Room-temperature direct alkenylation of 3-arylsydnones

Article abstract of DOI:10.1002/ejoc.201403211

A new efficient method for the direct alkenylation of 3-arylsydnones by palladium-catalyzed C-H functionalization was developed. The reaction proceeded smoothly at room temperature and delivered the product in yields up to 83%.

Full text of DOI:10.1002/ejoc.201403211

Job/Unit: O43211
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Date: 04-11-14 15:38:08
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403211
Room-Temperature Direct Alkenylation of 3-Arylsydnones
Yiwen Yang*[a] and Chunxiang Kuang*[b]
Keywords: Synthetic methods / C–H activation / Alkenylation / Nitrogen heterocycles / Palladium
A new efficient method for the direct alkenylation of 3-aryl-
sydnones by palladium-catalyzed C–H functionalization was
developed. The reaction proceeded smoothly at room tem-
perature and delivered the product in yields up to 83%.
which leads to low atom economy of these transformations.
The direct alkenylation of 3-arylsydnones by alkenes offers
a cleaner and more efficient method of meeting such goals;
no example of such a transformation has been reported.
Considering the great medicinal significance and applica-
tions of sydnones and inspired by the oxidative Heck-type
reaction, we became interested in the use of new methods
for the direct alkenylation of sydnones under mild and op-
erationally simple conditions.
In this paper, we report a new and convenient method
for the oxidative coupling of 3-arylsydnones with alkenes
through Pd-catalyzed C–H bond functionalization. The di-
rect alkenylation of 3-arylsydnones at room temperature by
the oxidative Heck-type reaction is exploited (Scheme 1).
Introduction
In recent years, transition-metal-catalyzed C–H bond ac-
tivation reactions have gained interest from academic and
industrial chemists,[1] because they can significantly simplify
and shorten a synthetic route and because they allow the
utilization of affordable, readily available starting materials.
The Pd-catalyzed direct cross-coupling of arenes and ole-
fins, also called the oxidative Heck-type reaction or the Fu-
jiwara–Moritani reaction,[2] is a representative of such reac-
tions. The transformation has high atom economy because
the formation of a C–C bond occurs from two C–H bonds.
However, previous reports on these reactions indicated that
the processes often require the use of elevated temperatures
(80 to 180 °C),[3] which severely limits the compatibility of
the substrates and their large-scale applications. Developing
milder reaction conditions that can proceed at ambient tem-
perature is necessary in widening the applicability of these
transformations.
Sydnones are unique, dipolar, five-membered heterocy-
cles that are part of an intriguing family of mesoionic com-
pounds.[4] Over the years, sydnones have gained significant
interest because of their biological value as antibacterial,[5]
antiinflammatory,[6] antimalarial,[7] analgesic, antipyretic,[8]
and antineoplastic[9] agents, in addition to their potential
use as therapeutic agents,[9] liquid crystals,[10] and electro-
lytic solvents.[11] Previous research on the olefination of syd-
nones focused on the use of sydnones (or 4-halosydnones)
and alkenyl halides (or alkenyl boronic acids) as the starting
materials;[12] these processes often need preformation of the
alkenyl halide, alkenyl boronic acid, or 4-halosydnone,
Scheme 1. Direct alkenylation of 3-arylsydnones.
Results and Discussion
To confirm the optimum reaction conditions, we selected
the reaction of 3-p-tolylsydnone (1a) with styrene (2a) as a
model reaction and conducted the experiment under vari-
ous reaction conditions. Table 1 shows that upon treating
1a with 2a (2.0 equiv.) in the presence of Pd(OAc)2 (10 mol-
%) and K2S2O8 (2.0 equiv.) in 1,2-dichloroethane (DCE) at
25 °C for 24 h, product 3a was isolated in 35% yield
(Table 1, entry 1). If the temperature was increased to 60,
90, and 120 °C, the yield decreased to 30, 32, and 28%,
respectively (Table 1, entries 2–4). Different solvents were
examined. If the DCE solvent was replaced by dichloro-
methane, ethoxyethane, acetone, or acetonitrile, product 3a
was obtained in 42, 33, 37, or 15% yield, respectively
(Table 1, entries 5–8). Various oxidants were studied. Upon
using O2 (101.3 kPa), Cu(OAc)2, benzoquinone (BQ), or no
oxidant, the yield of product 3a was 26, 24, 27, or 20%,
[a] Department College of Biological, Chemical Sciences and
Engineering, Jiaxing University,
118 Jiahang Road, Jiaxing 314001, P. R. China
E-mail: yangyiwen@mail.zjxu.edu.cn
http://cbcse.zjxu.edu.cn/home/article/article/id/144/model/
teachers
[b] Department of Chemistry, Tongji University,
1239 Siping Road, Shanghai 200092, China
E-mail: kuangcx@tongji.edu.cn
http://chemweb.tongji.edu.cn/Teachers/Details/a1a31ffb-88aa-
4733-8fa5-8db01611b440
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403211.
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Y. Yang, C. Kuang
SHORT COMMUNICATION
respectively (Table 1, entries 9–12). Surprisingly, if Ag2CO3 Table 2. Direct alkenylation of 3-p-tolylsydnone with various alk-
enes.[a]
or AgOAc was used as the oxidant, product 3a was ob-
tained in 76 or 81% yield, respectively (Table 1, entries 13
and 14). Upon reducing the dosage of Pd(OAc)2 to 0.05 and
0.02 equiv., the yields decreased to 65 and 52% (Table 1,
entries 15 and 16). The effects of different catalysts on the
formation of 3a were also remarkable. Upon using CuI,
Cu(OAc)2, or FeCl3 as the catalyst, product 3a was not ob-
tained (Table 1, entries 17–19). Ultimately, the optimized re-
action conditions were determined to include Pd(OAc)2
(0.1 equiv.) as the catalyst and AgOAc (2.0 equiv.) as the
oxidant in dichloromethane as the solvent at 25 °C with a
1a/2a molar ratio of 1:2 in air for 24 h (Table 1, entry 14).
Table 1. Screening for optimal reaction conditions.[a]
Entry
Catalyst
Oxidant
Solvent
T
[°C]
Yield[b]
[%]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2[Sc]2O8
O2
DCE
DCE
DCE
DCE
CH2Cl2
Et2O
acetone
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
60
90
120
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
35
30
32
28
42
33
37
15
26
24
27
20
76
81
65
52
0
9
10
11
12
13
14
15
16
17
18
19
Cu(OAc)2
BQ
none
Ag2CO3
Pd(OAc)2[d] AgOAc
Pd(OAc)2[e] AgOAc
Pd(OAc)2
CuI[f]
AgOAc
none
none
[f]
Cu(OAc)2
0
0
[g]
FeCl3
none
[a] Reaction conditions:
A mixture of 1a (0.2 mmol), 2a
(0.4 mmol), catalyst (0.1 equiv., unless otherwise noted), oxidant
(2 equiv.), and solvent (4 mL) was stirred in a sealed tube for 24 h.
[b] Yield of isolated product. [c] 101.3 kPa. [d] 0.05 equiv.
[e] 0.02 equiv. [f] 0.2 equiv. [g] 0.3 equiv.
To extend the present reaction, we allowed 1a to react
with various alkenes under the optimized reaction condi-
tions. These results are presented in Table 2. Alkenes such
as α-menthylstyrene (2b), acetates 2c and 2e, acrylamide
(2d), cyclohexene (2f), thiophene (2g), and acrylates 2h and
2i reacted with 1a to provide the coupled products in mod-
erate to good yields, whereas α-menthylstyrene (2b) and
thiophene (2g) resulted in slightly lower yields (Table 2, en-
tries 2 and 7). This may be caused by steric hindrance of 2b
or the low conversion of 2b and 2g at room temperature.
Interestingly, the use of vinyl acetate (2c) and cyclohexene
(2f) as the coupling partner led to the formation of terminal
alkene 3c and 4-(cyclohex-2-enyl) product 3f, respectively
(Table 2, entries 3 and 6). The latter may undergo double-
[a] Reaction conditions: A mixture of 1a (0.2 mmol), 2 (0.4 mmol),
Pd(OAc)2 (0.02 mmol), AgOAc (0.4 mmol), and CH2Cl2 (4 mL)
was stirred in a sealed tube at 25 °C for 24 h. [b] Yield of isolated
product.
2
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Room-Temperature Direct Alkenylation of 3-Arylsydnones
Table 3. Direct alkenylation of 3-arylsydnones with styrene.[a]
bond isomerization,[13] and the cause of the former may be
β-OAc elimination.[14]
The scope of the 3-arylsydnones was also examined, and
the results are summarized in Table 3. 3-Phenylsydnone (1d)
and its derivatives with electron-donating groups, such as
methoxy (see compound 1b) and methyl (see compound 1c),
or electron-withdrawing groups, including halo (see com-
pounds 1e–g and 1i) and trifluoromethyl (see compound
1h), on their aryl rings were smoothly alkenylated with styr-
ene in moderate to good yields (Table 3, entries 1–8). Com-
pared with 1d, the presence of an electron-donating group
in the aryl ring of 3-arylsydnone (see compounds 1b and
1c) remarkably increased the reaction yield (Table 3, en-
tries 1–3). By contrast, the presence of one or two electron-
withdrawing substituents on the aryl ring of 3-arylsydnone
(see compounds 1e–i) led to reactions that provided rela-
tively low yields of product 3 (Table 3, entries 4–8). Gen-
erally, substrates 1 consisted of electron-donating groups
that exhibited stronger electron-donating effects, and this
resulted in higher yields; substrates 1 with electron-donating
substituents in the para position provided higher yields than
those with substituents in the meta position. These observa-
tions are in contrast to the behavior of substrates 1 contain-
ing electron-withdrawing groups.
On the basis of the typical mechanism for Pd-catalyzed
dehydrogenative Heck reactions,[1a,3c] a possible reaction
mechanism is shown in Scheme 2. Initially, electronic attack
of PdII on 3-arylsydnone 1 and subsequent deprotonation
form species A,[15] which inserts into the alkene to provide
intermediate B. This step is followed by β-hydride elimi-
nation, which results in palladium hydride and product 3.
Reductive elimination of HPdOAc results in Pd0 and acetic
acid. PdII is regenerated from the oxidation of Pd0 by silver
acetate.
[a] Reaction conditions: A mixture of 1 (0.2 mmol), 2a (0.4 mmol),
Pd(OAc)2 (0.02 mmol), AgOAc (0.4 mmol), and CH2Cl2 (4 mL)
was stirred in a sealed tube at 25 °C for 24 h. [b] Yield of isolated
product.
Scheme 2. Possible mechanism for the formation of 3.
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Y. Yang, C. Kuang
SHORT COMMUNICATION
Conclusions
[1] a) X. Chen, K. M. Engle, D. Wang, J. Yu, Angew. Chem. Int.
Ed. 2009, 48, 5094; Angew. Chem. 2009, 121, 5196; b) P. B.
Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112,
5879.
[2] S. Moritani, Y. Fujiwara, Tetrahedron Lett. 1967, 8, 1119.
[3] a) H. Weissman, X. Song, D. Milstein, J. Am. Chem. Soc. 2001,
123, 337; b) C. Ying, S. Yan, W. Duan, Org. Lett. 2014, 16,
500; c) J. Wu, X. Cui, L. Chen, G. Jiang, Y. Wu, J. Am. Chem.
Soc. 2009, 131, 13888; d) C. Wang, H. Chen, Z. Wang, J. Chen,
Y. Huang, Angew. Chem. Int. Ed. 2012, 51, 7242; Angew. Chem.
2012, 124, 7354.
In summary, a mild and efficient method for the direct
palladium(II)-catalyzed alkenylation of 3-arylsydnones was
developed. The reaction was conducted at room tempera-
ture and provided the coupled product in moderate to good
yields. These products are important heterocyclic com-
pounds that are used in medicinal and biological research.
[4] a) F. H. C. Stewart, Chem. Rev. 1964, 64, 129; b) D. L. Browne,
J. P. A. Harrity, Tetrahedron 2010, 66, 553.
[5] M. A. Moustafa, M. M. Gineinah, M. N. Nasr, W. A. H. Bay-
oumi, Arch. Pharm. 2004, 337, 427.
[6] J. B. Hill, R. E. Ray, H. Wagner, R. L. Aspinall, J. Med. Chem.
1975, 18, 50.
Experimental Section
General Procedure for the Synthesis of Product 3: A mixture of 3-
arylsydnone
1 (0.2 mmol), alkene 2 (0.4 mmol), Pd(OAc)2
[7] D. J. McCaustland, W. H. Burton, C. C. Cheng, J. Heterocycl.
Chem. 1971, 8, 89.
[8] K. Satyanarayana, M. N. A. Rao, J. Pharm. Sci. 1995, 84, 263.
[9] C. S. Dunkley, C. Thoman, Bioorg. Med. Chem. Lett. 2003, 13,
2899.
[10] W. Chan, W. Zhang, Y. Szeto, Mater. Lett. 2000, 42, 280.
[11] Y. Sasaki, O. Hirobomi, M. Handa, Nippon Kagaku Kaishi
1993, 11, 1217.
[12] a) V. N. Kalinin, P. M. Se, J. Organomet. Chem. 1988, 352, C34;
b) A. Rodriguez, R. V. Fennessy, W. J. Moran, Tetrahedron
Lett. 2009, 50, 3942; c) C. Wu, Y. Fang, R. C. Larock, F. Shi,
Org. Lett. 2010, 12, 2234; d) D. L. Browne, J. B. Taylor, A.
Plant, J. P. A. Harrity, J. Org. Chem. 2009, 74, 396.
[13] X. Wu, J. Zhou, Chem. Commun. 2013, 49, 4794.
[14] J. Lindh, J. Saevmarker, P. Nilsson, P. J. R. Sjoeberg, M.
Larhed, Chem. Eur. J. 2009, 15, 4630.
(0.02 mmol), AgOAc (0.4 mmol), and dichloromethane (4 mL) was
stirred in a sealed tube at room temperature for 24 h. After the
reaction was complete (as monitored by TLC), the solvent was
evaporated in vacuo. The resulting residue was purified by prepara-
tive TLC (petroleum ether/ethyl acetate, 4:1 v/v) to yield 3.
Supporting Information (see footnote on the first page of this arti-
cle): Spectral data and copies of the 1H NMR and 13C NMR spec-
tra for all products 3.
Acknowledgments
This study was supported by the National Natural Science Founda-
tion of China (NSFC) (grant number 21272174), the Key Projects
of Shanghai in Biomedicine (grant number 08431902700), and the
Scientific Research Foundation of the State Education Ministry for
Returned Overseas Chinese Scholars. The authors also thank the
Center for Instrumental Analysis at Tongji University, China.
[15] a) H. Ge, M. J. Niphakis, G. I. Georg, J. Am. Chem. Soc. 2008,
130, 3708; b) Z. Lu, F. Luo, L. Wang, G. Zhu, J. Org. Chem.
2013, 78, 10894.
Received: September 13, 2014
Published Online: ᭿
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Room-Temperature Direct Alkenylation of 3-Arylsydnones
C–H Activation
Y. Yang,* C. Kuang* ........................ 1–5
Room-Temperature Direct Alkenylation of
3-Arylsydnones
Keywords: Synthetic methods / C–H acti-
vation / Alkenylation / Nitrogen hetero-
cycles / Palladium
A new efficient method for the direct alken-
ylation of 3-arylsydnones by palladium-
catalyzed C–H functionalization is devel-
oped. The reaction proceeds smoothly at
room temperature and delivers the prod-
ucts in yields up to 83%.
Eur. J. Org. Chem. 0000, 0–0
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