A unified synthesis of cyclic ethers or lactones via Pd-catalyzed intramolecular O-functionalization of sp3C[sbnd]H bonds

Article abstract of DOI:10.1016/j.tetlet.2016.08.086

A general approach for the synthesis of lactones or cyclic ethers via Pd-catalyzed C(sp³)[sbnd]H activation and intramolecular C[sbnd]O functionalization starting from carboxylic acids or alcohols using the bidentate directing group has been de

Full text of DOI:10.1016/j.tetlet.2016.08.086

Accepted Manuscript
A unified synthesis of cyclic ethers or lactones via Pd-catalyzed intramolecular
O-functionalization of sp3 C-H bonds
Haifeng Wang, Youhong Niu, Guoying Zhang, Xin-Shan Ye
PII:
S0040-4039(16)31123-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.086
TETL 48057
Reference:
Tetrahedron Letters
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Revised Date:
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26 August 2016
29 August 2016
Please cite this article as: Wang, H., Niu, Y., Zhang, G., Ye, X-S., A unified synthesis of cyclic ethers or lactones
via Pd-catalyzed intramolecular O-functionalization of sp3 C-H bonds, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.08.086
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A unified synthesis of cyclic ethers or
lactones via Pd-catalyzed intramolecular O-
functionalization of sp3 C-H bonds
Haifeng Wang, Youhong Niu, Guoying Zhang, Xin-Shan Ye*

1
Tetrahedron Letters
journal homepage: www.els evier.com
A unified synthesis of cyclic ethers or lactones via Pd-catalyzed intramolecular O-
functionalization of sp3 C-H bonds
Haifeng Wanga, b, †, Youhong Niub, †, Guoying Zhanga, Xin-Shan Yeb, ∗
aLaboratory of Molecular Pharmacology, School of Pharmacy, Yantai University, Qing Quan Lu, Yantai, Shandong Province, China
bState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A general approach for the synthesis of lactones or cyclic ethers via Pd-catalyzed C(sp3)-H activation
and intramolecular C-O functionalization starting from carboxylic acids or alcohols by using the
bidentate directing group has been developed. Substrates with both primary and secondary hydroxyl
groups can undergo this reaction to produce the corresponding cyclic ethers. Furthermore,
isobenzofuran-1(3H)-ones with either electron-rich or electron-deficient groups as well as aliphatic
lactones can be prepared by employing this reaction.
Available online
Keywords:
Cyclic ether
Lactone
C-H functionalization
Intramolecular C-O formation
Aliphatic alcohol-based cyclic ethers and lactones are
ubiquitous moieties in many medicinally valuable compounds,
they are also useful building blocks for the synthesis of complex
organic molecules.1 General approaches to the preparation of
cyclic ethers or lactones involve intramolecular nucleophilic
substitution using aliphatic alcohols, which means that two
functional groups are equipped in the same molecule, and the
extra preactivation manipulation is usually needed for the
synthesis of cyclic ethers or lactones. In contrast, C(sp3)-H
activation, followed by functionalization with intramolecular O-
type groups, represents a new direction for the step-economical
synthesis of cyclic ethers or lactones.
intramolecular reactions.7 Very limited reports have been
disclosed for the alkoxylation of C(sp3)-H bonds.8 In 2015, Dong
and coworkers reported the only one work of intramolecular
alkoxylation of the methyl group, affording different sizes of
cyclic ethers in moderate to excellent yields.9
Inert C-H functionalization catalyzed by transition metals has
attracted tremendous interest from organic chemists, and is
emerging as a powerful approach to form C-X bonds and
generate various scaffolds of compounds in modern synthetic
chemistry.2 Among these C-X formation approaches, the Pd-
catalyzed activation of C-H bond and subsequent formation of C-
O bond have been greatly accelerated in recent years.3 Up to date,
most methods focus on the ortho- alkoxylation or acyloxylation
2
−H bonds of arenes directed by various functional
of the C(sp )
groups.4, 5 Directing groups such as carboxylic acid and alcohol
sometimes can also act as reacting groups, and undergo
cyclization to afford benzofuranones and dihydrobenzofurans.6
Compared with C(sp2)-H bond activation, C(sp3)-H bond
activation which is followed by O-functionalization is still a
fundamental challenge. Most methods reported involve the
directed acyloxylation of C(sp3)-H bonds including
———
∗Corresponding author. Tel.: +86 10 8280 5736; fax: +86 10 8280 2724. E-mail address: xinshan@bjmu.edu.cn (X.-S. Ye).
†These authors contributed equally to this work.

2
Tetrahedron
`aReaction conditions: substrate (0.1 mmol), catalyst (10 mol%), oxidant (3.0
Scheme 1. Synthesis of cyclic ethers or lactones via Pd-
equiv), additive (2.0 equiv), solvent (1.0 mL), under N2. bDess-Martin reagent.
cIsolated yield. dPhI(OAc)2 (2.0 equiv). eDichloroethane.
catalyzed intramolecular C(sp3)-H functionalization
Previous reports by Chen,8a Shi,8b and Rao8c, 8d have shown
that C-H of ß-methylene of acids using different bidentate
directing groups can be activated and functionalized with
excessive alcohols to furnish linear ethers. Since we are
interested in synthesizing organic functional molecules through
C-H functionalization,10 we envisaged that C-H functionalization
with intramolecular oxygen-containing groups such as alcohols
and carboxylic acids would be a unified approach to the synthesis
of cyclic ethers and lactones, though several problems need to be
addressed: 1) the same directing group and reaction conditions
are suitable for both lactonization and synthesis of cyclic ethers;
2) the competitive reactions could occur if oxygen-containing
oxidative reagents are used. Herein we report the preparation of
cyclic ethers or lactones via Pd-catalyzed β-methylene activation
of carboxylic acid derivatives.
Our investigation commenced with screening directing
groups. The starting materials 1aa, 1ab, and 1a carrying 8-
aminoquinoline, 2-aminomethylpyridine, and 2-(pyridin-2-
yl)propan-2-amine functionalities respectively, which were
developed by Shi and coworkers,8b, 11 were synthesized. These
compounds were then treated with Pd(OAc)2 and PhI(OAc)2 in
o
toluene at 90 C for 24 h. As shown in Table 1, compound 1aa
gave the desired cyclic ether product in 27% yield, and several
byproducts such as acetyloxylation of 8-aminoquinoline and
acetylation of primary alcohol were also collected. For
compound 1ab, no cyclized product was obtained under the same
conditions. Noteworthily, when compound 1a was used, the
desired product was isolated in 57% yield. These results showed
that 2-(pyridin-2-yl)propan-2-amine is the most effective
directing group (DG) for the intramolecular C−O bond
formation. So we chose 1a as a substrate to optimize the
cyclization reaction conditions.
Table 1. Screening of the directing groups
Table 3. Synthesis of cyclic ethers via intramolecular
oxidation of β-C(sp3)−H bondsa
entry
1
DG
yield(%)
27(95a)
byproduct
entry
1
substrate
product
yield
(%)b
86
2
79
2
3
0
—
57
3
4
90
82
73
aThe total conversion yield of 1aa.
Table 2. Optimization of reaction conditionsa
5c
6c
7
69
71
82
entry
catalyst
oxidant
additive
solvent
T
yield
(%)c
57
55
-
(oC)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2 PhI(OAc)2
Pd(OTFA)2
PdCl2
Pd(OPiv)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
PhI(OAc)2
PhI(OPiv)2
K2S2O8
-
-
-
-
-
-
-
-
-
-
-
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCEe
m-xylene
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
90
90
90
90
90
90
90
90
90
90
90
90
90
90
55
95
105
120
oxone
-
-
DMRb
d
8
51
trace
-
46
33
54
-
74
80
43
82
86
71
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
78
9
K2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
aReaction conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%), PhI(OAc)2
(3.0 equiv), NaHCO3 (2.0 equiv) in toluene (1 mL) under N2 at 105 oC for 24
h. bIsolated yield. cSubstrate (0.1 mmol), Pd(OAc)2 (10 mol%), PhI(OAc)2
(1.5 equiv), NaHCO3 (2.0 equiv) in toluene (1 mL) under N2 at 85 oC for 5 h.

3
The optimization experiments were carried out. Various
oxidants such as PhI(OAc)2, PhI(OPiv)2, K2S2O8, oxone, and
Dess-Martin reagent were investigated, we found that PhI(OAc)2
(3 equivalents) is the most efficient oxidant for oxidative
cyclization (entries 1-5, Table 2). When the amount of PhI(OAc)2
was reduced to 2 equivalents, lower yield was obtained (entry 6,
Table 2). We then started to investigate the effect of catalysts on
C-H activation and cyclization. Catalysts including Pd(OTFA)2,
PdCl2, and Pd(OPiv)2 were employed in the reaction, and the
results showed that the yield of product was not improved
(entries 7-9, Table 2). The screening of solvents revealed that
dichloroethane or m-xylene gave the desired product in lower
yield, whereas dioxane resulted in no reaction (entries 10-12,
Table 2). In this reaction, the hydroxyl group-acetylated
byproduct was also identified. We reasoned that acetic acid
produced in the reaction could not only inhibit the coordination
of hydroxyl group to the Pd center, but also catalyze the
acetylation of alcohol. Therefore, the addition of base should
neutralize acetic acid, and could improve the reaction yield.
Based on this assumption, K2CO3 was added to the reaction, and
the yield of product 2a was remarkably increased to 74% (entry
13). When NaHCO3 was used as a base, product 2a was isolated
in 80% yield (entry 14). The reaction temperature was also
investigated and it was found that the reaction proceeded more
efficiently at 105 oC (entries 15-18). Thus, the optimized reaction
conditions for methylene activation and O-functionalization are
as follows: substrate (1.0 equiv), Pd(OAc)2 (10 mol%),
PhI(OAc)2 (3.0 equiv) and NaHCO3 (2.0 equiv) in toluene at 105
oC for 24 h under N2 atmosphere.
7
67
aReaction conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%), PhI(OAc)2
(3.0 equiv), NaHCO3 (2.0 equiv) in toluene (1 mL) under N2 at 105 oC for 24
h. bIsolated yield.
With the optimized conditions in hand, we began to examine
the scope of substrates. As shown in Table 3, the substrates
possessing either primary or secondary hydroxyl groups were
cyclized efficiently under the standard conditions, providing five-
membered or six-membered products in high yields (entries 1-4).
When 1.5 equivalents of PhI(OAc)2 were used, the methyl group
was also activated to undergo the intramolecular
functionalization, affording the cyclized products 2e and 2f
(entries 5 and 6). Furthermore, the more complicate substrate,
1,2-cis-cyclopentane derivative 1g was checked, and the desired
product 2g was obtained in 71% isolated yield (entry 7). When 2-
phenylethan-1-ol 1h was employed as the reactant, the
isochroman derivative 2h was obtained in high yield (entry 8).
The benzyl alcohol derivative 1p gave the oxidized product
benzaldehyde 2p instead of the cyclized product (entry 9). We
also tried to synthesize the seven-membered cyclic ethers, but
failed to get the products.
Since isobenzofuran-1(3H)-one derivatives possess a wide
range of biological activities,1c, 12 encouraged by the successful
synthesis of cyclic ethers via intramolecular oxidation of β-
3
−H bonds, we further explored the
C(sp )
application of this
protocol in the synthesis of isobenzofuran-type lactones. As
displayed in Table 4, it was found that the optimized reaction
conditions are also effective for the formation of both aromatic
and aliphatic lactones. Either the electron-rich or the electron-
deficient phenyl carboxylic acid substrates were transformed into
the corresponding isobenzofuran-1(3H)-one derivatives in good
yields (entries 1-4). Moreover, this reaction proceeded smoothly
on naphthyl carboxylic acid substrate 1m, producing lactone 2m
in 77% isolated yield (entry 5). Thienylcarboxylic acid 1n also
underwent this reaction, affording product 2n (entry 6). Besides
aromatic acids, the aliphatic δ-lactone derivative 2o was prepared
from the aliphatic acid 1o (entry 7). Finally, the directing group
was removed smoothly using the mild N-nitrosylation/hydrolysis
sequence, as exemplified in the deprotection of 2a (Scheme 2).
Table 4. Synthesis of lactones via intramolecular oxidation of
β-C(sp3)−H bondsa
entry
1
substrate
product
yield
(%)b
80
76
2
3
74
85
Scheme 2. Removal of the directing group
As shown in Table 3, when benzyl alcohol 1p was used as the
starting material, benzaldehyde 2p was obtained in 78% yield, no
cyclic product was detected. We reasoned that the coordination
of OH to Pd center would occur at the beginning, and this
intermediate thus could undergo β-H elimination of the benzyl
position to give the oxidized product benzaldehyde, other than C-
O reductive elimination to furnish the cyclized product. Based on
this result, a plausible mechanism for the cyclization reaction is
proposed (Scheme 3). A five-membered cyclopalladium (II)
intermediate A is initially formed by the coordination of PdII to
the bidentate directing group, which is followed by the oxidation
of PdII to PdIV to generate the intermediate B. The intermediate B
undergoes ligand exchange to form C. This intermediate C is
subsequently subjected to C-O reductive elimination, leading to
4
5
6
77
64

4
Tetrahedron
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the formation of product 2a, meanwhile Pd(OAc)2 is
regenerated from the PdIV species.
5. For some examples of Pd-catalyzed C(sp2)–H acyloxylation, see:
(a) ref 4c; (b) ref 6a; (c) Desai, L. V.; Stowers, K. J.; Sanford, M.
S. J. Am. Chem. Soc. 2008, 130, 13285; (d) Vickers, C. J.; Mei,
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Takenaka, K.; Akita, M.; Tanigaki, Y.; Takizawa, S.; Sasai, H.
Org. Lett. 2011, 13, 3506.
6.
(a) Yang, M.; Jiang, X.; Shi, W.-J.; Zhu, Q.-L.; Shi, Z.-J. Org.
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Q. Org. Lett. 2012, 14, 1078; (c) Zhao, J.; Zhang, Q.; Liu, L.; He,
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F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.;
Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 1236; (e) Li,
Y.; Ding, Y. J.; Su, Y. M.; Wang, X. S. Org. Lett. 2013, 15, 2574;
(f) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc. 2013, 135,
9350.
7. For some examples of Pd-catalyzed C(sp3)–H acyloxylation, see:
(a) ref 4a; (b) ref 4b; (c) Desai, L. V.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 9542; (d) Wang, D. H.; Hao, X.
S.; Wu, D. F.; Yu, J. Q. Org. Lett. 2006, 8, 3387; (e) Reddy, B. V.
S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391; (f) Zhang,
J.; Khaskin, E.; Anderson, N. P.; Zavalij, P. Y.; Vedernikov, A. N.
Chem. Commun. 2008, 3625; (g) Rit, R. K.; Yadav, M. R.; Sahoo,
A. K. Org. Lett. 2012, 14, 3724; (h) Ren, Z.; Mo, F.; Dong, G.-B.
J. Am. Chem. Soc. 2012, 134, 16991; (i) Chen, X.; Hao, X.-S.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790; (j)
Lee, J. M.; Chang, S.; Tetrahedron Lett. 2006, 47, 1375; (k)
Mahmoodi, N. O.; Salehpour, M. J. Heterocycl. Chem. 2003, 40,
875; (l) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White,
M. C. J. Am. Chem. Soc. 2006, 128, 9032; (m) Takenaka, K.;
Akita, M.; Tanigaki, Y.; Takizawa, S.; Sasai, H. Org. Lett. 2011,
13, 3506; (n) Novk, P.; Correa, A.; Gallardo-Donaire, J.; Martin,
R. Angew. Chem. Int. Ed. 2011, 50, 12236.
Scheme 3. Proposed mechanism
In summary, we have developed a unified method to
synthesize cyclic ethers and lactones via Pd(II)-catalyzed
intramolecular C-H functionalization of the β-methylene of
carboxylic acid derivatives using the bidentate directing group.
This protocol is more straightforward and step-economical than
the traditional approaches, affording the products in good to
excellent yields. The disclosed method may hold the promise for
the efficient synthesis of complex and therapeutically useful
molecules.
Acknowledgments
8. For some examples of Pd-catalyzed C(sp3)–H alkoxylations, see:
(a) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 7313; (b) Chen, F.-J.;
Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S. Q.; Shi, B.-F.
Chem. Sci. 2013, 4, 4187; (c) Shan, G.; Yang, X.; Zong, Y.; Rao,
Y. Angew. Chem. Int. Ed. 2013, 52, 13606; (d) Yang, X.-L.; Sun,
T.-Y.; Rao, Y. Chem. Eur. J. 2016, 22, 3273.
This work was financially supported by the Grants
(2012CB822100 and 2013CB910700) from the Ministry of
Science and Technology of China, and the National Natural
Science Foundation of China (Grant No. 21232002).
Supplementary data
9. Thompson, S. J., Thach, D. Q., Dong, G.-B. J. Am. Chem. Soc.
2015, 137, 11586.
10. Liu, M. L.; Niu, Y. H.; Wu, Y.-F.; Ye, X.-S. Org. Lett. 2016, 18,
Supplementary
data
(experimental
procedures,
characterization of compounds, and copies of NMR spectra)
associated with this article can be found, in the online version, at
http://
1836.
11. Shi’ work using 2-(pyridin-2-yl)propan-2-amine as directing
group: (a) Zhang, Q.; Chen, K.; Rao, W.-H.; Zhang, Y.; Chen, F.-
J., Shi, B.-F. Angew. Chem. Int. Ed. 2013, 52, 13588; (b) Zhang,
Q.; Yin, X.-S.; Zhao, S.; Fang, S.-L.; Shi, B.-F. Chem.
Commun. 2014, 50, 8353.
12. (a) Petrignet, J.; Ngi, S. I.; Abarbri, M.; Thibonnet, J.
Tetrahedron Lett. 2014, 56, 982; (b) Youn, S. W.; Song, S. H.;
Park, J. H. Org. Lett. 2014, 16, 1028.
References and notes
1. (a) Lorente, A.; Lamariano-Merketegi, J.; Albericio, F.; Álvarez,
M. Chem. Rev. 2013, 113, 4567; (b) Usia, T.; Watabe, T.; Kadota,
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2. For recent reviews on C-H activation, see: (a) Daugulis, O., Do
H.-Q., Shabashov, D. Acc. Chem. Res. 2009, 42, 1074; (b)
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780;
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Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902; (e) Lyons, T.
W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; (f) Gutekunst, W.
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3. For a review on C–O bond formation through C-H activation, see:
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4. For some examples of Pd-catalyzed C(sp2)–H alkoxylations, see:
(a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.

5
Highlights
ꢀ An efficient synthesis of lactones or cyclic
ethers has been realized.
ꢀ The reaction involves C(sp3)-H activation and
intramolecular C-O functionalization.
ꢀ Both lactones and cyclic ethers can be prepared
using the same conditions.
ꢀ This protocol is straightforward and step-
economical.