Pd-catalyzed oxidative coupling of monosubstituted sydnones and terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2011.05.058

The Pd-catalyzed oxidative coupling of N-substituted sydnones and terminal alkynes offers a quick, one-step synthesis of 4-alkynylsydnones in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2011.05.058

Tetrahedron Letters 52 (2011) 3797–3801
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed oxidative coupling of monosubstituted sydnones
and terminal alkynes
Chunrui Wu a, Pan Li a, Yuesi Fang b, Jingjing Zhao a, Weichao Xue a, Yang Li a,
a,
Richard C. Larock b, , Feng Shi
⇑
⇑
a Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng, Henan 475004, PR China
b Department of Chemistry, Iowa State University, Ames, IA 50010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 March 2011
Revised 4 May 2011
Accepted 13 May 2011
Available online 19 May 2011
The Pd-catalyzed oxidative coupling of N-substituted sydnones and terminal alkynes offers a quick,
one-step synthesis of 4-alkynylsydnones in moderate to good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sydnone
Pd-catalysis
Cross coupling
C–H functionalization
Sydnone1 belongs to a class of heterocycles typically referred to
as mesoionic rings (Fig. 1).2 Structurally sydnone has a 5-mem-
bered oxadiazole skeleton exhibiting aromaticity through a net
separation of formal positive and negative charges. Since its dis-
covery in 1935,3 sydnone has attracted significant attention from
a wide variety of research areas due to its interesting structure
and physicochemical properties. Sydnone derivatives have been
recognized to exhibit a spectrum of bioactivities, including anti-
bacterial,4 anticancer,5 anti-inflammatory,6 and antimalarial.7
Chemically, sydnone exhibits reactivity typical of arenes, specifi-
cally electrophilic aromatic substitution, including halogenation8
and acylation9 reactions. Recently, the chemistry of sydnones has
been more focused on its reactivity as a cyclic 1,3-dipole in [3+2]
cycloaddition reactions with alkynes to afford pyrazoles.10 Their
further development requires improved methods for the prepara-
tion of sydnones.
Traditionally, sydnones are prepared from N-substituted amino
acids by an N-nitrosation/cyclodehydration sequence.11 This pro-
cedure is still the most widely used preparation today, with differ-
ent modifications available.12 However, this method is limited to
amino acids that are readily available. In an ongoing investigation
in our two groups of aryne dipolar cycloaddition chemistry using
sydnones as the 1,3-dipole,13 we needed to prepare a variety of
sydnones bearing diverse substitution patterns. Unfortunately,
for many substituted sydnones, particularly 4-vinyl and 4-alkynyl
sydnones, the amino acid route is simply not viable, and alterna-
tive routes are needed.
In this regard, Moran et al. developed a Pd-catalyzed cross-
coupling reaction of N-substituted sydnones with vinylic/aryl ha-
lides,14 leading to an easy and efficient synthesis of 4-vinylic and
4-arylsydnones. However, in that report, there was only one exam-
ple using a 1-bromoalkyne as the electrophile to prepare 4-alky-
nylsydnones and the yield was only modest (Eq. 1).14b Besides
this protocol, there are only two general approaches available for
the preparation of 4-alkynylsydnones. One method developed by
Kalinin et al. (Eq. 2)15 involves the BuLi deprotonation of N-substi-
tuted sydnones, a low-temperature transmetallation to Cu(I),16
followed by a Sonogashira coupling with 1-bromo-2-(trimethyl-
silyl)acetylene, which has to be prepared. A subsequent removal
of the TMS group and finally another Sonogashira coupling with
a halide are required to complete the synthesis. The other method
developed by Turnbull et al. (Eq. 3)17 involves a Sonogashira cou-
pling of 4-bromosydnone with a terminal alkyne. Unfortunately,
neither of these methods seems attractive as the former consists
R2
R2
R2
O
R1
R3
R1
R3
R1
R3
R1
N
N
N
N
N
R2
O
O
O
S
O
S
O
⇑
Corresponding authors. Tel.: +1 515 294 4660; fax: +1 515 294 0105 (R.C.L.);
tel.: +86 378 286 4665; fax: +86 378 286 4665 (F.S.).
Münchnone
sydnone
thiomünchnone thioisomünchnone
E-mail addresses: larock@iastate.edu (R.C. Larock), fshi@henu.edu.cn (F. Shi).
Figure 1. Sydnone and other mesoionic rings.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.058

3798
C. Wu et al. / Tetrahedron Letters 52 (2011) 3797–3801
of a multi-step synthesis, and the latter calls for the use of near
stoichiometric amounts of metal catalysts, a 6.6-fold excess of 4-
bromosydnone, which was prepared through a multi-step synthe-
sis, and an extreme dilution (0.15 mmol scale in 250 mL of Et3N as
the solvent). Given this situation, there remains a lack of an effi-
cient, operationally friendly method to prepare 4-alkynylsydnones.
Table 1
Reaction optimizationa
Ph
Cl
Cl
cat. Pd-Cu, [O]
solvent, 110 o
1a:2a = 1:1.2
+ H
Ph
C
N
N
N
N
3aa
O
O
O
O
1a
2a
ð1Þ
ð2Þ
ð3Þ
Entry Pd
Cu (mol %)
Oxidant
(equiv)
Solvent
t
(h)
Yieldb
(%)
(5 mol %)
1
2
Pd(OAc)2
Pd(OAc)2
CuCI2 (10)
Cu(OAc)2
(10)
CuCI2 (10)
CuCI2 (10)
CuCI2 (10)
CuCI2 (10)
Ag2O (2.0)
Ag2O (2.0)
Toluene 18
Toluene 18
48
44
3
4
5
6
7
8
PdCI2
Ag2O (2.0)
Ag2CO3 (2.0)
Ag2O (2.0)
Ag2O (2.0)
Toluene 24
Toluene 24
DMF
Toluene 18
Toluene 18
Toluene 24
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Trace
0
24
Tracec
Trace
44
CuCI2 (200) None
CuCI2 (10) Ag2O (1.2)
a
b
c
Reaction conditions: 0.4 mmol scale, 5 mL of solvent.
Isolated yield.
Reaction was carried out under N2.
in portions, or more ideally with a syringe pump to reduce its con-
centration and therefore reduce homocoupling of the alkyne. Thus,
we added alkyne 2b, which did not work under the optimized con-
ditions shown in Table 1, entry 1, in six portions over 6 h, only to
find that the coupling failed again (Table 2, entry 1). Nonetheless,
lowering the temperature to 90 °C led to a modest yield of 25% (en-
try 2). The optimal temperature proved to be 75 °C (entry 3). We
realized, by TLC analysis, that the reaction seriously slowed down
toward the end, presumably because the Ag mirror formed in the
reaction may help Pd(0) deposit and therefore lose its activity.
Thus, the slow addition of another 5 mol % of the Pd catalyst to-
gether with 1.5 equiv of 2b via syringe pump was performed,
resulting in the best yield of 73% so far obtained (entry 5). It should
be pointed out that although this operation is still a bit awkward,
these reaction conditions are much improved when compared with
those in Eqs. 2 and 3.20
We then screened these newly optimized conditions against a
variety of sydnones and alkynes (Table 3). Different sydnones were
first investigated (entries 1–7). As can be seen, most N-aryl syd-
nones reacted well, affording the desired products in good yields,
except for N-(4-nitrophenyl)sydnone (entry 6). Even an aryl bro-
mide can be tolerated (entry 5). However, an N-methyl variant pro-
ceeded much less smoothly (entry 7).21 For alkynes, it was
Recently a variety of Pd-catalyzed oxidative coupling reactions
have been developed,18,19 among which terminal alkynes can be
used as the nucleophilic coupling partner.19 Such success encour-
aged us to investigate the feasibility of reacting N-substituted
sydnones directly with terminal alkynes under Pd-catalyzed
conditions employing a terminal oxidant (Scheme 1). Ideally, this
approach would offer the easiest way to synthesize 4-alky-
nylsydnones.
With this in mind, we first investigated the reaction of N-(4-
chlorophenyl)sydnone (1a) with phenylacetylene (2a) in refluxing
toluene (Table 1), using 5 mol % Pd(OAc)2 as the catalyst in combi-
nation with 10 mol % CuCl2 to help regenerate Pd(II), and 2.0 equiv
of Ag2O as the terminal oxidant. The reaction successfully afforded
the oxidatively coupled product 3aa in a 48% yield (entry 1).
Although CuCl2 can be replaced by Cu(OAc)2 without significantly
affecting the yield (entry 2), replacing Pd(OAc)2 with PdCl2 (entry
3), or Ag2O with Ag2CO3 (entry 4), or toluene with DMF (entry 5)
led to complete failure of the reaction. Somewhat surprisingly,
although theoretically Ag2O can serve as the oxidant, it is critical
to run the reaction in air (open flask). Running the reaction under
nitrogen failed to work (entry 6), and replacing Ag2O with a stoi-
chiometric quantity of Cu(II) also afforded only a trace of the de-
sired alkynylsydnone (entry 7). Use of less than 2 equiv of Ag2O
afforded a comparable yield (entry 8), but was less favorable due
to the long reaction time and lower conversion.
Table 2
Second-round optimizationa
With these conditions optimized, we screened other substrates.
To our surprise, we soon realized that these ‘optimized’ reaction
conditions did not work for other substrates. In those reactions,
oxidative dimerization of the terminal alkyne was the major,
sometimes exclusive, event. Therefore, further optimization was
needed. We hypothesized that alkyne 2 should be added slowly
Entry
Addition of 2b
T (°C)
Yieldb (%)
1
2
3
Portionwise, 0.2 equiv/h
Portionwise, 0.2 equiv/h
Portionwise, 0.2 equiv/h
Portionwise, 0.2 equiv/h
Via syringe pump
110
90
75
60
Trace
25
50
45
73
4
5c
75
a
Reaction conditions: 0.4 mmol scale, 5 mL of toluene (half in the flask, half to
dissolve 2b).
b
Isolated yield.
c
1.5 equiv of 2b and another 5 mol % Pd in 2.5 mL of toluene.
Scheme 1. Oxidative coupling of sydnone and an alkyne.

C. Wu et al. / Tetrahedron Letters 52 (2011) 3797–3801
3799
Table 3
Reaction scopea
Entry
R
R0
Product
Yieldb (%)
Entry
R
R0
Product
Yieldb (%)
Ph
OMe
Cl
Cl
4-ClC6H4
(1a)
Ph
(2a)
4-ClC6H4
(1a)
3-(MeO)C6H4
(2b)
N
N
3aa
1
69
8
73
O
N
N
O
O
O
3ab
Me
Ph
Cl
Ph
(1b)
Ph
(2a)
4-ClC6H4
(1a)
4-MeC6H4
(2c)
N
N
2
72
9
78
O
O
N
N
O
3ba
O
3ac
Ac
Ph
Me
Cl
Cl
N
N
4-MeC6H4
(1c)
Ph
(2a)
4-ClC6H4
(1a)
4-AcC6H4
(2d)
O
3
69
10
76
O
3ca
N
N
O
O
3ad
Ph
Cl
O
O
N
N
3da
3,4-(OCH2O)C6H4
(1d)
Ph
(2a)
4-ClC6H4
(1a)
3-ClC6H4
(2e)
O
4
72
11
66
O
N
N
O
O
3ae
Ph
Br
S
Cl
Cl
38c
N
N
4-BrC6H4
(1e)
Ph
(2a)
4-ClC6H4
(1a)
2-Thiophenyl
(2f)
5
60
12
O
O
N
N
O
3ea
O
3af
N
N
4ag
N
4-(O2N)C6H4
(1f)
Ph
(2a)
4-ClC6H4
(1a)
2-Pyridyl
(2g)
6
7
0
13
14
25d
CO2CH3
Cl
Me
(1g)
Ph
(2a)
4-ClC6H4
(1a)
CO2Me
(2h)
29
33
N
N
O
O
3ah
a
b
c
All reactions are carried out on a 0.4 mmol scale.
Isolated yields.
Incomplete conversion, 37% of 1a was recovered.
d
The [3+2] cycloaddition was not observed under the same conditions in the absence of Pd, Cu, and Ag.

3800
C. Wu et al. / Tetrahedron Letters 52 (2011) 3797–3801
observed that substituted phenylacetylenes worked best (entries
8–11), with either an electron-donating group (entry 8) or an elec-
tron-withdrawing group (entry 10) tolerated. Heterocyclic acety-
lenes reacted much more slowly and gave substantially lower
conversions to alkynylsydnones (entries 12 and 13). For example,
2-ethynylthiophene (2f) only gave a 38% yield of the desired prod-
uct, with 37% of 1a recovered (entry 12). 2-Ethynyl pyridine on the
other hand afforded a product apparently arising by a [3+2] cyclo-
addition, followed by elimination of CO2 (entry 13). Interestingly,
this process seemed to be promoted by the metal catalysts present
in the reaction mixture as no such cycloaddition was observed in
the absence of Pd, Cu, and Ag. Alkyl-substituted alkynes unfortu-
nately did not work well. While methyl propiolate (2h) gave a
low conversion of the sydnone and only a 33% yield, no other such
alkynes worked, including heptyne, N-(3-butynyl)phthalimide, 1-
ethynylcyclohexanol, and homopropargyl alcohol. Thus, the scope
of the current reaction is limited to arylacetylenes. Literature prep-
arations by Kalinin and Turnbull are in agreement with this obser-
vation as they are also limited to acetylenes with sp2 bonded
carbon substitutents.15–17 It should be noted that Kalinin’s method
is capable of preparing the desired product of 1b and 2g in a low
yield, while our method could not.
slow addition of alkynes and the scope of the alkynes is still lim-
ited, it is much more operationally friendly than previous methods.
Acknowledgments
This project was financially supported by the National Natural
Science Foundation of China (No. 21002021 to F.S.), Key Project
of Chinese Ministry of Education (No. 210127 to F.S.), and the Uni-
ted States National Science Foundation. We thank Mr. Lei Liu, Pro-
fessor Shrong-Shi Lin, Dr. Jiang Zhou (all Peking University), Mr.
Yong Wang (Henan University), and Dr. Kamel Harrata (Iowa State
University) for their help in the spectroscopic analysis. W.X. and
Y.L. acknowledge summer undergraduate support from Henan
University.
References and notes
1. For excellent reviews of sydnones, see: (a) Browne, D. L.; Harrity, J. P. A.
Tetrahedron 2010, 66, 553; (b) Stewart, F. H. C. Chem. Rev. 1964, 64, 129; (c)
Baker, W.; Ollis, W. D. Q. Rev. (London) 1957, 11, 15.
2. (a) Padwa, A. 1, 3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New
York, 1984; (b) Padwa, A.; Pearson, W. H. Synthetic Applications of 1, 3-Dipolar
Cycloaddition Chemistry toward Heterocycles and Natural Products; Wiley: New
York, Chichester, 2002.
The putative mechanism of this reaction is straightforward
(Scheme 2). Starting with Pd(II), transmetallation with a presumed
copper or silver acetylide generates an alkynyl Pd species (I). Co-
ordination of the sydnone (1) to the Pd center generates a cationic
species (II). Subsequent loss of the acidic proton at C4 results in the
formation of a 4-palladiosydnone (III), which reductively elimi-
nates the desired product 3 and affords Pd(0). The Cu and Ag salts
regenerate Pd(II) from Pd(0) to complete the cycle. Although this
mechanism explains the product formation, it should be consid-
ered as a simplified version, since the precise involvement of
air22,23 and the regeneration of Pd(II) from Pd(0) remain elusive.
In conclusion, we have developed a straightforward synthesis of
4-alkynylsydnones from terminal alkynes under Pd-catalyzed oxi-
dative coupling conditions. Although this reaction still requires the
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J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008, 130, 11270; (i) Reed, S.
A.; Mazzotti, A. R.; White, M. C. J. Am. Chem. Soc. 2009, 131, 11701; (j) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (k)
Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315; (l) Liégault,
B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022;
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Scheme 2. Putative mechanism (simplified).

C. Wu et al. / Tetrahedron Letters 52 (2011) 3797–3801
3801
19. (a) Ye, Z.; Liu, M.; Lin, B.; Wu, H.; Ding, J.; Cheng, J. Tetrahedron Lett. 2009, 50,
530; (b) Yang, L.; Zhao, L.; Li, C.-J. Chem. Commun. 2010, 46, 4184; (c) Chen, M.;
Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010, 132, 4101; (d) Kim, S. H.;
Yoon, J.; Chang, S. Org. Lett. 2011, 13, 1474; For a brief review of oxidative
coupling involving terminal alkynes catalyzed by other metals, see: (e) Shao,
Z.; Peng, F. Angew. Chem., Int. Ed. 2010, 49, 9566.
20. Representative procedure (Table 3, entry 1): To an oven-dried 10 mL round-
bottom flask equipped with a stirrer bar was added 79 mg of 1a (0.4 mmol),
followed by 4.8 mg of Pd(OAc)2 (0.021 mmol, 5 mol %), 6.0 mg of CuCl2
(0.045 mmol, 11 mol %), and 186 mg of Ag2O (0.8 mmol, 2.0 equiv). Toluene
(2.5 mL) was added and the mixture was stirred at 75 °C while open to air. To
this flask was added a solution containing 62 mg of 2a (0.6 mmol, 1.5 equiv)
and another 4.8 mg of Pd(OAc)2 (0.021 mmol, 5 mol %) in 2.5 mL of toluene via
syringe pump over 6 h. After complete addition, the reaction was continued for
2 h and judged complete by TLC. The mixture was then cooled to ambient
temperature, filtered, and washed with EtOAc. The filtrate was washed once
with brine and the aqueous layer was extracted twice with EtOAc. The
combined organic extracts were dried over MgSO4, filtered, and evaporated.
The residue was purified by column chromatography (petroleum ether/EtOAc =
4:1), to afford 81 mg of 3aa (69%) as a brown solid; mp 133-135 °C; 1H NMR
(400 MHz, CDCl3) d 7.87-7.81 (m, 2 H), 7.67-7.61 (m, 2 H), 7.44-7.31 (m, 5 H);
13C NMR (100 MHz, CDCl3) d 166.9, 138.9, 132.7, 131.3, 130.2, 129.6, 128.5,
124.8, 121.1, 103.4, 95.4, 72.8; HRMS (ESI) calcd for C17H12ClN2O3 (M+H)
297.0425, found 297.0422.
21. An N-benzyl variant was also attempted. It resulted in a mixture containing the
desired product, but we were not able to purify the product.
22. For reports of the mechanistic details of aerobatic oxidation of Pd(0) to Pd(II),
see: (a) Konnick, M. M.; Decharin, N.; Popp, B. V.; Stahl, S. S. Chem. Sci. 2011, 2,
326; (b) Popp, B. V.; Stahl, S. S. Chem. Eur. J. 2009, 15, 2915; (c) Konnick, M. M.;
Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 5753.
23. It should be noted that Moran’s cross-coupling reactions were also carried out
in air. See Ref.14