Metal-free, NHPI catalyzed oxidative cleavage of C-C double bond using molecular oxygen as oxidant

Article abstract of DOI:10.1021/ol3018215

A metal-free N-hydroxyphthalimide (NHPI) catalyzed aerobic oxidative cleavage of olefins has been developed. Molecular oxygen is used as the oxidant and reagent for this oxygenation reaction. This methodology has prevented the use of toxic metals or overstoichiometric amounts of traditional oxidants, showing good economical and environmental advantages. Based on the experimental observations, a plausible mechanism is proposed.

Full text of DOI:10.1021/ol3018215

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Metal-Free, NHPI Catalyzed Oxidative
Cleavage of CÀC Double Bond Using
Molecular Oxygen as Oxidant
000–000
†
Riyuan Lin, Feng Chen, and Ning Jiao*
†
,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking University,
School of Pharmaceutical Sciences, Peking University, Xue Yuan Road 38,
Beijing 100191, China, and State Key Laboratory of Organometallic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
jiaoning@bjmu.edu.cn
Received July 3, 2012
ABSTRACT
A metal-free N-hydroxyphthalimide (NHPI) catalyzed aerobic oxidative cleavage of olefins has been developed. Molecular oxygen is used as the
oxidant and reagent for this oxygenation reaction. This methodology has prevented the use of toxic metals or overstoichiometric amounts of
traditional oxidants, showing good economical and environmental advantages. Based on the experimental observations, a plausible mechanism
is proposed.
2
The oxidative cleavageofa CÀC double bond represents
1
chemistry. According to the literature, there are mainly
four kinds of methodologies for the oxygenation of olefins
Scheme 1): (1) Traditional methods carried out by
ozonolysis or using the LemieuxÀJohnson Protocol
3
(OsO followed by NaIO ), although their utility is often
a broad class of fundamental transformations in organic
4
4
limited by safety concerns; (2) Using transition metals as
10
4
5
6
7
8
catalysts, such as Mn, Mo, Ru, Pd, Re, Fe, Au,
9
1
Os, and Ce in combination with peroxides, peracids,
1
12
(
†
Peking University.
‡
(
5) Biradar, A. V.; Sathe, B. R.; Umbarkar, S. B.; Dongare, M. K.
J. Mol. Catal. A: Chem. 2008, 285, 111.
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Catal. Commun. 2007, 9, 416.
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Chinese Academy of Sciences.
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(
(
Organic Compounds; Academic Press: New York, 1981. (b) Stewart, R.
Oxidation in Organic Chemistry; Wiberg, K., Ed.; Academic Press: New
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Chemical Society Monograph 186; American Chemical Society: Washington
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(
(
(
2
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(
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(
1
4
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1
0.1021/ol3018215 r XXXX American Chemical Society

and other oxidizing reagents; (3) Nonmetal reactions that
The R-methylstyrene (1a) was first investigated using
NHPI as the catalyst, which has attracted much attention
1
include using equivalent oxidants, such as mCPBA,
3
3
19,20
PCC, and the recently developed aryl-γ -iodane-based
for aerobic oxidation in recent years.
To our surprise,
1
4
methods for CÀC double bond cleavage; (4) Through
R-methylstyrene (1a) could be converted to acetophenone
(2a) in 58% yield by only using 20 mol % NHPI in MeCN
under anO atmosphere, without any other additives. Sub-
photochemical methods, which need additional photosen-
1
5
sitizers and special implements. Despite great progress
having been made in the field of olefin oxidative cleavage,
these processes generally suffer from safety concerns, the
use of expensive and toxic metals, or the use of over-
stoichiometric amounts of oxidants, which also have high
expenses and would produce a large amount of byproduct.
Therefore, development of a safe and metal-free method is
still desirable for these synthetic transformations.
2
sequently, various parameters were screened to improve
the reaction efficiency (Table 1). The experiments showed
that the solvent (entries 1À9, Table 1) had great influence on
the reaction yield and DMA (N,N-dimethylacetamide)
was proven to be the most suitable candidate for this
transformation (80% yield, entry 5, Table 1). As previous
2
1
literature revealed, NHPI had very low solubility in a
nonpolar organic medium, and this is consistent with
our experiment results: a polar solvent generally provided
better results (see Supporting Information (SI)). Then
In contrast, on behalf of green and sustainable chemis-
try, molecular oxygen is considered as an ideal oxidant due
to its natural, inexpensive, and environmentally friendly
characteristics and, therefore, offers attractive academic
1
6
and industrial prospects. However, the oxygenation meth-
ods using O as the oxidant are limited by high oxygen
a
2
Table 1. Oxidative Cleavage of R-Methylstyrene (1a)
17a
17b
pressure or low yields. Based on our previous work
related to dioxygen activation and using molecular oxygen as
18
the terminal oxidant, we also think about using the molec-
ular oxygen as the oxidant for the cleavage of olefins. Herein,
we report a facile and operationally convenient oxygenation
for the oxidative cleavage of olefins catalyzed by NHPI
catalyst
(mol %)
metal salt
(5 mol %)
yield
(
N-hydroxyphthalimide) with O as the oxidant and reagent.
2
b
entry
solvent
MeCN
(%)
1
2
3
4
5
6
7
8
9
NHPI (20)
À
À
À
À
À
À
À
À
À
À
À
À
À
58
NHPI (20)
NHPI (20)
NHPI (20)
NHPI (20)
NHPI (20)
NHPI (20)
NHPI (20)
NHPI (20)
NHPI (10)
NAPI (10)
Tempo (20)
4-MeOTempo (20)
NHPI (10)
NHPI (10)
NHPI (10)
NHPI (10)
NHPI (10)
NHPI (10)
toluene 25
Scheme 1. Traditional Methods for Cleavage of Alkenes
HOAc
EA
61
58
DMA
DME
PhCN
EtOH
DMF
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
80
62
<10
28
<10
80
68
1
0
c
11
12
13
14
15
16
17
18
19
trace
trace
55
FeCI
CoCI
2
2
79
CuBr
14
Mn(OAc)
2
3 2H2
O
25
d
e
À
À
29
trace
a
Reaction conditions: 1a (0.2 mmol), catalyst (10À20 mol %), and
solvent (1 mL) reacted at 80 °C under an O (1 atm) atmosphere for 24 h.
GC yield using n-dodecane as an internal standard. NAPI: N-acetyl-
2
b
c
d
e
phthalimide. Under an air atmosphere. Under an Ar atmosphere.
(14) (a) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,
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Chem. Soc. 2009, 131, 1382. (c) Thottumkara, P. P.; Vinod, T. K. Org.
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(
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(
(
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(
3
Velusamy, S.; Iqbal, J. Chem. Rev. 2005, 105, 2329. (d) Muzart, J. Chem.
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B
Org. Lett., Vol. XX, No. XX, XXXX

the catalyst loading was decreased from 20 to 10 mol %, and
a comparable reaction efficiency was shown (entry 10,
a
17b
Table 2. Oxidative Cleavage of Substituted Styrenes
Table 1). Compared with the previous result
Hayashi’s group which used molecular oxygen and gave
1% 2a, we achieved a higher yield (80%, entry 10) by this
from
4
present NHPI catalysis. A lower yield of 2a was obtained
when an analogue of NHPI, NAPI (N-acetylphthalimide),
was used (entry 11, Table 1). The other commonly used O
1
2
3
b
2
entry
R
R
R
yield (%)
2
2
activators, such as Tempo and 4-MeOTempo, just gave
trace results (entries 12À13, Table 1). According to litera-
ture, plenty of NHPI catalytic systems were coupled with
1
2
3
4
5
C
6
H
5
CH
CH
3
H
2a (80)
2b (85)
2c (52)
2d (75)
2e (57)
2f (60)
4-FC
6
H
5
3
H
H
H
H
H
H
H
H
H
H
H
H
H
4-CH C H
3
6
5
CH3
1
9
metals, such as the well-known “Ishii catalytic system”.
1-naphthyl
CH
CH
3
C
C
C
C
C
C
H
6 5
H
6 5
H
6 5
H
6 5
H
6 5
H
6 5
5
5
5
2
CH
3
In order to confirm whether an ultratrace amount of metal
has an effect on our catalytic system, several commonly
used metals were added, but the reaction did not proceed
c
6
e
(CH
(CH
2
)
)
3
CH
CH
3
d
7
2
8
3
2g (48)
d
8
C
6
H
5
2h (74)
well except for the CoCl , which gave similar results
2
d
9
4-CH
2-CH
3
C
6
H
5
2i (67)
(
entries 14À17, Table 1). These results might exclude
f
d
10
3
C
6
H
5
2j (36)
g
d
the effect of metal. When the reaction was carried out
under air or an Ar atmosphere, the reaction yield was
dramatically reduced, which addressed the importance of
11
12
C H
4-CH OC H
5
2k (74)
6
3
6
d
C
C
6
H
H
4-FC
6
H
5
2l (78)
d
13
14
15
6
2-Thienyl
2m (40)
2n (26)
2n (40)
e
4-CH
4-CH
3
OC
OC
6
H
H
5
H
H
O (entries 18À19, Table 1).
2
g
3
6
5
CH
3
A range of substrates were investigated as listed in
Table 2. When R-alkyl aryl ethylenes were used as substrates,
the reactions ran smoothly, and corresponding products
were produced in moderate to good yields. With either
electron-donating or -withdrawing groups at the para
a
Reaction conditions: 1 (0.2 mmol), NHPI (10 mol %), and DMA
(1 mL) reacted at 80 °C under an O
n-dodecane as an internal standard. NHPI (20 mol %); temperature:
100 °C. Isolated yields. 1 (0.5 mmol), NHPI (10 mol %), acetone
oxime (10 mol %), and DMA (0.5 mL). Isolated as a mixture, phenyl
(o-tolyl)methanone/2-phenyl-2-(o-tolyl)oxirane = 3:2.43. For the mechanism,
see Supporting Information. 1(0.5 mmol), NHPI (20 mol %), acetone oxime
10 mol %), and DMA (0.5 mL).
b
2
(1 atm) atmosphere. GC yield using
c
d
e
f
1
position of the aryl group R , oxidative reactions ran
g
efficiently (entries 1À3, Table 2). The reaction was slower
with substrates bearing substituted groups at the ortho
position of the phenyl group and the reaction yield also
decreased (cf. entries 9 and 10, Table 2), and when 1-methyl-
(
could promote the generation of the PINO radical fron
2
0b
NHPI, although in moderate yield (entry 15, Table 2).
To shed light on the mechanism of the above reactions,
we designed the following experiments (eqs 6 and 7). The
reaction was carried out with 2-methyl-2-phenyloxirane
2
-(prop-1-en-2-yl)benzene was used as the substrate, the
reaction yield was <10%. These results indicated that steric
hindrance plays a significant role in affecting the efficiency
2
of oxidation. When the alkyl group of R was prolonged, we
were pleased to find that the desired product even with a
nonyl group could also be obtained in moderate yield (entry
2
3
3a, which was prepared from R-methyl styrene 1a.
However, only 23% of acetophenone 2a was observed.
7, Table 2). The reactivity of substituted geminal biaryl
ethylenes was also demonstrated, and they were smoothly
cleaved to the corresponding biaryl methanone (entries
8
À13, Table 2). A heteroaryl group was compatible in this
catalytic system as well (entry 13, Table 2). Substituted
styrene was converted into the benzaldehyde in low yield
(
entry 14, Table 2); it seems that the styrene would aggregate
in this catalytic system. And the 1,2-substituted alkene could
also be converted into the corresponding aldehyde 2n (40%,
entry 15) in the presence of acetone oxime (10 mol %) which
(20) For some recently published NHPI catalyzed reactions:
a) Nechab, M.; Kumar, D. N.; Philouze, C.; Einhorn, C.; Einhorn, J.
(
Angew. Chem., Int. Ed. 2007, 46, 3080. (b) Zheng, G.; Liu, C.; Wang, Q.;
Wang, M.; Yang, G. Adv. Synth. Catal. 2009, 351, 2638. (c) Nakamura,
R.; Obora, Y.; Ishii, Y. Adv. Synth. Catal. 2009, 351, 1677. (d) Wu, W.;
Xu, J.; Huang, S.; Su, W. Chem. Commun. 2011, 47, 9660. (e) Aguadero,
A.; Falcon, H.; Campos-Martin, J. M.; Al-Zahrani, S. M.; Fierro,
J. L. G.; Alonso, J. A. Angew. Chem., Int. Ed. 2011, 50, 6557. (f) Melone,
L.; Gambarotti, C.; Prosperini, S.; Pastori, N.; Recupero, F.; Punta, C.
Adv. Synth. Catal. 2011, 353, 147. (g) Zhang, Q.; Chen, C.; Xu, J.; Wang,
F.; Gao, J.; Xia, C. Adv. Synth. Catal. 2011, 353, 226.
(
(
21) Taha, N.; Sasson, Y. Org. Process Res. Dev. 2010, 14, 701.
22) (a) Vogler, T.; Studer, A. Synthesis 2008, 13, 1979. (b) Tebben,
(23) Robinson, M. W. C.; Pillinger, K. S.; Mabbett, I.; Timms, D. A.;
Graham, A. E. Tetrahedron 2010, 66, 8377.
L.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 5034.
Org. Lett., Vol. XX, No. XX, XXXX
C

PINO radical A is initially generated from NHPI
2
5b
through homolysis.
Then the PINO radical A will
Scheme 2. Proposed Mechanism for Cleavage of Alkenes
add electrophilically to the CÀC double bond to gen-
9
d
erate a carbon radical B, which could be further
trapped by molecular oxygen to give a peroxyl radical
C. Subsequently, dioxetane intermediate D is pro-
duced with the formation of PINO radical A to com-
plete the catalytic circle. The dioxetane D readily
cleaves thermally into the corresponding carbonyl
2
5a
products.
In summary, we have developed a facile and operation-
ally convenient method for the oxidative cleavage of
alkenes. Molecular oxygen is used as the oxidant and
reagent for this oxygenation reaction employing NHPI
as the catalyst. This methodology has prevented the use of
toxic metals or overstoichiometric amounts oxidants,
showing good economical and environmental advantages.
Further studies to probe the mechanism of these transfor-
mations, and the application of this reaction, are ongoing
in our laboratory.
This result indicates the epoxide might not be the inter-
mediate of this transformation. We also found that this
oxidation was completely inhibited by BHT (2,6-di-tert-
2
4
butyl-4-methylphenol) (eq 7), which was a traditional
radical scavenger, and this might suggest a radical initia-
Acknowledgment. Financial support from National Basic
Research Program of China (973 Program 2009CB825300),
National Science Foundation of China (No. 21172006), and
Peking University are greatly appreciated. We also thank
Yuepeng Yan in this group for reproducing the results of 2g
and 2h.
1
8
tion pathway. Furthermore, we designed two O labeled
1
experiments and the reaction of 1h in the presence of O2
8
1
1 atm) generated the O labeled product O-2 h in 72%
8
18
(
yield (eqs 8 and 9). This result shows that the oxygen atom
originated from molecular dioxygen.
9d,25
On the basis of the above results and previous studies,
the mechanism of this transformation is proposed (Scheme 2).
Supporting Information Available. Experimental pro-
cedures, characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
(
24) Xie, J.; Jiang, H.; Cheng, Y.; Zhu, C. Chem. Commun. 2012, 979.
25) (a) Frimer, A. A. Chem. Rev. 1979, 79, 359. (b) Ishii, Y.; Kato, S.;
Iwahama, T.; Sakaguchi, S. Tetrahedron Lett. 1996, 37, 4993.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX