Copper-catalyzed α-aminoxylation of ketones with 2,2,6,6- tetramethylpiperidine-1-oxyl (TEMPO)

Article abstract of DOI:10.1002/adsc.201300630

An efficient copper-catalyzed α-aminoxylation of ketones with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) is presented for the synthesis of 2-aryloxy-1-aryl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)ethanones in moderate to excellent yields. It is notewort

Full text of DOI:10.1002/adsc.201300630

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DOI: 10.1002/adsc.201300630
Copper-Catalyzed a-Aminoxylation of Ketones with 2,2,6,6-Tetra-
methylpiperidine-1-oxyl (TEMPO)
Ye-Xiang Xie,a Ren-Jie Song,a,* Yu Liu,a Yan-Yun Liu,a Jian-Nan Xiang,a
and Jin-Heng Lia,*
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, Peopleꢀs Republic of China
Fax : (+86)-731-8871-3642; phone: (+86)-731-8871-3642; e-mail: srj0731@hnu.edu.cn or jhli@hnu.edu.cn
Received: July 18, 2013; Revised: September 18, 2013; Published online: November 14, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300630.
Abstract: An efficient copper-catalyzed a-aminoxy-
lation of ketones with 2,2,6,6-tetramethylpiperidine-
1-oxyl (TEMPO) is presented for the synthesis of
2-aryloxy-1-aryl-2-(2,2,6,6-tetramethylpiperidin-1-yl-
a transition metal catalyst be recoverable and reusa-
ble from environmental and atom-economical points
of view. Herein we report a new and efficient route to
the a-aminoxylation of 2-aryloxy-1-arylethanones
with TEMPO[9] using a reusable Cu/Fe catalyst
(Scheme 1).[10] This method is the first example for
the Cu-catalyzed oxyamination reaction of ketones
with TEMPO.
ACHTUNGTRENNUNGoxy)ethanones in moderate to excellent yields. It is
noteworthy that the copper/iron (Cu/Fe) catalyst
can be recovered and reused several times with
high catalytic reactivity.
The reaction between 2-phenoxy-1-phenylethanone
(1a) and TEMPO was investigated to optimize the re-
action conditions, and the results are summarized in
Table 1. The results demonstrated that the reaction
could not take place without a metal catalysts
(entry 1). However, only a trace of the target product,
2-phenoxy-1-phenyl-2-(2,2,6,6-tetramethyl-piperidin-
1-yloxy)ethanone (2a), was observed in the presence
À
Keywords: a-aminoxylation; C H cleavage;
copper; ketones; TEMPO; 2,2,6,6-tetramethylpiper-
idine-1-oxyl (TEMPO)
Oxygen-bearing stereocenters are fundamental struc- of CuO (entry 2). To our delight, a 38% yield of prod-
tural units that are found in natural products and uct 2a was obtained when the reaction was carried
pharmaceutical agents.[1] Moreover, alkoxyamines can out using 10 mol% Cu
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
izers, peroxide substitutes (rheology modifiers), or ders, were tested, we found that copper powders
fireproofing agents.[3] There has been an ongoing in- (purity: wt% Cu=98.3938%) were more efficient, af-
terest in the development of simple, efficient methods fording product 2a up to 90% yield (entries 4–10), the
for synthesizing N-alkoxyamines. To the best of our yield was enhanced to 91% using the purity of
knowledge, however, the scope of substrates is limited 99.5 wt% Cu and to 92% yield at the purity of
to aldehydes, and other carbonyl compounds includ- 99.999 wt% Cu (entries 11 and 12). On the contrary,
ing ketones remain an unexploited area. For example, the catalytic activities of Fe powers were decreased
the MacMillan group[4] and the Zhong group[5] have with increasing purity (entries 13–16). While commer-
independently reported l-proline-catalyzed enantiose- cially available common Fe powders (purity: wt%
lective a-oxidation of aldehydes. Later, Sibi and co-
workers[6] have described an alternative method for
preparing alkoxyamines using an FeCl3/amine organo-
catalyst system. Recently, the MacMillan group[7] and
other groups[8] also developed some new approaches
to the enantioselective a-oxidation of aldehydes using
a synergistic combination of copper and organocata-
lysts. Despite impressive progress in transition metal-
catalyzed oxyamination reactions, it is desirable that Scheme 1. Copper-catalyzed a-oxyamination reaction.
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Table 1. Screening for the optimal reaction conditions.[a]
Entry [M] (mol%)
Solvent T [oC] Yield [%][b]
1
2
3
4
5
6
7
8
–
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
MeCN 80
0
CuO (10)
trace
38
56
71
81
49
41
54
90
91
92
11
7
Cu
CuCl2 (10)
Cu(OTf)2 (10)
CuSO4 (10)
CuI (10)
Cu2O (10)
CuBr2 (10)
Cu (98.3938%) (10) MeCN 80
Cu (99.5) (10)
Cu (99.999%) (10)
Fe (88.2667%) (10) MeCN 80
Fe (99.8%) (10)
ACHTUNGTRENNUNG(OAc)2 (10)
ACHTUNGTRENNUNG
Figure 1. Recycling of the Cu/Fe catalyst.
9
10
11
12
13
14
15
16
17[c]
18[d]
19[e]
20
21
22
23
24
25[f]
a number of solvents, DCE, DMF and toluene, was
tested in the presence of the Cu on Fe catalyst: they
were ineffective for the reaction (entries 22–24). It is
noteworthy that the reaction can be carried out at rel-
atively lower loading of Cu [0.075 mol% Cu (Cu/Fe)]
to furnish the desired product 2a in 89% yield for
24 h (TON=118,000, entry 25).
MeCN 80
MeCN 80
MeCN 80
MeCN 80
Fe (99.998%) (10)
Fe on SiO2 powder MeCN 80
3
trace
93
73
71
90
85
15
3
Cu/Fe (10)
Cu/Fe (10)
Cu/Fe (10)
Cu/Fe (5)
Cu/Fe (1)
Cu/Fe (10)
Cu/Fe (10)
Cu/Fe (10)
Cu/Fe (10)
MeCN 80
MeCN 45
MeCN 25
MeCN 80
MeCN 80
Importantly, the copper on iron catalyst could be
simply recovered and reused by use of magnetic
forces (Figure 1). The catalytic reactivity of Cu/Fe
was still high after eight runs of recycling and reuse,
albeit with gradually decreasing the chemical yields.
To elucidate these, a catalyst leaching experiment was
performed (Scheme S1 in the Supporting Informa-
tion). The experimental results revealed that catalyst
leaching was observed. Thus, the reason for the grad-
ually decreasing chemical yields is that some Cu/Fe
catalyst was lost during both the reaction process and
the post-treatment process.
As shown in Table 2, the scope of 2-aryloxy-1-aryl-
AHCTUNGTRENNGeUN thanones 1 with respect to TEMPO was explored
under the optimal conditions. We were pleased to
find that a variety of 2-aryloxy-1-arylethanones 1b–q
were compatible with the optimal conditions (prod-
ucts 2b–q), and no obvious electronic effects of the
aryl rings were observed. Initially, a number of sub-
DCE
DMF
80
80
toluene 80
MeCN 80
<5
89
[a]
Reaction conditions: 1a (0.2 mmol), TEMPO (1.1 equiv.),
[M] and solvent (2 mL) for 24 h, Cu/Fe (wt%): 37.5000%
Cu, 31.3000% Fe and about 31.2% SiO2.
Isolated yield.
An old Cu/Fe catalyst (prepared over one year previous-
ly) was also tested, and it gave the identical results.
Reaction time: 5 days.
Reaction time: 7 days.
1a (10 mmol) and Cu (0.075 mol%, Cu/Fe) for 24 h, and
the TON was 118,000.
[b]
[c]
[d]
[e]
[f]
Fe =88.2667%) afforded product 2a in 11% yield stituents, including Me, MeO and F groups, on the ar-
(entry 13), the yield of 2a was decreased to 7% using omatic ring of the arylethanone moiety were evaluat-
99.5% purity Fe and to 3% yield with 99.998% purity ed (products 2b–f): they are viable for the reaction
Fe (entries 14 and 15). However, the use of Fe on with TEMPO, and the reactive order of the substitu-
SiO2 powders resulted in no detectable product 2a ents is para and meta>ortho. For examples, substrates
(entry 16). Interestingly, the reaction proceeded 1b–1d bearing Me, F or MeO groups gave the corre-
smoothly when 10 mol% Cu (Cu/Fe) was added, pro- sponding products 2b–d in good yields. Gratifyingly,
viding the expected product 2a in 93% yield treatment of 1-(naphthalen-1-yl)-2-phenoxyethanone
(entry 17). Among the reaction temperatures exam- (1g) with TEMPO afforded the desired product 2g in
ined, it turned out that the reaction rate decreased 88% yield. Extensive screening revealed that substitu-
when the temperature was lowered (entries 18 and ents such as Me, MeO, Cl, I, NO2 and allyl groups, on
19). The amount of Cu/Fe was also evaluated, and the the aromatic ring of the phenoxy moiety were well
yield of 2a was lowered slightly at 5 mol% or 1 mol% tolerated (Products 2h–o). For instance, p-Me- or p-
Cu/Fe (entry 17 vs. entries 20 and 21). Finally, MeO-substituted substrates 1h and 1i underwent the
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Copper-Catalyzed a-Aminoxylation of Ketones with 2,2,6,6-Tetramethylpiperidine-1-oxyl
Table 2. Cu-catalyzed oxyamination of ketones 1 with TEMPO.[a]
[a]
Reaction conditions: 1 (0.2 mmol), TEMPO (1.1 equiv.), Cu/Fe (10 mol%) and MeCN
(2 mL) at 808C for 24 h.
1 mmol scale of substrate 1 was tested, and the yield is given in the parenthesis after
[b]
24 h.
For 36 h.
[c]
reaction with TEMPO smoothly, providing the corre-
A possible mechanism as outlined in Scheme 3 was
sponding products 2h and 2i in quantitative yields. In- proposed.[6–8] Complexation of substrate 1 with the
terestingly, the optimized conditions were compatible active [Cu] species affords intermediates A and B. In-
with both 2-(naphthalen-1-yloxy)-1-phenylethanone termediate C is generated from intermediate B by
(1p) and 1-phenyl-2-(quinolin-8-yloxy)ethanone (1q) a single electron transfer (SET) process. The addition
(products 2p and 2q). It was noted that benzofuran-
3(2H)-one (1r) was found to be a suitable substrate
with TEMPO, leading to the desired product 2r in
56% yield. Using AcO-substituted substrate 1s,
a good yield was still achieved under the optimal con-
ditions (product 2s).
Aryl glyoxylate motifs play an important role in
biological processes as useful intermediates in the
synthesis of some natural products, such as the 3-
deoxy-2-ulosonic acids and their derivatives.[11] Com-
pounds 2a and 2p could react under the reported
methods[11] to give the corresponding products 3a and
3p in 92% and 98% yields, respectively (Scheme 2).
Scheme 2. Utilizations of products 2a and 2p.
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Acknowledgements
We thank the Natural Science Foundation of China (No.
21172060), Specialized Research Fund for the Doctoral Pro-
gram of Higher Education (No. 20120161110041), and
Hunan Provincial Natural Science Foundation of China (No.
13JJ2018) for financial support. Dr. R.-J. Song also thanks
the Hunan Province Science and Technology Project (No.
2013RS4026) and China Postdoctoral Science Foundation
(No. 2012M511716).
Scheme 3. Possible mechanism.
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Typical Experimental Procedure for the Copper-
Catalyzed a-Aminoxylation Reaction
To a Schlenk tube were added a-arlyoxyacetophenones
1 (0.2 mmol), 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
2 (1.2 equiv.), 10 mol% Cu (Cu/Fe=3.4 mg) and MeCN
(2 mL). Then the contents of the tube was stirred at 808C
for the indicated time until complete consumption of start-
ing material as monitored by TLC and/or GC-MS analysis.
After the reaction was finished, the reaction mixture was
washed with brine. The aqueous phase was re-extracted with
ethyl acetate. The combined organic extracts were dried
over Na2SO4, concentrated under vacuum, and the resulting
residue was purified by silica gel column chromatography
(hexane/ethyl acetate) to afford the pure product.
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2-Phenoxy-1-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yl-
oxy)ethanone (2a): White soild, mp 77.8–78.68C (uncorrect-
1
ed); H NMR (500 MHz): d=8.27 (d, J=7.5 Hz, 2H), 7.56
(t, J=7.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 2H), 7.23 (t, J=
7.5 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 6.95 (t, J=7.5 Hz,
1H), 6.02 (s, 1H), 1.59–1.45 (m, 5H), 1.37 (s, 3H), 1.32–1.31
(m, 1H), 1.21 (s, 3H), 1.16 (s, 3H), 1.02 (s, 3H); 13C NMR
(125 MHz): d=192.6, 156.7, 133.4, 133.0, 130.4, 129.4, 128.2,
122.0, 109.8, 61.1, 60.0, 40.1, 40.0, 33.8, 33.1, 20.9, 20.2, 17.0;
IR (KBr): n=1687, 1507 cmÀ1; LR-MS (EI, 70 eV): m/z
(%)=367 (M+, 1), 352 (1), 183 (3), 156 (100); HR-MS (EI):
m/z=368.2230, calcd. for C23H30NO3 [(M+H)+]: 368.2226.
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