abstract of DOI:10.1039/c5cc06746d

Arylacetaldehydes were successfully synthesized by the anti-Markovnikov Wacker-type oxidation of vinylarenes using 1 atm O₂ as a terminal oxidant under mild conditions. Electron-deficient alkenes, such as maleic anhydride and maleimides, were effective additives and would operate as ligands to stabilize the Pd(0) species during the reaction.

Full text of DOI:10.1039/c5cc06746d

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DOI: 10.1039/C5CC06746D
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Maleimides-assisted Anti-Markovnikov Wacker-type Oxidation of
Vinylarenes Using Molecular Oxygen as a Terminal Oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Sonoe Nakaoka, Yuka Murakami, Yasutaka Kataoka, and Yasuyuki Ura*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Arylacetaldehydes were successfully synthesized by the anti- (>8 atm).12
Markovnikov Wacker-type oxidation of vinylarenes using 1 atm O2
On the other hand, ruthenium13 and iron14 can also
as a terminal oxidant under mild conditions. Electron-deficient catalyze the oxidation of vinylarenes to arylacetaldehydes. In
alkenes, such as maleic anhydride and maleimides, were effective this case, epoxides are proposed as intermediates (a tandem
additives and would operate as ligands to stabilize the Pd(0) epoxidation-isomerization pathway), and thus the reaction
species during the reaction.
mechanism is different from that of the Wacker-type oxidation
(Scheme 1). These ruthenium and iron-catalyzed oxidations
proceed efficiently at room temperature; however, elaborate
catalysts such as metal porphyrins,13, 14b and/or stoichiometric
amounts of the oxidants, 2,6-dichloropyridine N-oxide13b and
iodosylbenzene,14 are required. Therefore, the development of
a simple and efficient catalytic system for the oxidation of
vinylarenes, using molecular oxygen, remains challenging.
Arylacetaldehydes are frequently used as synthetic building
blocks for natural products, such as alkaloids1 and bisabolane
sesquiterpenes,2 and biologically active compounds.3
Oxidation of vinylarenes using molecular oxygen is a simple
and
atom-efficient
method
to
synthesize
the
arylacetaldehydes. Palladium-catalyzed Wacker-type oxidation
is a candidate for achieving such a transformation. However,
the Wacker-type oxidation of terminal alkenes generally
follows Markovnikov’s rule to afford methyl ketones, while
alkenes with a directing group favor aldehyde formation.4
Recently, the anti-Markovnikov Wacker-type oxidation of
unactivated, aliphatic terminal alkenes using a nitrite co-
catalyst was also reported.5 In the case of vinylarenes,
although Markovnikov products, i.e. acetophenone derivatives,
are generally obtained, anti-Markovnikov oxidations proceed
to afford arylacetaldehydes in some cases.4a, 6 In the latter
reactions, a stoichiometric amount of heteropolyacid7 or p-
benzoquinone8 is required as an oxidant (Scheme 1). One-pot
formal anti-Markovnikov hydration9 and hydroamination10 of
vinylarenes were also accomplished by combining the anti-
Markovnikov oxidation with either transfer hydrogenation or
condensation with an amine and subsequent transfer
hydrogenation, respectively. With respect to hydroamination,
anti-Markovnikov oxidative amination was also achieved.11 An
aerobic anti-Markovnikov oxidation for the flow-synthesis of
arylacetaldehydes was also reported recently. This reaction
requires appropriate microreactors and a high oxygen pressure
Recently, we have reported
a
palladium-catalyzed
synthesis of terminal acetals from vinylarenes. This reaction
proceeds via a selective anti-Markovnikov nucleophilic attack
of a bulky diol, i.e. pinacol, to the coordinated vinylarenes.15 In
our continuous investigation on the Wacker-type oxidation
and related reactions, we discovered the anti-Markovnikov
oxidation of vinylarenes to arylacetaldehydes. This proceeds
using a simple PdCl2(MeCN)2/maleimide/CuCl catalyst system
and molecular oxygen (1 atm) as a terminal oxidant under mild
reaction conditions (Scheme 1). Maleimides were found to be
key additives in stabilizing the palladium complex during the
reaction.
a. Department of Chemistry, Faculty of Science, Nara Women’s University,
Kitauoyanishi-machi, Nara, 630-8506 (Japan), Fax: (+81) 742-20-3979, E-mail:
ura@cc.nara-wu.ac.jp
Electronic Supplementary Information (ESI) available: Experimental procedures,
NMR data and spectra of compounds 2. See DOI: 10.1039/x0xx00000x
Scheme
1 Transition metal-catalyzed Markovnikov and anti-Markovnikov
oxidation of vinylarenes to acetophenone derivatives and arylacetaldehydes.
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Since bulky alcohols are known to be effective to control
the regioselectivity in an anti-Markovnikov manner,8, 15-16 we
first attempted the oxidation of styrene (1a) using a t-AmylOH
solvent, which is easier to handle than t-BuOH (mp 26 °C) at
near room temperature, with a catalytic amount (10 mol%) of
PdCl2(MeCN)2 and H2O (3 eq) under 1 atm of O2 at 40 °C
(Scheme 2). The reaction proceeded slowly to give
phenylacetaldehyde (2a) and acetophenone (3a) with yields of
only 7% and 3%, respectively, after 24 h. The addition of a
catalytic amount (10 mol%) of CuCl significantly accelerated
the reaction, giving 34% of 2a after 3 h (Scheme 2). In these
reactions, benzaldehyde was also obtained in 10% and 26%, as
another by-product. This can be produced by the further
oxidation of the formed 2a. Such aerobic oxidations from 2a to
benzaldehyde, catalyzed by palladium and/or copper
complexes, were reported previously.12, 17
Table 1 Effects of additives on the anti-Markovnikov Wacker-type oxidation of styrene
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a
DOI: 10.1039/C5CC06746D
using O2
Yield (%)b
Entry
Additive
Time (h)
2a
34
29
42
47
53
42
50
56
65
58
55
60
45
13
45
41
0
3a
4
1
2
none
BQc
3
2
3
3
2,5-Me2BQ
Me4BQ
4
3
4
2
14
5
5
2,5-Ph2BQ
4
6
2,5-(MeO)2BQ
2,6-(MeO)2BQ
maleic anhydride
maleimide
N-methylmaleimide
N-t-butylmaleimide
N-phenylmaleimide
dimethyl fumarate
2,6-xylylNC
P(OMe)3
2
8
7
2
10
4
8
2
9
3
12
8
10
11
12
13
14
15
16
17
18
19
2
2
6
3
10
9
2
48
4
24
17
4
Scheme 2 Effect of CuCl on the anti-Markovnikov Wacker-type oxidation of
styrene using O2.
P(OPh)3
4
In order to further optimize the reaction conditions for the
anti-Markovnikov Wacker-type oxidation of styrene, effects of
a catalytic amount of additives were then examined (Table 1).
Initially, p-benzoquinone derivatives, which have been used
PPh3
24
48
3
0
NEt3
7
46
17
25
pyridine
DMAPd
46
34
not only as oxidants but also as 
-acidic 2 or 4 ligands for
20
5
zerovalent palladium complexes,18 were tested. Although p-
benzoquinone was ineffective (entry 2), substituted p-
benzoquinones gave 2a in better yields (≤53%) (entries 3–7).
Maleic anhydride and maleimides, which are also electron-
deficient cyclic alkenes and able to operate as ligands for
zerovalent19 and divalent20 palladium species, afforded higher
yields of 2a (entries 8–12). Among them, maleimide gave the
best results (entry 9). Dimethyl fumarate was also slightly
effective (entry 13). Although 2,6-xylylisonitrile was tested as
an electron-withdrawing 1 ligand, the reaction was sluggish
and both the yield and aldehyde selectivity were low (entry 14).
Several phosphorus and nitrogen ligands were also examined;
however, the yields of 2a were ≤46%, and the aldehyde
selectivities were generally low with the exception of P(OPh)3
(entries 15–20). When NEt3 was used, 3a was obtained as a
major product (entry 18). The reversal of regioselectivity by
NEt3 has been observed in the aerobic oxidative amination of
styrenes reported by Stahl et al.11
a
Reaction conditions: 1a (0.50 mmol), PdCl2(MeCN)2 (0.05 mmol), additive
(0.05 mmol), CuCl (0.05 mmol), H2O (1.5 mmol), t-AmylOH (2.0 mL), 40 °C,
b
c
d
O2 (1 atm), 1–48 h. GC yields. BQ = p-benzoquinone. DMAP = N,N-
dimethylaminopyridine.
co-catalyst to oxidize the Pd(0) complex at the beginning of the
reaction. As a result, the oxidation proceeded moderately to
give 2a and 3a in 56% and 2% yields after 1 h, respectively. In
comparison, another Pd(0) complex, Pd2(dba)3 (dba
=
dibenzylideneacetone), which is a synthetic precursor of Pd(2
-
To further examine the effect of additives such as maleic
anhydride and maleimides, a Pd(0) complex, Pd(2-mah)2(2
-
cyclopentene) (mah = maleic anhydride),19a was prepared and
used as a catalyst for the anti-Markovnikov Wacker-type
oxidation (Scheme 3). CuCl2 was employed instead of CuCl as a
Scheme
3 Anti-Markovnikov Wacker-type oxidation of styrene using Pd(0)
complexes as catalysts.
2 | J. Name., 2012, 00, 1-3
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mah)2(2-cyclopentene) and does not have mah ligands, was
also examined as a catalyst. In this case, only 20% yield of 2a
was given, indicating that the mah ligand enhances the
catalytic activity.
Table 2 Scope of substrates for the anti-Markovnikov Wacker-type oxidation of
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a
DOI: 10.1039/C5CC06746D
vinylarenes using O2
The reaction conditions using maleimide as an additive
were further finely optimized (see Table S1), and the optimal
conditions were applied to various vinylarenes (Table 2). High
aldehyde selectivities were achieved in most cases. t-AmylOH
appeared to be more appropriate than t-BuOH, which is also a
popular tertiary alcohol, as a solvent for the present oxidation
(entries 1 and 2). Styrenes with methyl, halogen, or strong
electron-withdrawing groups gave the corresponding
Yield (%)b
Vinylarene
Time
(h)
Entry
1
2
3
74 (62)c
10
1a
1a
1
3
2
2d
65
11
3
arylacetaldehydes
and 8–16). Notably, 2-substituted styrenes tended to give
higher yields of along with the formation of smaller amounts
of benzaldehyde derivatives (entries 3, 6, 10, and 12).
Presumably, this occurred because the overoxidations from
2 in good to high NMR yields (entries 3–6
84 (69)c
1b
3
2
2
71 (49)e
72 (61)e
9 (4)e
3 (3)e
1c
4
5
3
4
2
to the benzaldehyde derivatives were sterically suppressed by
the substituents at the 2-positions in these substrates. When
highly electron-deficient pentafluorostyrene (1h) was used as a
substrate, the formation of 3h and overoxidation from 2h were
both suppressed, although the yield of 2h was moderate (entry
9). On the other hand, styrene with an electron-donating
acetoxy group (1f) gave 2f in a moderate yield (entry 7). In this
case the conversion of 1f was low (80%), whereas in other
1d
1e
6
3
78 (67)
2
57 (56)f
71 (39)
3
3
1f
7
8
2
2
1g
cases, the conversions of
1 were almost a 100%. Prolonged
reaction times, however, did not increase the yield of 2f
because of its competitive overoxidation.
1h
9
3
56 (42)
0
A proposed reaction mechanism for the maleimide-assisted
anti-Markovnikov oxidation is shown in Scheme 4. Initially,
styrene coordinates to palladium in an 4-manner,7 and is
attacked by t-AmylOH at the terminal carbon (anti-
1i
1j
10
11
12
3
2
3
84 (77)
74 (53)
75 (51)
2
2
2
Markovnikov nucleophilic attack) to give a relatively stable -
benzyl intermediate. The combination of vinylarenes and bulky
nucleophiles may lead to anti-Markovnikov selectivity.8-10, 15
1k
After isomerization to a
-benzyl intermediate, -hydrogen
elimination gives alkenyl ethers and a Pd(0) species along with
the release of a proton. The alkenyl ethers are hydrolyzed to
2a, which is further oxidized to benzaldehyde catalyzed by
palladium and/or copper complexes under O2.12, 17 The formed
Pd(0) species is oxidized by CuCl2 to reproduce LnPdCl2. CuCl is
then reoxidized to CuCl2 by O2 and HCl.
According to the results shown in Scheme 3, the role of
maleic anhydride and maleimides can be rationalized to
operate as a ligand to stabilize the in-situ formed Pd(0) species
and prevent the aggregation to Pd black. The fact that, in the
present reaction, the catalyst was immediately deactivated at
temperatures higher than 60 °C supports the weak
coordination of maleic anhydride or maleimides to palladium.
Although they are easier to dissociate from Pd(II) than Pd(0)
1l
1m
1n
1o
13
14
15
2
2
70 (45)
80 (53)
73 (35)
61 (56)
4
3
2
2
1
16
0.8
a
Reaction conditions: 1 (0.50 mmol), PdCl2(MeCN)2 (0.05 mmol), maleimide
(0.05 mmol), CuCl (0.10 mmol), H2O (2.5 mmol), t-AmylOH (5.0 mL), 40 °C,
O2 (1 atm), 0.8–4 h. b NMR yields. Isolated yields are shown in parentheses. c
d
Isolated as 2,4-dinitrophenylhydrazone derivatives. t-BuOH was used as a
solvent. e Isolated as a mixture of 2 and 3 by HPLC. f N-methylmaleimide was
used as an additive for isolation.
due to weak -back donation, they possibly keep staying on
palladium during the whole catalytic cycle. There are a few
examples in which maleic anhydride coordinates to even Pd(II)
species.20
In conclusion, we have developed a palladium-catalyzed
anti-Markovnikov Wacker-type oxidation of vinylarenes to
arylacetaldehydes using 1 atm of O2. The procedure is simple
and the reaction proceeds under mild conditions. The use of
maleimide, which would operate as a ligand to stabilize the
palladium complex during the reaction, was critical. Further
investigations to increase the catalytic activity and aldehyde
selectivity, as well as to suppress the overoxidation are in
progress.
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7
8
9
J. A. Wright, M. J. Gaunt and J. B. Spencer, Chem. Eur. J.,
2006, 12, 949.
P. Teo, Z. K. Wickens, G. Dong and R. H. Grubbs, Org. Lett.,
2012, 14, 3237.
G. Dong, P. Teo, Z. K. Wickens and R. H. Grubbs, Science,
2011, 333, 1609.
View Article Online
DOI: 10.1039/C5CC06746D
10 S. M. Bronner and R. H. Grubbs, Chem. Sci., 2014, 5, 101.
11 (a) V. I. Timokhin, N. R. Anastasi and S. S. Stahl, J. Am. Chem.
Soc., 2003, 125, 12996; (b) V. I. Timokhin and S. S. Stahl, J.
Am. Chem. Soc., 2005, 127, 17888.
12 S. L. Bourne and S. V. Ley, Adv. Synth. Catal., 2013, 355, 1905.
13 (a) G. Jiang, J. Chen, H.-Y. Thu, J.-S. Huang, N. Zhu and C.-M.
Che, Angew. Chem., Int. Ed., 2008, 47, 6638; (b) J. Chen and
C.-M. Che, Angew. Chem., Int. Ed., 2004, 43, 4950.
14 (a) A. D. Chowdhury, R. Ray and G. K. Lahiri, Chem. Commun.,
2012, 48, 5497; (b) G.-Q. Chen, Z.-J. Xu, C.-Y. Zhou and C.-M.
Che, Chem. Commun., 2011, 47, 10963.
15 M. Yamamoto, S. Nakaoka, Y. Ura and Y. Kataoka, Chem.
Commun., 2012, 48, 1165.
16 (a) B. L. Feringa, J. Chem. Soc., Chem. Commun., 1986, 909;
(b) T. Ogura, R. Kamimura, A. Shiga and T. Hosokawa, Bull.
Chem. Soc. Jpn., 2005, 78, 1555.
Scheme 4 Proposed mechanism.
This work was supported by Grants-in-Aid for Scientific
Research (C) (25410116) from The Ministry of Education,
Culture, Sports, Science, and Technology (MEXT), Japan.
17 S. J. Jin, P. K. Arora and L. M. Sayre, J. Org. Chem., 1990, 55
,
3011.
18 (a) R. A. Klein, P. Witte, R. van Belzen, J. Fraanje, K. Goubitz,
M. Numan, H. Schenk, J. M. Ernsting and C. J. Elsevier, Eur. J.
Inorg. Chem., 1998, 319; (b) K. Selvakumar, A. Zapf, A.
Notes and references
Spannenberg and M. Beller, Chem. Eur. J., 2002, 8, 3901; (c)
1
(a) A. Ruiz-Olalla, M. A. Würdemann, M. J. Wanner, S.
Ingemann, J. H. van Maarseveen and H. Hiemstra, J. Org.
Chem., 2015, 80, 5125; (b) N. Z. Burns and P. S. Baran, Angew.
Chem., Int. Ed., 2008, 47, 205; (c) C. P. Forbes and G. L.
Wenteler, J. Chem. Soc., Perkin Trans. 1, 1981, 29.
Y. Yamamoto, T. Ohno and K. Itoh, Organometallics, 2003, 22
2267; (d) L. Canovese, F. Visentin, C. Santo and V. Bertolasi, J.
Organomet. Chem., 2014, 749, 379.
,
19 (a) K. Itoh, F. Ueda, K. Hirai and Y. Ishii, Chem. Lett., 1977,
877; (b) F. Gómez-de la Torre, F. A. Jalón, A. López-Agenjo, B.
R. Manzano, A. Rodríguez, T. Sturm, W. Weissensteiner and
M. Martínez-Ripoll, Organometallics, 1998, 17, 4634; (c) K.
Selvakumar, M. Valentini, P. S. Pregosin and A. Albinati,
Organometallics, 1999, 18, 4591; (d) A. M. Kluwer, C. J.
Elsevier, M. Bühl, M. Lutz and A. L. Spek, Angew. Chem., Int.
Ed., 2003, 42, 3501; (e) T. Iwasawa, T. Komano, A. Tajima, M.
Tokunaga, Y. Obora, T. Fujihara and Y. Tsuji, Organometallics,
2006, 25, 4665; (f) C. Foltz, M. Enders, S. Bellemin-Laponnaz,
H. Wadepohl and L. H. Gade, Chem. Eur. J., 2007, 13, 5994;
(g) R. Zalubovskis, A. Bouet, E. Fjellander, S. Constant, D.
Linder, A. Fischer, J. Lacour, T. Privalov and C. Moberg, J. Am.
Chem. Soc., 2008, 130, 1845; (h) J.-Y. Lee, P.-Y. Cheng, Y.-H.
Tsai, G.-R. Lin, S.-P. Liu, M.-H. Sie and H. M. Lee,
Organometallics, 2010, 29, 3901; (i) S. Warsink, I. H. Chang, J.
J. Weigand, P. Hauwert, J.-T. Chen and C. J. Elsevier,
2
3
A. Gualandi, P. Canestrari, E. Emer and P. G. Cozzi, Adv. Synth.
Catal., 2014, 356, 528.
(a) S. K. Lee and J. K. Park, J. Org. Chem., 2015, 80, 3723; (b)
R. Yan, X. Kang, X. Zhou, X. Li, X. Liu, L. Xiang, Y. Li and G.
Huang, J. Org. Chem., 2014, 79, 465; (c) G. Dagousset, W. Erb,
J. Zhu and G. Masson, Org. Lett., 2014, 16, 2554; (d) C. Zhang,
L. Zhang and N. Jiao, Adv. Synth. Catal., 2012, 354, 1293; (e) J.
Pataki, P. Di Raddo and R. G. Harvey, J. Org. Chem., 1989, 54
840; (f) E. M. Beccalli, E. Erba, M. L. Gelmi and D. Pocar, J.
Chem. Soc., Perkin Trans. 1, 1996, 1359.
,
4
(a) J. Muzart, Tetrahedron, 2007, 63, 7505; (b) J. M. Takacs
and X.-t. Jiang, Curr. Org. Chem., 2003, 7, 369; (c) J. J. Dong,
M. Fañanás-Mastral, P. L. Alsters, W. R. Browne and B. L.
Feringa, Angew. Chem., Int. Ed., 2013, 52, 5561; (d) B. W.
Michel, L. D. Steffens and M. S. Sigman, in Organic Reactions,
John Wiley & Sons, Hoboken, 2014, vol. 84, pp. 75; (e) R. Jira,
in Applied Homogeneous Catalysis with Organometallic
Compounds, eds. B. Cornils and W. A. Herrmann, Wiley-VCH,
Weinheim, 2nd edn., 2002, vol. 1, pp. 386; (f) S. E. Mann, L.
Benhamou and T. D. Sheppard, Synthesis, 2015, 47, 3079.
Z. K. Wickens, B. Morandi and R. H. Grubbs, Angew. Chem.,
Int. Ed., 2013, 52, 11257.
Organometallics, 2010, 29, 4555; (j) R. Malacea, N. Saffon, M.
Gomez and D. Bourissou, Chem. Commun., 2011, 47, 8163;
(k) D. M. Roundhill, Inorg. Chem., 1970,
20 (a) V. G. Albano, C. Castellari, M. E. Cucciolito, A. Panunzi and
A. Vitagliano, Organometallics, 1990, , 1269; (b) C.
9, 254.
9
5
6
Fernández-Rivas, D. J. Cárdenas, B. Martín-Matute, Á. Monge,
E. Gutiérrez-Puebla and A. M. Echavarren, Organometallics,
2001, 20, 2998.
(a) J. Guo and P. Teo, Dalton Trans., 2014, 43, 6952; (b) J. J.
Dong, W. R. Browne and B. L. Feringa, Angew. Chem., Int. Ed.,
2015, 54, 734.
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