Palladium-catalyzed alkynylative lactonization of unsaturated bicyclic carboxylic acids: Synthesis of fused polycyclic γ-lactone compounds

Article abstract of DOI:10.1002/ejoc.201300037

Unsaturated bicyclic carboxylic acids undergo palladium-catalyzed coupling with bromoalkynes to produce γ-alkynyl lactones in moderate to good yields with excellent chemo- and regioselectivity. The reaction conditions were extremely mild, and functional groups such as methyl, methoxy, chloro, and bromo were tolerated under the optimized reaction conditions. Moreover, γ-chloroalkenyl lactones were facilely synthesized through chloropalladation/carboesterification of electron-deficient C≡C bonds by using molecular oxygen as the sole oxidant. Facile and tandem Pd-catalyzed synthesis of γ-alkynyl lactone and γ-chloroalkenyl lactone derivatives by using readily accessible bromoalkynes and unsaturated bicyclic carboxylic acids is reported. Two subsequent steps, namely, C(sp or sp ²)-C(sp³) bond formation and C-O bond formation, are catalyzed by a single Pd catalyst. The reactions proceed with good yields of the products. Copyright

Full text of DOI:10.1002/ejoc.201300037

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300037
Palladium-Catalyzed Alkynylative Lactonization of Unsaturated Bicyclic
Carboxylic Acids: Synthesis of Fused Polycyclic γ-Lactone Compounds
Ning Sun,*[a,b] Yibiao Li,*[b] Gengming Yin,[b] and Shaohua Jiang[b]
Keywords: Synthetic methods / Polycycles / Lactones / Alkynes / Palladium
Unsaturated bicyclic carboxylic acids undergo palladium-
catalyzed coupling with bromoalkynes to produce γ-alkynyl
lactones in moderate to good yields with excellent chemo-
and regioselectivity. The reaction conditions were extremely
mild, and functional groups such as methyl, methoxy, chloro,
and bromo were tolerated under the optimized reaction con-
ditions. Moreover, γ-chloroalkenyl lactones were facilely syn-
thesized through chloropalladation/carboesterification of
electron-deficient CϵC bonds by using molecular oxygen as
the sole oxidant.
Introduction
The lactone unit is one of the most abundant and rel-
evant esters in natural products and pharmaceuticals. De-
spite the existence of numerous methods for the synthesis
and derivatization of lactone rings, the development of new,
more efficient methods is of great importance.[1] Halo-
alkynes represent an attractive alternative to aryl halides or
terminal alkyne derivatives because of their higher reactiv-
ity, tolerance under milder conditions, their availability
from inexpensive acetylides, and because additional oxidant
and base are not required in several applications.[2] More-
over, highly functionalized alkenynes have been prepared
through the bromoalkynylation of internal alkynes.[3] Fur-
ther research on haloalkynes has revealed other possibilities
for the synthesis of complex molecules. Norbornene deriva-
tives are an appealing group of organic molecules because
of their strained structure and high reactivity. They tend to
coordinate to transition metals and have potential applica-
tions in various areas of industry; as such, they have at-
tracted considerable research interest from organic chem-
ists.[4] To date, various synthetic methods have been devel-
oped for the synthesis phenylsulfenyl lactones and halolact-
ones through intramolecular lactonization of unsaturated
carboxylic acids (Scheme 1).[5]
Scheme 1. Usual lactonization procedure for bicyclic carboxylic
acids.
Recent research into the transition-metal-catalyzed reac-
tions of norbornenes by the group of Jiang[6] and others[7]
led us to investigate the intermolecular alkynylation and
carboesterification of this class of molecules. The Pd-cata-
lyzed intramolecular oxy- and aminoalkynylation of nonac-
tivated olefins with the use of a benziodoxolone-derived hy-
pervalent iodine reagent or (2-bromoethynyl)triiospropylsil-
ane as an alkyne transfer reagent was reported by Waser
and co-workers for the preparation of tetrahydrofurans and
pyrrolidines (Scheme 2, a).[8] Unfortunately, when using
phenylethynyl bromides or phenylethylethynyl bromides as
substrates, complex mixtures of products were obtained.
[a] Jiangmen Polytechnic,
Jiangmen, Guangdong Province 529090, China
Homepage: http://www.jmpt.cn/
[b] School of Chemical & Environmental Engineering, Wuyi
University,
Jiangmen, Guangdong Province 529090, China
Fax: +86-0750-3299391
E-mail: wyuchemsn@126.com
leeyib268@126.com
Homepage: http://stu.wyu.edu.cn/hhxy/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300037.
Scheme 2. Pd-catalyzed oxyalkynylation of olefins with haloalk-
ynes.
Eur. J. Org. Chem. 2013, 2541–2544
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Sun, Y. Li, G. Yin, S. Jiang
SHORT COMMUNICATION
Herein, we report a general protocol for the alkynylation
Using the Pd(OAc)2-catalyzed system (Table 1, entry 3),
and carboesterification of unsaturated bicycle carboxylic we examined the generality of the synthesis of substituted
acids to give functional γ-alkynyl lactone derivatives fused polycyclic γ-lactone compounds. Varying the aryl
(Scheme 2, b). This approach is another utilization of alkyl substituent of bromoalkynes 2 (Table 2) showed that sub-
or aryl bromoalkynes for the formation of lactone rings un- strates bearing electron-donating (Table 2, 3b–g) and elec-
der palladium catalysis. As such, bicycle alkynyl lactones tron-withdrawing groups (Table 2, 3h–l) were well tolerated.
may be readily converted into alkynyl hydrins, γ-oxocarbox- Notably, the C–Br bond remained intact when a bromine
ylic acids, and epoxides.[9] Furthermore, we extended this substituent was introduced on the aryl ring, and therefore
methodology to other internal electron-deficient alkynes the product may undergo additional functionalization at
and successfully obtained the corresponding chloropallad- the C–Br bond (Table 2, 3k and 3p). Next, the effects of the
ation/carboesterification products in good yields.
unsaturated carboxylic acid moiety in the synthesis of γ-
alkynyl lactones were examined. The reaction of 3-(meth-
oxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid un-
der the standard reaction conditions afforded the corre-
sponding γ-alkynyl lactones in good yields (Table 2, 3n–p).
In addition to aryl bromoalkynes, aliphatic bromoalkynes
were also found to be suitable substrates for the alkynylative
lactonization reaction (Scheme 3). When 2-(6-bromohex-5-
ynyl)isoindoline-1,3-dione, 1-(2-bromoethynyl)cyclohex-1-
ene, 1-bromooct-1-yne, and 1-(3-bromoprop-2-ynyl)benz-
ene were employed, the desired products were formed and
isolated in excellent yields (Scheme 3, 3r–u).
Results and Discussion
At the onset, through the screening of a variety of condi-
tions, we found that several palladium salts could effect the
alkynylative lactonization of phenylethynyl bromide (1a)
with endo-norborn-5-ene-2-carboxylic acid (2a, Table 1). In
experiments to optimize the reaction, we found that the sol-
vent played a very important role in the process (Table 1,
entries 1–3). The best results were obtained with a catalytic
amount of Pd(OAc)2 in CH3CN. Under these conditions,
conversion was complete within 8 h at 50 °C without the
addition of base or ligand (Table 1, entry 3). The alk-
ynylative lactonization of 2a with 1a under Pd(PPh3)4 catal-
ysis led to low conversion and the starting material was
recovered (Table 1, entry 5). The use of Pd2(dba)3 as the
catalyst gave good results (Table 1, entry 6). The addition of
a base such as K2CO3 did not disturb the reaction (Table 1,
entry 7). We next focused on PPh3 and 1,10-phenanthroline
(phen) as ligands, and both hampered the oxyalkynylation
process (Table 1, entries 8 and 9). Notably, the reaction was
sluggish when CuI was employed instead of a palladium
salt (Table 1, entry 10). The reaction did not occur without
a palladium catalyst (Table 1, entry 11).
Table 2. Scope of the alkynylative lactonization reaction.[a]
Entry
Ar
R1 (2)
Product
Yield [%][b]
1
2
3
4
5
6
7
8
C6H5
H (2a)
H (2a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
93
95
92
83
87
95
90
83
87
88
87
86
92
85
81
83
4-MeC6H4
3-MeC6H4
2,4-Me2C6H3
4-EtC6H4
4-tBuC6H4
4-EtOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
Table 1. Optimization of the reaction conditions.[a]
H (2a)
9
H (2a)
10
11
12
13
14
15
16
H (2a)
H (2a)
H (2a)
4-PhC6H4
4-EtC6H4
2-ClC6H4
4-BrC6H4
H (2a)
COOMe (2b)
COOMe (2b)
COOMe (2b)
Entry
Catalyst
Solvent
Additive Yield [%][b]
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuI
DMSO
NEt3
–
–
–
–
–
–
35
–
[a] Reaction conditions: Pd(OAc)2 (5 mol-%), norbornene
(1.5 mmol), bromoalkyne (1.0 mmol), and CH3CN (3 mL) at 50 °C
for 6–8 h. [b] Isolated yield.
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
93
83
42
91
85
45
28
–
K2CO3
PPh3
phen
–
The above studies dealt only with bromoalkynes as the
reactive point in the substrates. To extend the substrate
scope, we used other electronic-deficient compounds, such
as ethyl 3-phenylpropiolate, to investigate the possibility of
this transformation (Scheme 4). The reaction of endo-nor-
born-5-ene-2-carboxylic acid with ethyl 3-phenylpropiolate
afforded chloropalladation/carboesterification product 5a
with high Z/E selectivity. In addition, 3-(methoxycarbonyl)-
9
10[c]
11[d]
–
–
–
[a] Reaction conditions: phenylethynyl bromide (1.0 mmol), nor-
bornene (1.5 mmol), catalyst (5 mol-%), and additive (10 mol-%) in
solvent (3 mL) at 50 °C for 8 h. [b] Isolated yield. [c] 1,4-Di-
phenylbuta-1,3-diyne was obtained as the major product. [d] Start-
ing material was recovered.
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Synthesis of Fused Polycyclic γ-Lactone Compounds
The basic mechanistic features of the alkynylative lacton-
ization reaction are reasonably well established and are
shown in Scheme 5.[6,8] Bromoalkyne 1 first undergoes oxi-
dative addition with the low-valent palladium to give alk-
ynyl palladium(II) intermediate A. Intermediate A coordi-
nates to norbornene 2 to generate intermediate B, which is
followed by trans oxypalladation to give alkynyl alkyl palla-
dium intermediate C with well-defined stereochemistry.
Subsequent reductive elimination of C generates γ-alkynyl
lactone product 3 and the active catalyst species.
Conclusions
In conclusion, we have developed the Pd-catalyzed alk-
ynylative lactonization of unsaturated bicyclic carboxylic
acids by using common bromoalkynes as substrates. This
protocol is compatible with a large variety of bromoalk-
ynes, and fused polycyclic γ-alkynyl lactones and γ-chlo-
roalkenyl lactones were obtained in good yields. Further
synthetic application of these fused polycyclic γ-alkynyl
lactones and direct alkynylative lactonization of straight-
chain unsaturated carboxylic acids is ongoing. The results
will be reported in due course.
Scheme 3. Pd-catalyzed oxyalkynylation of bicyclo[2.2.1]hept-5-
ene-2-carboxylic acid with bromoalkynes.
bicyclo[2.2.1]hept-5-ene-2-carboxylic acid was equally
adaptable to the applied reaction conditions and formed
corresponding product 5b in good yield.
Experimental Section
Typical Procedure for the Reaction of Bromoalkynes with Unsatu-
rated Bicyclic Carboxylic Acids: Pd(OAc)2, (12 mg, 0.05 mmol),
CH3CN (3 mL), endo-norborn-5-ene-2-carboxylic acid (208 mg,
1.5 mmol), and phenylethynyl bromide (180 mg, 1.0 mmol) were
added successively to a Schlenk tube. After stirring for 8 h at 50 °C,
the solution was filtered though a small amount of silica gel. The
residue was purified by silica gel preparative TLC (n-hexane/ethyl
acetate = 10:1), which furnished 3a (221 mg, 93%) as a pale-yellow
oil.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures, characterization data, 1H NMR
and 13C NMR spectra, MS data, and IR spectra.
Scheme 4. Synthesis of γ-chloroalkenyllactone products.
Acknowledgments
The work was financially supported by the Guangdong Science and
Technology Department of China through the Youth Science
Research Fund of Wuyi University (Key Project No.
2012B091000077, Major Program No. 2012A090300004). The au-
thors thank the Jiang group for fruitful discussions and for re-
cording the NMR spectra.
[1] For reviews, see: a) I. Shiina, Chem. Rev. 2007, 107, 239–273;
b) Y. S. Rao, Chem. Rev. 1976, 76, 625–694; c) E. Genin, P. Y.
Toullec, S. Antoniotti, C. Brancour, J.-P. Genêt, V. Michelet, J.
Am. Chem. Soc. 2006, 128, 3112–3113; d) L. Huang, H. Jiang,
C. Qi, X. Liu, J. Am. Chem. Soc. 2010, 132, 17652–17654; e)
C. A. Leverett, V. C. Purohit, A. G. Johnson, R. L. Davis, D. J.
Tantillo, D. Romo, J. Am. Chem. Soc. 2012, 134, 13348–13356;
f) D. H. Paull, C. Fang, J. R. Donald, A. D. Pansick, S. F. Mar-
tin, J. Am. Chem. Soc. 2012, 134, 11128–11131; g) P. Langer,
N. N. R. Saleh, V. Köhler, Eur. J. Org. Chem. 2002, 1566–1572;
h) A. Albrecht, Ł. Albrecht, T. Janecki, Eur. J. Org. Chem.
Scheme 5. Proposed mechanism for the alkynylative lactonization
process.
Eur. J. Org. Chem. 2013, 2541–2544
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N. Sun, Y. Li, G. Yin, S. Jiang
SHORT COMMUNICATION
2011, 2747–2766; i) L. Chang, H. Jiang, J. Fu, B. Liu, C. Li,
Z. Yang, J. Org. Chem. 2012, 77, 3609–3614.
2006, 128, 6837–6846; d) M. Waibel, N. Cramer, Angew. Chem.
2010, 122, 4557–4560; Angew. Chem. Int. Ed. 2010, 49, 4455–
4458; e) Q. Liu, H. Duan, X. Luo, Y. Tang, G. Li, R. Huang,
A. Lei, Adv. Synth. Catal. 2008, 350, 1349–1354; f) M. Catel-
lani, E. Motti, N. D. Cá, Acc. Chem. Res. 2008, 41, 1512–1522;
g) E. Motti, N. D. Cá, D. Xu, A. Piersimoni, E. Bedogni, Z.-
M. Zhou, M. Catellani, Org. Lett. 2012, 14, 5792–5795.
[5] a) K. C. Nicolaou, Z. Lysenko, J. Chem. Soc., Chem. Commun.
1977, 293–294; b) S. G. Davies, J. C. Walker, J. Chem. Soc.,
Chem. Commun. 1986, 609–610; c) N. S. Zefirov, N. V. Zyk,
S. I. Kolbasenko, A. G. Kutateladze, J. Org. Chem. 1985, 50,
4539–4543.
[6] Y. Li, X. Liu, H. Jiang, B. Liu, Z. Chen, P. Zhou, Angew. Chem.
2011, 123, 6465–6469; Angew. Chem. Int. Ed. 2011, 50, 6341–
6345.
[7] a) H. Liu, C. Chen, L. Wang, X. Tong, Org. Lett. 2011, 13,
5072–5075; b) M. Catellani, Top. Organomet. Chem. 2005, 14,
21–53; c) D. A. Candito, M. Lautens, Org. Lett. 2010, 12,
3312–3315.
[2] a) J. P. Brand, J. Waser, Chem. Soc. Rev. 2012, 41, 4165–4179;
b) Y. Li, X. Liu, H. Jiang, Z. Feng, Angew. Chem. 2010, 122,
3410–3413; Angew. Chem. Int. Ed. 2010, 49, 3338–3341; c) Y.
Li, J. Zhao, H. Chen, B. Liu, H. Jiang, Chem. Commun. 2012,
48, 3545–3547; d) Y. Li, X. Liu, D. Ma, B. Liu, H. Jiang, Adv.
Synth. Catal. 2012, 354, 2683–2688; e) B. Liu, Y. Liu, M. Yin,
W. Wu, H. Jiang, Chem. Commun. 2012, 48, 11446–11448; f)
Z. Chen, J. Li, H. Jiang, S. Zhu, Y. Li, C. Qi, Org. Lett. 2010,
12, 3262–3265; g) Z. Chen, H. Jiang, Y. Li, C. Qi, Chem. Com-
mun. 2010, 46, 8049–8051; h) H. Jiang, W. Zeng, Y. Li, W. Wu,
L. Huang, W. Fu, J. Org. Chem. 2012, 77, 5179–5183; i) M.
Yamagishi, J. Okazaki, K. Nishigai, T. Hata, H. Urabe, Org.
Lett. 2011, 13, 34–37; j) M. Yamagishi, K. Nishigai, T. Hata,
H. Urabe, Org. Lett. 2011, 13, 4873–4875.
[3] a) T. Morishita, H. Yoshida, J. Ohshita, Chem. Commun. 2010,
46, 640–642; b) T. Wada, M. Iwasaki, A. Kondoh, H. Yorim-
itsu, K. Oshima, Chem. Eur. J. 2010, 16, 10671–10674; c) X.
Chen, W. Kong, H. Cai, L. Kong, G. Zhu, Chem. Commun.
2011, 47, 2164–2166.
[8] a) S. Nicolai, S. Erard, D. F. González, J. Waser, Org. Lett.
2012, 14, 384–387; b) S. Nicolai, J. Waser, Org. Lett. 2011, 13,
6324–6327.
[4] For reviews on the uses of norbornene derivatives, see: a) A.
Martins, B. Mariampillai, M. Lautens, Top. Curr. Chem. 2010, [9] For reviews, see: a) D. H. Paull, C. Fang, J. R. Donald, A. D.
292, 1–33; b) K. C. Nicolaou, A. Ortiz, H. Zhang, P. Dagneau,
A. Lanver, M. P. Jennings, S. Arseniyadis, R. Faraoni, D. E.
Lizos, J. Am. Chem. Soc. 2010, 132, 7138–7152; c) Y. Cho, V.
Zunic, H. Senboku, M. Olsen, M. Lautens, J. Am. Chem. Soc.
Pansick, S. F. Martin, J. Am. Chem. Soc. 2012, 134, 11128–
11131; b) H. Ruholl, H.-J. Schäfer, Synthesis 1987, 4, 408–409.
Received: January 10, 2013
Published Online: March 21, 2013
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Eur. J. Org. Chem. 2013, 2541–2544