Copper-Catalyzed Cleavage of Unstrained C-C Bonds for the Synthesis of 1-Acyloxy-2,2,6,6-tetramethylpiperidines from Cyclic or Acyclic Ketones

Article abstract of DOI:10.1055/s-0036-1590805

A copper-catalyzed approach for the synthesis of 1-acyloxy-2,2,6,6-tetramethylpiperidines through the C-C bond cleavage of cyclic or acyclic ketones was developed. In this chemistry, a combination of CuCl ₂ ·2H ₂ O, 1,10-phenanthroline monohydrate, and aniline was crucial for the formation of the desired products by the reaction of ketones with TEMPO. This research provides a new strategy for the further transformation of α-aryl cyclic or acyclic ketones.

Full text of DOI:10.1055/s-0036-1590805

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
Q. Jiang et al.
Letter
Synlett
Copper-Catalyzed Cleavage of Unstrained C–C Bonds for the Syn-
thesis of 1-Acyloxy-2,2,6,6-tetramethylpiperidines from Cyclic or
Acyclic Ketones
Qijian Jianga
Luo Yangc
Wang Zhou*a,b
O
R2
R3
R2
O
cat. [Cu], ligand
O
N
O
amine, air
N
0
0
0
0
0-
0
0
1
8-
6
2
9
0-
8
6
X
R1
O
+
R1
a College of Chemical Engineering, Xiangtan University, Xiangtan
411105, P. R. of China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking
University, Xue Yuan Road 38, Beijing 100191, P. R. of China
c College of Chemistry, Xiangtan University, Xiangtan 411105,
P. R. of China
R3
11 examples
up to 93% yield
wzhou@xtu.edu.cn
Received: 17.04.2017
Accepted after revision: 22.05.2017
Published online: 13.07.2017
workers conducted pioneering research on the copper-cat-
alyzed esterification of 1,3-diones10a and simple ketones.10b
However, these methods could be successfully applied to
acyclic ketones only. We recently developed a copper-cata-
lyzed oxidative C−C bond cleavage reaction of unstrained
ketones with air and amines (Scheme 1, Path a),11 in which
both cyclic and acyclic ketones are well tolerated to give oxo
amides or aldehydes and amides as products. In mechanis-
tic studies, we found that in the presence of a stoichiomet-
ric amount of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEM-
PO), β-tetralone [3,4-dihydronaphthalen-2(1H)-one] was
converted into a 1-acyloxy-2,2,6,6-tetramethylpiperidine
derivative rather than the corresponding oxo amide. In a
continuing effort to explore this reaction, we report here a
copper-catalyzed synthesis of 1-acyloxy-2,2,6,6-tetrameth-
ylpiperidines from cyclic or acyclic ketones (Scheme 1, Path b).
DOI: 10.1055/s-0036-1590805; Art ID: st-2017-w0266-l
Abstract A copper-catalyzed approach for the synthesis of 1-acyloxy-
2,2,6,6-tetramethylpiperidines through the C–C bond cleavage of cyclic
or acyclic ketones was developed. In this chemistry, a combination of
CuCl2·2H2O, 1,10-phenanthroline monohydrate, and aniline was crucial
for the formation of the desired products by the reaction of ketones
with TEMPO. This research provides a new strategy for the further trans-
formation of α-aryl cyclic or acyclic ketones.
Key words copper catalysis, acyloxypiperidines, C–C bond cleavage,
ketones, TEMPO
The importance of investigations on the cleavage of C–C
bonds stems from the unique potential of this reaction for
efficient rearrangements or multifunctionalizations of the
carbon skeletons of organic compounds.1,2 Compared with
strained C–C bonds, the cleavage of unstrained C–C bonds is
challenging from the energy point of view, but more desir-
able in terms of its synthetic applications and the easy
availability of starting materials.3
In the past few decades, a great deal of attention has
been focused on the cleavage of C–C(CO) bonds, because
carbonyl compounds such as ketones and aldehydes exist
widely in nature4 and are also commercially available or
readily accessible through chemical synthesis. The develop-
ment of transformations based on C–C bond cleavage of ke-
tones will undoubtedly enrich the range of tools available
for the utilization of carbonyl compounds.5
a) Our previous work
O
H
O
cat. [Cu]
ligand / air
O
R
NHR1R2
HNR1R2
+
R
b ) This work
R2
O
N
R2
R3
O
cat. [Cu], ligand
amine, air
O
O
N
R1
O
+
R1
R3
Scheme 1 Copper-catalyzed cleavage of unstrained C–C bonds
In relation to green and sustainable chemistry, the cop-
per/air catalytic system has many merits and is considered
an ideal choice for organic transformations.6 In the past de-
cade, copper-catalyzed cleavage of nonstrained open-chain
ketones for the synthesis of amides,7 aldehydes,8 or other
compounds9 has been achieved. In addition, Jiao and co-
After a slight change from the standard conditions pre-
viously reported, namely, the use of acetonitrile as a sol-
vent, we obtained 2-{3-oxo-3-[(2,2,6,6-tetramethylpiperi-
din-1-yl)oxy]propyl}benzaldehyde (3aa) in 93% isolated
yield by the reaction of β-tetralone with TEMPO (Table 1, en-
try 4).12 The combination of a copper catalyst (CuCl2·2H2O), a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
Q. Jiang et al.
Letter
Synlett
Table 1 Screening of Reaction Conditionsa
O
catalyst (10 mol%)
ligand (20 mol%)
aniline (10 mol%)
O
N
O
H
O
+
N
solvent (2 mL), 40 °C
air, 24 h
O
1a
2a
3aa
Entry
Catalyst
Ligand
Solvent
Yieldb (%)
1
2
Cu(OTf)2
1,10-phen·H2O
1,10-phen·H2O
1,10-phen·H2O
1,10-phen·H2O
1,10-phen·H2O
none
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
81
55
88
93
0
Cu(OAc)2·H2O
CuI
3
4
CuCl2·2H2O
none
5
6
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
0
7c
8d
9
1,10-phen·H2O
1,10-phen·H2O
pyridine
0
10
69
81
69
53
88
39
87
43
10
11
12
13
14
15e
16f
2,2′-bipyridyl
TMEDA
1,10-phen·H2O
1,10-phen·H2O
1,10-phen·H2O
1,10-phen·H2O
1,10-phen·H2O
acetone
DMSO
MeCN
MeCN
a Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol), catalyst (0.025 mmol), ligand (0.05 mmol), aniline (0.025 mmol), solvent (2 mL), stirring, 40 °C, 24 h,
under air (1 atm).
b Isolated yield.
c Without aniline.
d 10 mol% of 1,10-phen·H2O was used.
e At r.t.
f At 50 °C.
bidentate ligand (1,10-phenanthroline monohydrate; 1,10-
phen·H2O), and aniline proved to be crucial for this trans-
formation (entries 5–7). Note that the reaction became
sluggish when the amount of 1,10-phenanthroline mono-
hydrate was decreased to 10 mol% (entry 8). Other combi-
nations of copper salts with nitrogen-containing ligands
also catalyzed this reaction, albeit with lower efficiencies
(entries 1–3 and 9–11). In addition, changing the solvent or
temperature had significant impacts on the yield (entries
12–16).
Having noted the perplexing role of aniline in this reac-
tion, we screened a variety of amines to probe the exact
function of the amine (Table 2). For primary amines, an ani-
line with an electron-donating substituent gave a better re-
sult than one with an electron-withdrawing substituent
(Table 2, entries 1 and 2). A slight decrease in yield was ob-
served when butylamine or tert-butylamine was used (Ta-
ble 2, entries 4 and 5). As for secondary amines, the reac-
tion proceeded in the presence of diaryl or dialkyl amines,
providing similar outcomes (entries 6–8). Moreover, tertia-
ry amines also mediated this transformation (entries 9 and
10). Taken in combination with the observed negative effect
of decreasing the loading of the ligand (Table 1, entry 8),
these results imply that the amine might serve as a base
rather than as a ligand. However, the mechanistic details of
this chemistry are still unclear.
With the optimum reaction conditions in hand, we
commenced an exploration of the substrate scope (Table 3).
β-Tetralones bearing various substituents on the aromatic
ring were successfully converted into the desired products
in moderate to good yields (Table 3, entries 1–5). As for
benzo ketones, although indan-2-one was tolerated (entry
6), 2-benzosuberone (5,7,8,9-tetrahydro-6H-benzocyclo-
hepten-6-one) was incompatible (not shown). When α-
phenyl cyclic ketones with six- to eight-membered rings
were employed, decreased yields of the corresponding
products were obtained (entries 7–9). The scope could be
extended to an open-chain ketone (entry 10); in this reac-
tion, the over-quantitative yield of aldehyde 3ja′ originates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
Q. Jiang et al.
Letter
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Table 2 Screening of Aminesa
O
CuCl2⋅2H2O (10 mol%)
1,10-phen H2O (20 mol%)
amine (10 mol%)
O
N
O
H
+
O
CH3CN (2 mL), 40 °C, air, 24 h
N
O
1a
2a
3aa
Entry
amines
Yieldb of 3aa (%)
1
2
(4-methoxyphenyl)amine
4-aminobenzonitrile
1-naphthylamine
BuNH2
90
69
76
83
79
82
73
73
71
67
3
4
5
t-BuNH2
6
Ph2NH
7
PhNHMe
8
morpholine
Ph3N
9
10
Et3N
a Reaction conditions, 1a (0.5 mmol), 2a (0.25 mmol), CuCl2·2H2O (0.025 mmol), 1,10-phen·H2O (0.05 mmol), amine (0.025 mmol), MeCN (2 mL), stirring
40 °C, 24 h, under air (1 atm).
b Isolated yield.
from the side reaction of excess ketone.13 However, α-te-
tralone could not be used successfully in this transforma-
tion (entry 11).
Moreover, this reaction provides ready access to 1-acyl-
oxy-2,2,6,6-tetramethylpiperidines with various substitu-
ents in the 4-position of the piperidine ring (Scheme 2).
Table 3 Substrate Scope of Ketonesa
Entry
Substrate
Product
Yieldb (%)
O
O
H
1
93
81
76
80
O
N
1a
O
3aa
O
O
H
2
3
4
O
Br
Br
N
1b
O
3ba
O
MeO
MeO
O
H
O
N
1c
O
3ca
O
Me
O
Me
H
O
N
1d
3da
O
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
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Synlett
Table 3 (continued)
Entry
5
Substrate
Product
Yieldb (%)
O
O
H
72
O
N
Br 1e
Br
O
O
3ea
O
O
O
6c
53
N
1f
3fa
O
O
Ph
O
O
7d
50
22
Ph
N
N
O
3ga
1g
O
O
Ph
Ph
8e
Ph
( )2
O
O
3ha
1h
O
O
O
9e
36
Ph
N
( )3
3ia
1i
O
OMe
O
O
H
N
10f
74 (3ja) 109 (3ja′)
O
+
MeO
MeO
3ja
1j
MeO
3ja'
O
O
N
O
O
11
(not detected)
H
1k
3ka
a For reaction conditions, see Table 1, entry 4.
b Isolated yield.
c PhNHAc and MeCN–acetone (3:1) were used as the amine and solvent, respectively, at r.t.
d 60 °C, 48 h.
e 80 °C, 48 h.
f 60 °C, 36 h.
Finally, a set of reactions was conducted to demonstrate
the synthetic value of this transformation (Scheme 3). Prod-
uct 3aa was converted into oxime 4 by condensation with
hydroxylamine. The terminal alkene 5 and alkyne 6 were
readily synthesized by reaction of 3aa with a Wittig reagent
and the Ohira–Bestmann reagent [MeCOC(=N2)P(O)(OMe)2],
respectively. Sodium borohydride selectively reduced 3aa to
give the benzyl alcohol derivative 7. Complete reduction of
the two carbonyl groups of 3aa to give diol 8 was achieved
by treatment with LiAlH4 in THF.
In conclusion, we have developed a copper/air catalytic
system for the cleavage of unstrained C–C bonds of cyclic or
acyclic ketones. The results of this research will enrich
range of tools available for the utilization of α-aryl cyclic or
acyclic ketones.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
Q. Jiang et al.
Letter
Synlett
O
O
O
H
H
H
O
O
O
N
N
O
N
O
O
O
O
R
N
Me
O
H
R = Me, 3ab, 74%a
H, 3ac, 79%
3ad, 91%
3ae, 67%a
Scheme 2 Scope of TEMPO derivatives. Reaction Conditions: see Table 1, entry 4. Isolated yields are reported. a 48 h.
O
N
O
5, 54%
b
OH
H
O
N
H
a
c
O
O
O
N
N
N
O
O
O
3aa (0.1 mmol)
6, 96%
4, 78%
e
d
OH
OH
O
N
OH
O
7, 81%
8, 78%
Scheme 3 Further transformations. Reagents and conditions: (a) NH2OH·HCl, NaHCO3, EtOH–H2O, r.t., overnight; (b) Ph3PCH3Br, t-BuOK, anhyd THF,
0 °C to r.t., 16 h; (c) Ohira–Bestmann reagent, K2CO3, MeOH, r.t.; (d) NaBH4, THF–H2O; (e) LiAlH4, THF.
Funding Information
(5) For selected recent examples on cleavage of C–C bonds of
unstrained ketones or aldehydes, see: (a) Shuai, Q.; Yang, L.;
Guo, X.; Baslé, O.; Li, C.-J. J. Am. Chem. Soc. 2010, 132, 12212.
(b) Lei, Z.-Q.; Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Sun,
J.; Shi, Z.-J. Angew. Chem. Int. Ed. 2012, 51, 2690. (c) Lei, Z.-Q.;
Pan, F.; Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Li, Y.-X.;
Sun, J.; Shi, Z.-J. J. Am. Chem. Soc. 2015, 137, 5012. (d) Xia, Y.; Lu,
G.; Liu, P.; Dong, G. Nature 2016, 539, 546. (e) Morioka, T.;
Nishizawa, A.; Furukawa, T.; Tobisu, M.; Chatani, N. J. Am. Chem.
Soc. 2017, 139, 1416.
(6) For some recent reviews on metal-catalyzed aerobic oxidation,
see: (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3381. (b) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736.
(c) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851.
(7) (a) Tang, C.; Jiao, N. Angew. Chem. Int. Ed. 2014, 53, 6528.
(b) Subramanian, P.; Indu, S.; Kaliappan, K. P. Org. Lett. 2014, 16,
6212.
Financial support from National Science Foundation of China (No.
21372188), Hunan Provincial Natural Science Foundation (14JJ6012),
and the State Key Laboratory of Natural and Biomimetic Drugs are
greatly appreciated.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590805.
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References and Notes
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Murakami, M.; Chatani, N., Eds.; Wiley-VCH: Weinheim, 2016.
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(a) Dermenci, A.; Coe, J. W.; Dong, G. Org. Chem. Front. 2014, 1,
567. (b) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114, 8613.
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organic Chemistry: A Biochemical Approach to Enzyme Action;
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

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Letter
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was stirred at 40 °C under air. When the reaction was complete
(TLC), the mixture was cooled to r.t., dried under vacuum, and
purified by column chromatography [silica gel, PE–EtOAc (5:1)]
1
to give a solid; yield: 74 mg (93%); mp 56–57 °C. H NMR (400
MHz, CDCl3): δ = 10.23 (s, 1 H), 7.81 (d, J =7.6 Hz, 1 H), 7.50 (t, J
= 7.4 Hz, 1 H), 7.44–7.36 (m, 2 H), 3.41 (t, J = 7.6 Hz, 2 H), 2.69 (t,
(12) 2-{3-Oxo-3-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]pro-
pyl}benzaldehyde (3aa); Typical Procedure
J = 7.6 Hz, 2 H), 1.72–1.35 (m, 6 H), 1.09 (s, 6 H), 0.95 (s, 6 H); 13
C
NMR (100 MHz, CDCl3): δ = 192.7, 172.3, 142.7, 133.8, 133.7,
133.6, 131.5, 127.0, 59.8, 38.8, 34.0, 31.8, 28.2, 20.4, 16.9.
(13) (a) Arora, P. K.; Sayre, L. M. Tetrahedron Lett. 1991, 32, 1007.
(b) Atlamsani, A.; Brégeault, J.-M. Synthesis 1993, 79. (c) Cossy,
J.; Belotti, D.; Bellosta, V.; Brocca, D. Tetrahedron Lett. 1994, 35,
6089.
A tube equipped with a condenser was successively charged
with 2-tetralone (1a, 0.5 mmol, 73.1 mg), TEMPO (2a, 0.25
mmol, 39.1 mg), CuCl2·2 H2O (0.025 mmol, 4.3 mg), 1,10-
phenanthroline monohydrate (0.05 mmol, 9.9 mg), aniline
(0.025 mmol, 2.3 mg, 2.3 μL), and MeCN (2 mL), and the mixture
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F