Cobalt(II)-catalyzed oxidative coupling of aromatic tertiary amines with enol silyl ethers leading to β-aminoketone derivatives

Article abstract of DOI:10.1055/s-0036-1588097

We demonstrated that a cobalt(II)-TBHP (tert-butyl hydroperoxide) oxidizing system efficiently catalyzes the coupling of aromatic tertiary amines with enol silyl ethers, producing the corresponding β-aminoketones.

Full text of DOI:10.1055/s-0036-1588097

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
N. Sakai et al.
Letter
Synlett
Cobalt(II)-Catalyzed Oxidative Coupling of Aromatic Tertiary
Amines with Enol Silyl Ethers Leading to β-Aminoketone Deriva-
tives
Norio Sakai*
SiMe3
X
O
O
Takuya Muraoka
Shun Matsumoto
Akihiro Mutsuro
Yohei Ogiwara
cat. CoBr2/TBHP
Ar
Ar
+
N
H
N
X
MeCN, Δ
under air
Me
Me
12–75%
X = alkyl, aryl or OR
Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo University of Science (RIKADAI), Noda,
Chiba 278-8510, Japan
sakachem@rs.noda.tus.ac.jp
Received: 04.09.2016
Accepted after revision: 23.10.2016
Published online: 11.11.2016
the presence of N-hydroxyphthalimide (NHPI), which cata-
lyzed a similar oxidative coupling of tertiary amines with
enol silyl ethers leading to β-aminoketones.6,7 Therefore, we
believe that there is ample room to further explore this
type of oxidative coupling using other metal catalysts and
oxidants. Among transition metals, it has been recently re-
ported that a variety of cobalt complexes contain a high po-
tential to induce useful molecular conversions, such as a C–
H functionalization,8a hydrosilylation,8b hydroformylation,8c
and an enantioselective transformation,8d as well as a clas-
sical Pauson–Khand reaction.8e In this context, we reported
a cobalt(II)–TBHP oxidizing system whereby α-cyanation of
aromatic tertiary amines leads to β-aminonitriles,9 and as a
further extension, attempted to apply this simple cobalt-
oxidizing system to the direct preparation of β-aminoke-
tones using aromatic tertiary amines and enol silyl ethers.10
In this letter, we report the preliminary results.
On the basis of our previous work, when the coupling of
N,N-dimethylaniline with an enol silyl ether (2 equiv per
the amine), which was derived from acetophenone, was ex-
amined using a catalytic amount of CoCl2 (5 mol% per the
aniline) and TBHP (1.5 equiv per the aniline) in methanol at
60 °C for two hours under an ambient atmosphere, the ex-
pected oxidative coupling proceeded smoothly to produce
β-aminoketone 1 in a 62% yield (Table 1, entry 1).11 When a
similar reaction with two equivalents of dimethylaniline for
the nucleophile was then examined, the yield of 1was
slightly increased (Table 1, entry 2). The coupling was then
examined under conditions involving a cobalt catalyst (5
mol% per the enol silyl ether) and an oxidant (1.5 equiv per
the enol silyl ether). Attempts were made using several oxi-
dants, most of which led to a decrease in the product yield
(Table 1, entries 3–6). Molecular oxygen was also ineffec-
tive for the oxidative coupling (Table 1, entry 7). Gratifying-
ly, the use of CoBr2, instead of CoCl2, slightly improved the
product yield (Table 1, entry 8). Moreover, the coupling
DOI: 10.1055/s-0036-1588097; Art ID: st-2016-u0583-l
Abstract We demonstrated that a cobalt(II)-TBHP (tert-butyl hydro-
peroxide) oxidizing system efficiently catalyzes the coupling of aromat-
ic tertiary amines with enol silyl ethers, producing the corresponding β-
aminoketones.
Key words cobalt, oxidation, aromatic tertiary amine, enol silyl ether,
β-aminoketone
β-Aminoketone derivatives have occupied one of the
central positions of nitrogen-containing valuable com-
pounds, because their structure is commonly found in the
central structure of natural products, biologically active
substances, and functional materials.1 Thus far, convention-
al approaches to the production of β-aminoketones have
generally amounted to either a Mannich-type reaction in-
volving amines, aldehydes, and enolizable carbonyl com-
pounds,1a,2 or the aza-Michael-type reaction using α,β-un-
saturated carbonyl compounds and amines or their ana-
logues.3 On the other hand, over the past two decades, the
direct introduction of a variety of functional groups at
C(sp3)–H that is adjacent to a nitrogen atom on the amine
has been demonstrated through the transition-metal-cata-
lyzed oxidative coupling of tertiary amines with nucleo-
philes in the presence of an appropriate organic oxidizing
agent and molecular oxygen.4 With this procedure in hand,
several groups have achieved the one-pot preparation of β-
aminoketone derivatives through the association of tertiary
amines and a representative carbon nucleophile, an enol si-
lyl ether.5 However, most of the reported methods have
been limited to an oxidizing catalytic system using either a
copper(I) or a copper(II) catalyst. The only reported exam-
ples other than a copper catalyst have involved either a vis-
ible-light photoredox system using Ru(bpy)Cl2 or NaSbCl6 in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
N. Sakai et al.
Letter
Synlett
Me
N
with CoBr2 could be extended to an acetonitrile solution
(Table 1, entry 10). When the reaction was conducted at 40
°C, the oxidative coupling proceeded without a drastic loss
of β-aminoketone 1 (Table 1, entry 11).
SiMe3
Ph
cat. CoBr2
TBHP
Me
N
O
Ph
+
Ar
Ar
Me
Me
MeCN, 40 °C
O
2-11
Me
Me
Table 1 Examination of the Reaction Conditionsa
Me
N
Ph
Ph
N
Ph
O
O
O
Me
N
SiMe3
Ph
Me
N
O
[Co]/oxidant
2: 69% (1 h)
3: 62% (2 h)
Ph
+
Ph
solvent, temp, 2 h
Ph
Me
Me
N
Me
N
O
1
Ph
O
O
Entry [Co]
Oxidant
Solvent
Temp (°C) NMR yield (%)
Me
MeO
4: 70% (1 h)
5: 61% (30 h)
1b
2
3
4
5
6
7
8
9
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoCl2
CoBr2
CoBr2
CoBr2
CoBr2
TBHP
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeCN
60
60
60
60
60
60
60
60
40
60
40
62
Me
N
Me
N
TBHP
73
Ph
Ph
DTBPc
MCPBAd
trace
4
O
Br
NO2
6: 32% (0.5 h)
7: 15% (4 h)
e
H2O2
38
DDQf
O2
n.r.
18
Et
N
O
N
R
Ph
Ph
N
Ph
O
TBHP
TBHP
TBHP
TBHP
79 (75)g
58
Me
O
Ph
Ph
10: 0% (2 h)
11: 0% (2 h)
R = Ph, 8: 71% (24 h)
R = Me, 9: trace (24 h)
10
11
79
75
Scheme 1 Substrate scope of tertiary aromatic amines. Reagents and
conditions: aromatic amine (1 mmol), enol silyl ether (0.5 mmol), CoBr2
(0.025 mmol), TBHP (0.75 mmol), MeCN (0.5 mL).
a Standard conditions: amine (1 mmol), enol silyl ether (0.5 mmol), [Co]
(0.025 mmol), TBHP (0.75 mmol), solvent (0.5 mL).
b The molar ratio: aromatic amine/enol silyl ether = 1:2.
c Di-tert-butyl peroxide.
d m-Chloroperoxybenzoic acid.
e 30% Aqueous solution.
The substrate effect of several enol silyl ethers was then
investigated using the optimal conditions (Scheme 2). Any
sort of substituent next to the carbonyl moiety, such as a 4-
MeC6H4 group, a tert-butyl group, or a methyl group, did
not show the direct effect on the yield in production of the
corresponding β-aminoketone derivatives 12–14 in 50–60%
yields. Also, in the case with an α-methyl-substituted enol
silyl ether, although a decrease in the product yield was ob-
f 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.
g Isolated yield.
Then, the oxidative catalytic system was applied to aro-
matic tertiary amines possessing several functional groups
(Scheme 1). When substrates had an electron-donating
group, such as a methyl group, on the aromatic ring, the ox-
idative coupling proceeded smoothly to produce the ex-
pected β-aminoketones 2–4 in relatively good yields, re-
gardless of the location of the methyl group. Also, the
amines with a methoxy group yielded aminoketone 5 in a
practical yield. In contrast, the substrates with an electron-
withdrawing group, such as bromo and nitro groups, man-
aged to undertake the coupling to produce the correspond-
ing β-aminoketones 6 and 7 in rather low yields. On the
other hand, for N-phenyltetrahydroisoquinoline, the ex-
pected aminoketone 8 was obtained in a good yield, in
which the carbon nucleophile was introduced at the benzyl
position next to a nitrogen atom. In contrast, a trialkyl-
amine-type substrate, N-methyltetrahydroisoquinoline
hardly undertook the coupling. These results strongly im-
plied that a phenyl group requires stabilizing the reaction
intermediate. Unfortunately, the oxidative introduction of a
phenacyl group onto the substrates with an N,N-diethyl-
amino group and a cyclic amino moiety, such as piperidine,
did not occur.
SiMe3
cat. CoBr2
TBHP
O
Me
N
Me
N
+
Ph
Ph
Ph
Me
MeCN, 40 °C
O
11–16
Me
Me
Me
N
N
p-tol
N
t-Bu
Me
Ph
Ph
O
O
O
12: 60% (0.5 h)
13: 56% (3 h)
14: 50% (2 h)
Me
N
Me
Me
N
Me
N
Ph
Ph
Ph
Ph
O
O
O
15: 37% (3 h)
16: 69% (3 h)
17: 62% (2 h)
Scheme 2 Substrate scope of enol silyl ethers. Reagents and conditions:
N,N-dimethylaniline (1 mmol), enol silyl ether (0.5 mmol), CoBr2 (0.025
mmol), TBHP (0.75 mmol), MeCN (0.5 mL).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
N. Sakai et al.
Letter
Synlett
served, the desired coupling proceeded to give β-aminoke-
tone 15. Moreover, the couplings with six- or seven-mem-
bered cyclic enol silyl ethers yielded β-aminoketones 16
and 17 in satisfactory yields.
CoCl2 (5 mol%)
TBHP (1 equiv)
scaveanger
Me
N
Me
N
OSiMe3
Ph
Ph
+
Ph
MeCN, 40 °C, 2 h
Ph
Me
O
(2 equiv)
1
In contrast, two ketene silyl acetals with either a
branched reaction site or an unsubstituted reaction moiety
led to a drastic decrease in the product yields (Scheme 3).
However, there was no reasonable reason for these results.
The low yield from the use of the ketene silyl acetal was in
agreement with a similar coupling using CuCl2·2H2O under
an O2 atmosphere.5b
BHT
TEMPO (1 equiv)
(1 equiv)
41% (NMR)
35% (NMR)
Scheme 5 Control experiment with a radical inhibitor
Scheme 6 shows the plausible reaction path for the
Co(II)–TBHP oxidative coupling of a tertiary aromatic amine
with an enol silyl ether. On the basis of the report by Doyle
et al.,14 we assume that the oxidation coupling series would
proceed via two key steps involving (i) the generation of the
tert-butylperoxy radical derived from a cobalt(II) catalyst
and TBHP and (ii) the formation of an iminium intermediate
via the oxidation of an aromatic amine with an in situ gen-
erated tert-butylperoxy radical. An aromatic amine would
be oxidized with a tert-butylperoxy radical through both
single-electron transfer (SET) and proton transfer (PT) to
produce the corresponding iminium intermediate. Then,
the iminium intermediate would be coupled with the enol
silyl ether, which would lead to the production of a β-ami-
noketone derivative. The oxidized cobalt(III) species would
be reduced again with the formed t-BuOOH to regenerate a
cobalt(II) complex.
Me
N
OSiMe3
OMe
R R
CoBr2 (5 mol%)
TBHP (1.5 equiv)
Me
N
OMe
R
+
Ph
MeCN, 40 °C, 12 h
Ph
Me
O
R
(1 mmol)
(2 equiv)
R = Me, 18: 12%
R = H, 19: CM
Scheme 3 Application of the oxidative coupling using a ketene silyl
acetal
Then, to show the utility of the present oxidative cou-
pling, a direct coupling using acetophenone was attempted
(Scheme 4). For example, when the mixture of N,N-dimeth-
ylaniline and acetophenone (2 equiv per N,N-dimethylani-
line) was treated with the Co(II)–TBHP oxidizing system in
the presence of L-proline (1 equiv) as an additive, the ex-
pected oxidative coupling proceeded, but afforded 1 in only
an 8% yield.12,13 In addition, when a similar reaction was
conducted in the presence of Me3SiOTf and Hünig’s base (i-
Pr2NEt) in an effort to realize the in situ formation of the
corresponding enol silyl ether, β-aminoketone 1 was ob-
tained in a 16% yield.
[Co(II)]
t-BuOOH
t-BuOO
t-BuOOH
t-BuO
[Co(III)]
t-BuOH
t-BuOO
t-BuOO t-BuOO
CH3
CH3
CH2
CoBr2 (5 mol%)
TBHP (1.5 equiv)
additive (1 equiv)
N
N
Ar
N
Me
Ar
Me
N
O
Ar
N
Ph
t-BuOOH
+
Ph
[Co(III)]
solvent, 60 °C, 20 h
Ph
Ph
Me
Me
(2 equiv)
O
1
[Co(II)]
L-proline in MeOH
8% (NMR)
16% (NMR)
0% (NMR)
OSiMe3
t-BuOO
t-BuOO
O
Me3SiOTf / Hünig's base in MeCN
no additive
+
CH2
R
N
N
R
Me3SiOOt-Bu
Ar
Scheme 4 Trials involving the direct oxidative coupling of N,N-dimeth-
Ar
ylaniline with acetophenone
Scheme 6 Plausible reaction path for oxidative coupling using the
CoBr2–TBHP system
To better understand the reaction pathway for the series
of preparations of β-aminoketones, a control experiment
was conducted (Scheme 5). When the coupling was carried
out in the presence of a radical scavenger, 2,6-di(tert-
butyl)-p-cresol (BHT) and 2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (TEMPO), the formation of 1 was half restrained.
This result suggested that a coupling with the cobalt–TBHP
system would mainly proceed through a single-electron
transfer (SET) rather than an ionic path.
Acknowledgment
We deeply thank Shin-Etsu Chemical Co., Ltd., for the gift of chloro-
trimethylsilane.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588097.
S
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
N. Sakai et al.
Letter
Synlett
References and Notes
(d) Pellissier, H.; Clavier, H. Chem. Rev. 2014, 114, 2775.
(e) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem.
Soc., Perkin Trans. 1 1973, 975; and references cited therein.
(9) Sakai, N.; Mutsuro, A.; Ikeda, R.; Konakahara, T. Synlett 2013, 24,
1283.
(10) For recent examples of an oxidative converstion using a cobalt-
TBHP oxidizing system, see: (a) Kong, D.-L.; Cheng, L.; Yue, T.;
Wu, H.-R.; Feng, W.-C.; Wang, D.; Liu, L. J. Org. Chem. 2016, 81,
5337. (b) Yu, J.; Zhang-Negrerie, D.; Du, Y. Eur. J. Org. Chem.
2016, 562. (c) Zhang, F.; Du, P.; Chen, J.; Wang, H.; Luo, Q.; Wan,
X. Org. Lett. 2014, 16, 1932. (d) Zhu, T.-H.; Xu, X.-P.; Cao, J.-J.;
Wei, T.-Q.; Wang, S.-Y.; Ji, S.-J. Adv. Synth. Catal. 2014, 356, 509.
(11) General Procedure for a Cobalt-Catalyzed Oxidative Coupling
of Aromatic Tertiary Amines with Enol Silyl Ethers
(1) (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed.
1998, 37, 1044; and the references cited therein. (b) Hwang, J.
Y.; Arnold, L. A.; Zhu, F.; Kosinski, A.; Mangano, T. J.; Setola, V.;
Roth, B. L.; Guy, R. K. J. Med. Chem. 2009, 52, 3892.
(2) Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791; and
the references cited therein.
(3) Selected papers: (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.-i.;
Tomioka, K. J. Am. Chem. Soc. 2003, 125, 2886. (b) Kobayashi, S.;
Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319. (c) Loh, T.-P.;
Wei, L.-L. Synlett 1998, 975. (d) Asao, N.; Shimada, T.; Sudo, T.;
Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara, T.; Yamamoto,
Y. J. Org. Chem. 1997, 62, 6274. (e) Matsubara, S.; Yoshioka, M.;
Utimoto, K. Chem. Lett. 1994, 23, 827. (f) Cabral, J.; Laszlo, P.;
Mahé, L.; Montaufier, M.-T.; Randriamahefa, S. L. Tetrahedron
Lett. 1989, 30, 3969.
(4) Selected reviews and papers: (a) Murahashi, S.-I.; Zhang, D.
Chem. Soc. Rev. 2008, 37, 1490; and the references cited therein.
(b) Li, C.-J. Acc. Chem. Res. 2008, 42, 335; and the references
cited therein. (c) Boess, E.; Schmitz, C.; Klussmann, M. J. Am.
Chem. Soc. 2012, 134, 5317. (d) Li, Z.; Bohle, D. S.; Li, C.-J. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (e) Catino, A. J.; Nichols, J.
M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648.
(f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968. (g) Li, Z.; Li,
C.-J. Eur. J. Org. Chem. 2005, 3173. (h) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2004, 126, 11810. (i) Murahashi, S.-I.; Komiya, N.; Terai, H.;
Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312. (j) Murahashi, S.;
Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.; Akutagawa,
S. J. Am. Chem. Soc. 1990, 112, 7820. (k) Murahashi, S.-I.; Naota,
T.; Miyaguchi, N.; Nakato, T. Tetrahedron Lett. 1992, 33, 6991.
(l) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1993, 66, 1297.
(5) (a) Gao, R.; Yi, C. S. ACS Catal. 2011, 1, 544. (b) Sureshkumar, D.;
Sud, A.; Klussmann, M. Synlett 2009, 1558. (c) Chu, L.; Zhang, X.;
Qing, F.-L. Org. Lett. 2009, 11, 2197. (d) Huang, L.; Zhang, X.;
Zhang, Y. Org. Lett. 2009, 11, 3730.
(6) Zhao, G.; Yang, C.; Guo, L.; Sun, H.; Chen, C.; Xia, W. Chem.
Commun. 2012, 48, 2337.
(7) Tanoue, A.; Yoo, W.-J.; Kobayashi, S. Adv. Synth. Catal. 2013, 355,
269.
(8) For example, see: (a) Moselage, M.; Li, J.; Ackermann, L. ACS
Catal. 2016, 6, 498. (b) Sun, J.; Deng, L. ACS Catal. 2016, 6, 290.
(c) Hebrard, F.; Kalck, P. Chem. Rev. 2009, 109, 4272.
To a screw-capped test tube (5 mL) under ambient atmosphere
containing freshly distilled MeCN (0.5 mL) were successively
added 0.5 M MeCN solution of CoBr2 (50 μL, 0.025 mmol),
aniline (1.0 mmol), enol silyl ether (0.50 mmol), and 5.5 M tert-
butyl hydroperoxide in decane (136 μL, 0.750 mmol). After the
tube was sealed with a cap that contained a PTFE septum, the
mixture was heated at 40 °C (bath temperature) and monitored
by GC and TLC analysis. The reaction was quenched with a
Na2CO3 aq solution (5 mL). The aqueous layer was extracted
with CHCl3, the organic phases were dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure. The
crude product was purified by silica chromatography (hexane–
EtOAc = 4:1) to give the corresponding β-aminoketone.
(3-Methylphenylamino)-1-phenyl-1propanone (1)
White solid; 75% (90 mg). 1H NMR (300 MHz, CDCl3): δ = 8.00–
8.02 (m, 2 H), 7.64–7.51 (m, 3 H), 7.37–7.31 (m, 2 H), 6.85–6.79
(m, 3 H), 3.95–3.90 (t, J = 6.9 Hz, 2 H), 3.34–3.30 (t, J = 6.9 Hz, 2
H), 3.01 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 199.4, 148.5,
136.8, 133.1, 129.3, 128.6, 128.0, 116.5, 112.3, 47.9, 38.5, 35.1.
MS (EI): m/z (%) = 239 (100) [M+].
(12) For the examples of the direct coupling of tertiary amines with
ketones, see: (a) Alagiri, K.; Devadig, P.; Prabhu, K. R. Chem. Eur.
J. 2012, 18, 5160. (b) Yang, F.; Li, J.; Xie, J.; Huang, Z.-Z. Org. Lett.
2010, 12, 5214. (c) Shen, Y.; Li, M.; Wang, S.; Zhan, T.; Tan, Z.;
Guo, C.-C. Chem. Commun. 2009, 953. (d) Sud, A.; Sureshkumar,
D.; Klussmann, M. Chem. Commun. 2009, 3169.
(13) The addition of L-proline promoted the direct vanadium-cata-
lyzed coupling of amimes with ketones, see ref. 12d.
(14) Ratnikov, M. O.; Doyle, M. P. J. Am. Chem. Soc. 2013, 135, 1549.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D