Application of the Cu(i)/TEMPO/O2 catalytic system for aerobic oxidative dehydrogenative aromatization of pyrrolidines

Article abstract of DOI:10.1039/c9gc01932d

A Cu(i)/TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)-catalyzed aerobic oxidative dehydrogenative aromatization reaction of fully saturated pyrrolidines to synthesize multi-substituted pyrroles was developed for the first time. The use of a non-precious metal catalyst, green oxidant and environmentally friendly solvent made the reaction more sustainable.

Full text of DOI:10.1039/c9gc01932d

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DOI: 10.1039/C9GC01932D
COMMUNICATION
Application of Cu(I)/TEMPO/O2 Catalytic System for Aerobic
Oxidative Dehydrogenative Aromatization of Pyrrolidines
Zheng Luo,a,b Yan Liu,a,b Chao Wang,a Danjun Fang,c Junyu Zhouc and Huayou Hu*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
a) Catalytic aerobic oxidative dehydrogenation aromatization of cyclohexanones or clclohexenes
A
Cu(I)/TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy)-catalyzed
O
OH
aerobic oxidative dehydrogenative aromatization reaction of fully
saturated pyrrolidines to synthesize multi-substituted pyrroles
was developed for the first time. The use of non-precious metal
catalyst, green oxidant and environmentally friendly solvent made
the reaction more sustainable.
Pd cat.
O2
or
or
R
R
R
R
b) Catalytic aerobic oxidative dehydrogenation aromatization of six-membered N-heterocycles
H
Z
Y
Various catalysts
O2
Z
Y
R2
R1
H
R2
R1
X
H
X
Oxidative dehydrogenative aromatization protocols which could
synthesize aromatic compounds from saturated cyclic compounds,
have long attracted considerable attention from synthetic chemists
because of high atom economy.1 However, harsh reaction
conditions or stoichiometric toxic oxidants are typically required in
those protocols, which result in high cost and environmental
pollution. Using cheap and readily available oxygen gas as the
oxidant make oxidative dehydrogenative aromatization reactions
more economical and environmentally friendly because water is the
only by-product. In 2011, Stahl and co-workers reported a
palladium catalyzed aerobic oxidative dehydrogenation reaction of
cyclohexanone derivatives to produce phenols (Scheme 1a).2a
Modified protocols successfully prepared poly-substituted aromatic
rings from cyclohexanone and cyclohexene derivatives by the same
group.2 In addition, transition metal catalyzed aerobic oxidative
dehydrogenative aromatization reaction of several partially
saturated N-heterocycles, including six-membered N-heterocycles3
(Scheme 1b) and five-membered N-heterocycles4 (Scheme 1c) also
had been reported. However, no effective methods for transition
metal catalyzed aerobic oxidative dehydrogenative aromatization
reactions of fully saturated cyclohexane derivatives or heterocycles
under mild conditions emerged. These results may due to the fact
that such reactions were both kinetic and thermodynamically
unfavourable under conventional conditions.
X, Y, Z = N or CR
c) Catalytic aerobic oxidative dehydrogenation aromatization of five-membered N-heterocycles
R2
R2
R
R
N
N
N
N
R3
R3
R1
R1
or
Various catalysts
O2
or
HN
HN
N
N
R
R
Scheme 1 Reported methods for transition metal catalyzed aerobic oxidative
dehydrogenation aromatization of partially saturated cyclic compounds.
Pyrroles are an important class of compounds that display a
variety of biological activities, including anti-mycobacterial, anti-
tumor, anti-fungal, anti-inflammatory, anti-tubercular and anti-HIV
activity.5 Many synthetic drugs, materials and dyes contain pyrrole
units.6 Therefore, the synthesis of pyrroles has long drawn much
attention from synthetic chemists.7 Stoichiometric amounts of 4,5-
dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (DDQ), o-
iodoxybenzoic acid (IBX), manganese dioxide and benzoyl peroxide
(BPO) have been reported to promote non-catalytic oxidative
dehydrogenative aromatization of pyrrolidines (Scheme 2a).8
However, those oxidants are often expensive or toxic, and the
formation of stoichiometric amounts of by-products in the reaction
limited their use. Although Rueping and co-workers reported a
photo-redox dehydrogenative aromatization-sulfonylation reaction
of pyrrolidines in 2018 (Scheme 2b),9 the development of low-cost
transition metal catalyzed aerobic oxidative dehydrogenative
aromatization reactions of pyrrolidines is still remain challenge.
Cu(I)/nitroxyl/O2 catalytic systems have emerged as the most
versatile method to oxidize alcohols and amines.10 However, to the
best of our knowledge, it has never been used in oxidative
dehydrogenative aromatization reaction of fully saturated cyclic
a. School of Material Science and Engineering, Southwest University of Science and
Technology, Mianyang 621010, P. R. China.
b. Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of
Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian 223300,
P. R. China.
c. Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu
210029, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
compounds. Herein, we developed
a CuCl/TEMPO (2,2,6,6-
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Green Chemistry
Page 2 of 5
COMMUNICATION
Journal Name
Co-catalyst (mol
%)
tetramethyl-1-piperidinyloxy)
dehydrogenative aromatization reaction of pyrrolidines (Scheme
2c).
catalyzed
aerobic
oxidative
Entry Cu salt (mol %)
Solvent ViewYAiertlidcle(%O)naline
DOI: 10.1039/C9GC01932D
Other metal
1 b
TEMPO (10)
DMC
24-37
salts (10)
2
3
4
5
6
CuCl (10)
CuCl (10)
-
CuCl (10)
CuCl (10)
TEMPO (10)
-
TEMPO (10)
4-OH-TEMPO (10)
4-NHAc-TEMPO
DMC
DMC
DMC
DMC
DMC
Other
solvents
DMC
DMC
DMC
DMC
DMC
40
0
trace
17
a) Stoichiometric oxidative dehydrogenative aromatization
R
R
Stoichiometric amount
DDQ, IBX, MnO2, BPO
N
N
23
H
H
7 c
CuCl (10)
TEMPO (10)
trace-27
b) Photo-redox dehydrogenative aromatization-sulfonylation
O
O
8
9
10
11 d
12 e
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
TEMPO (20)
TEMPO (30)
TEMPO (50)
TEMPO (30)
TEMPO (30)
64
68
44
O
S
O
Ir cat., hv
R1
S
N
R
Cl
R1
base, additives
2-methylbutyronitrile
77
N
81 (76 f)
R
R = alkyl, benzyl
Reaction conditions: 10 % of metal salt and TEMPO derivatives as the catalyst, 0.2
mmol 1a, 2 mL solvent, were stirred under O2 (balloon) at 80 oC for 19h. a Yields
were determined by 1H NMR using CH2Br2 as an internal standard. b Details in SI. c
Including EtOH, MeCN, EtOAc and toluene. 1.0 mL solvent. 0.3 mmol of 1a in
1.0 mL solvent. f Isolated yield.
c) This work
R2
R3
R2
R3
CuCl/TEMPO cat.
d
e
air or O2 gas
dimethyl carbonate
R1
CO2R
R1
CO2R
N
N
H
H
With the optimized conditions established, we studied the scope
of pyrrolidines (Scheme 3). When the phenyl ring at the 5-position
was substituted with electron-withdrawing groups (1b–1e), the
corresponding pyrroles were isolated in good to excellent yields
(74%–99%). Pyrrolidine substituted with 2-naphthyl at the 5-
position also worked well and provided 2f in 87% yield. When
strong electron-donating groups were substituted on phenyl ring at
the 5-position (1h–1j), the corresponding pyrroles were isolated in
lower yields (48%–50%). These results may be because the
electron-rich benzylic position was unstable under the copper
catalytic aerobic oxidation process.11 Further optimization of the
reaction conditions revealed that under a milder condition
(condition B: increased the amount of CuCl to 20 mol % and
replaced O2 with air, for details of optimization see the Supporting
Information Table S2), the yields of the corresponding pyrroles (2h–
2j) were significantly increased (64%–81%). Heterocycles, including
pyridyl (1l), thienyl (1m) and N-Boc piperidinyl (1n) substituted at 5-
position, were also tolerated and gave the corresponding products
in good yield (77%–83%). Pyrrolidine substituted with an electron-
rich furanyl (1k) gave pyrrole in 50% yield under condition A and
59% yield under the milder reaction condition B. Alkyl was also
tolerated, the corresponding product (2o) was isolated in 84% yield.
Surprisingly, when pyrrolidine was substituted with 3-cyclohexenyl
at the 5-position, the corresponding pyrrole (2p) was afforded in
71% yield, and the double bond was unaffected under copper
catalyzed aerobic oxidation conditions.
* No base and additives
Scheme 2 Our and reported methods for oxidative dehydrogenative aromatization of
pyrrolidines.
Trimethyl 5-phenylpyrrolidine-2,3,4-tricarboxylate (1a) under O2
atmosphere (balloon) was used to optimize the reaction conditions.
First, several metal salts were investigated by using TEMPO as the
co-catalyst and dimethyl carbonate (DMC) as the solvent at 80 °C
(Table 1, entry 1–2). Successfully, trimethyl 5-phenyl-1H-pyrrole-
2,3,4-tricarboxylate (2a) was produced in 40% yield with CuCl as the
catalyst. Both CuCl and TEMPO were essential to this reaction
(entry 3–4). Several TEMPO derivatives were proven as less efficient
than TEMPO (entry 5–6). DMC was proved to be the best solvent
(entry 2 and 7). We then optimized the amount of TEMPO (entry 8–
10). When the catalyst loading of TEMPO was increased to 30 mol
%, the yield of 2a increased to 68% (entry 9). However, increasing
the TEMPO loading to 50 mol % reduced the yield of 2a to 44%
(entry 10). Increasing the reaction concentration to 0.2 M and 0.3
M resulted in an increased product yield of 77% and 81%,
respectively (entry 11–12). The optimized reaction conditions were
established as: 0.30 mmol 1a as the starting material, 0.03 mmol
CuCl as the catalyst, 0.09 mmol TEMPO as the co-catalyst and 1.0
mL DMC as solvent at 80 °C for 19h under an O2 atmosphere. 2a
was isolated in 76% yield under these standard reaction conditions
(entry 12, condition A).
Table 1 Optimization of reaction conditions
CO2Me
MeO2C
CO2Me
MeO2C
Cu salt, cocatalyst
℃
Solvent (2 mL), O2, 80 , 19h
CO2Me
CO2Me
N
H
N
H
2a
1a
, 0.2 mmol
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Green Chemistry
Journal Name
COMMUNICATION
R2
CO2Me
CO2Me
CO2Me
CO2Me
R1
R2
MeO2C
MeO2C
R1
View Article Online
Cu/TEMPO Cat.
Cu/TEMPO cat.
DOI: 10.1039/C9GC01932D
DMC 1 mL, 80 oC, 19h
CO2R
N
R
R
CO2R
N
N
H
DMC 1 mL, 80 oC, 19h
N
H
R3
R3
2
2 or 4
1, 0.3 mmol
CO2Me
1 or 3, 0.3 mmol
BuO2C
EtO2C
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
MeO2C
CO2Me
N
CO2Me
CO2Me
N
H
CO2Me
MeO2C
CO2Me
CO2Me
N
H
H
N
H
N
N
H
H
2r, 76% b
2s, 69% b
F
2q, 68% b
O2N
2b, 87% a
2d, 74% a
2c, 99% a
Cl
CO2Me
CO2Me
HN
CO2Me
MeO2C
MeO2C
MeO2C
N
NC
O
O
CO2Me
CO2Me
CO2Me
N
H
N
H
N
CO2Me
N
H
CO2Me
Br
N
H
CO2Me
H
N
2e, 83% a
2f, 87% a
CO2Me
MeO2C
H
2g, 78% a
2v, 70% b
2u, 59% b
CO2Me
2t, 60% b
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Bu
BuO2C
CO2Me
MeO2C
CO2Me
CO2Me
N
CO2Me
MeO
N
H
N
H
H
MeO
CO2tBu
OMe
2j, 50% a (64% b
CO2Me
N
CO2Et
OMe
2h, 48% a (79% b
N
N
H
MeO
H
2i, 49% a (81% b
)
H
)
)
2w, 75% a
CO2Me
CO2Me
2x, 75% a
MeO2C
2y, 76% a
CO2Me
MeO2C
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
MeO2C
N
N
N
H
H
H
O
S
N
CN
CO2Me
CO2Me
2l, 83% a
2m, 77% a
CO2Me
N
H
2k, 50% a (59% b
)
N
N
Br
Bu
Ts
2z, 30% a
MeO2C
CO2Me
4b, 0% a, d
CO2Me
MeO2C
MeO2C
4a, 25% a, c
Isolated yield. a Condition A: CuCl 10%, TEMPO 30%, O2.
.
b Condition B: CuCl 20%,TEMPO 30%, air.
CO2Me
CO2Me
c 3a was recovered in 28% yield. d 3b was recovered in 98% yield.
CO2Me
N
N
H
N
H
N
H
Boc
2n, 77% a
2p, 71% a
2o, 84% a
Scheme 4 Substrate scope of pyrrolidines.
Isolated yield. a Condition A: CuCl 10%, TEMPO 30%, O2.
.
b Condition B: CuCl 20%,TEMPO 30%, air.
To demonstrate the practicality of the reaction, we successfully
increased the reaction scale to gram-scale (Scheme 5a). Under
condition A, 1.18 grams of 2a was isolated, and the yield was
Scheme 3 Substrate scope with different groups at 5-position of pyrrolidines.
We then studied the substrate scope with different groups at comparable to yields from the small scale reactions. A successful
other positions on pyrrolidine (Scheme 4). First, pyrrolidines with one-pot method for the synthesis of pyrroles from Schiff bases and
different groups at the 4-position, which include acrylates, electron deficient alkenes was designed by combining our method
acrylamides and acrylonitrile (1q–1v), did not react well under the with a previously reported 1,3-dipolar cycloaddition reaction
optimized reaction condition A. The corresponding pyrroles, (Scheme 5b).8i Pyrrole 3b was isolated in 73% yield, which provides
however, were produced smoothly under reaction condition B and a highly efficient method from simple and readily available starting
isolated in yields from 59% to 76%. Notably, compared with N,N- materials to prepare multi-substituted pyrroles.
dimethyl acrylamide (1t), no declined yield was observed when
CO2Me
CO2Me
MeO2
C
MeO2C
using N-(4-chlorophenyl)acrylamide (1u) as the starting material.
When the methyl group at the 2-position was replaced by ethyl (1x)
or steric tert-butyl (1y) groups, the yields of the corresponding
pyrroles were unaffected. When methyl ester was replaced by a
cyano group, the yield of 2z dropped to 30%. The p-toluenesulfonyl
protected pyrrolidine (3b) did not react under standard reaction
conditions, but N-Bu pyrrolidine (3a) could produce corresponding
pyrrole (4a) in 25% yield with 28% recovered 3a under condition A.
CuCl (10 mol %), TEMPO (30 mol %)
DMC (16.7 mL), O2, 80 oC, 19h
CO2Me
CO2Me
a)
N
N
H
H
1a, 5.0 mmol
2a, 1.18 g (74%)
1. AgOAc (10 mol %),
LiOH (18 mol %) cat,
0.5 mL DMC, 40 oC, 24h
CO2Me
MeO2
C
CO2Me
N
CO2Me
b)
CO2Me
N
CO2Me
6, 0.3 mmol
F
2. CuCl (10 mol %),
TEMPO (30 mol %),
0.5 mL DMC, 80 oC,
O2, 19h
H
F
5, 0.36 mmol
2b, 73.5 mg (73 %)
Sheme 5 Gram-scale reaction and one-pot reaction for synthesis of pyrroles.
To reveal the reaction mechanism,
a series of control
experiments were conducted. 5.0 equivalent copper acetate
monohydrate, TEMPO and 2.5 equivalent 2,2,6,6-tetramethyl-1-
- 12
oxopiperidin-1-ium fluoroborate (TEMPO+BF4 ) were reacted with
1a under argon atmosphere respectively. Pyrrole 2a was isolated in
14% yield and no 1a was recovered using copper acetate as the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Green Chemistry
Page 4 of 5
COMMUNICATION
Journal Name
oxygen as the oxidant and green solventsViemw Aardticele Otnhlinies
oxidant (Scheme 6a). Pyrrole 2a was isolated in 46% yield and 1a
was recovered in 26% yield using TEMPO as the oxidant (Scheme
6b). Pyrrole 2a was isolated in 95% yield and no 1a was recovered
transformation environmentally friendly.
DOI: 10.1039/C9GC01932D
-
using TEMPO+BF4 as the oxidant (Scheme 6c).
Conflicts of interest
There are no conflicts to declare.
MeO2C
Ph
CO2Me
CO2Me
MeO2C
Ph
CO2Me
CO2Me
Cu(OAc)2.H2O (5.0 equiv)
DMC (1 mL), Ar, 80 oC, 19h
N
a)
b)
c)
N
H
H
1a, 0.30 mmol
2a, 14%
Acknowledgements
We gratefully acknowledged Jiangsu Province (No.
BK20161307 and “333” Talents Project for H. Hu) and Huaiyin
Normal University (No. JSKC18014) for their financial support.
MeO2C
CO2Me
CO2Me
MeO2C
CO2Me
CO2Me
2a, 46%
MeO2C
Ph
CO2Me
TEMPO (5.0 equiv)
DMC (1 mL), Ar, 80 oC, 19h
+
Ph
Ph
N
CO2Me
N
N
H
H
H
1a, 26%
1a, 0.30 mmol
MeO2C CO2Me
Ph CO2Me
1a, 0.30 mmol
MeO2C
CO2Me
CO2Me
2a, 95%
TEMPO+ BF4- (2.5 equiv)
DMC (1 mL), Ar, 80 oC, 19h
N+
Ph
-
N
N
BF4
H
O
H
TEMPO+ BF4
Notes and references
1
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V. Iosub, S. S. Stahl, ACS Catal., 2016, 6, 8201. (c) T. Diao, D.
Pun, S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 8205. (d) D.
Pun, T. Diao, S. S. Stahl, J. Am. Chem. Soc., 2013, 135, 8213.
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Scheme 6 The control experiments.
Base on above results and previous results, 2,2,6,6-tetramethyl-
1-oxopiperidin-1-ium (TEMPO+) was proven to be an active oxidant
and the copper catalyst could help to regenerate the oxidant under
oxygen gas. Therefore, the suggested mechanism was show in
scheme 7. First, TEMPO was going disproportionation to generate
TEMPOH (2,2,6,6-tetramethylpiperidin-1-ol) and TEMPO+.13 Then,
pyrrolidines was oxidized by TEMPO+ to form imine intermediate
(5).14 Next, intermediate 5 was oxidized by copper(II), TEMPO+ or
oxygen gas to form pyrrole product. Copper(I) was oxidized by
oxygen gas to generate copper(II). At last, copper(II) reacted with
TEMPOH to regenerate TEMPO and copper(I).
2
3
+
H+
+
N+
N
N
OH
O
O
TEMPO+
TEMPO
TEMPOH
R2
R3
R2
R3
TEMPO+
4
5
R1
CO2R
R1
CO2R
- TEMPOH, H+
N
N
H
5
1
R2
R3
CO2R
R2
R3
CO2R
Cu(II), TEMPO+ or O2
R1
R1
N
H
N
5
2
O2
Cu(II)
+
Cu(I)
Cu(II)
+
Cu(I)
N
O
N
OH
Scheme 7 Plausible mechanism.
Conclusions
In summary, a Cu(I)/TEMPO catalyzed aerobic oxidative
dehydrogenative aromatization reaction to synthesize multi-
substituted pyrroles from pyrrolidines has been developed.
This reaction tolerated functional groups well and was easy to
conduct at gram scale. Using cheap and readily available
4 | J. Name., 2012, 00, 1-3
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Green Chemistry
Journal Name
COMMUNICATION
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