Metal-Free Decarboxylative Alkoxylation of 2-Picolinic Acid and Its Derivatives with Cyclic Ethers: One Step Construction of C-O and C-Cl Bonds

Article abstract of DOI:10.1021/acs.orglett.8b02896

A new strategy for the metal-free decarboxylative alkoxylation of 2-picolinic acid and its derivatives is described. The three-component reaction of 2-picolinic acid or its derivatives, cyclic ethers, and ^tBuOCl proceeded smoothly in the presence of a catalytic amount of p-chloranil to produce 2-alkoxylated pyridines with an ω -chlorine atom in satisfactory to excellent yields. New C-O and C-Cl bonds were generated in one step. The ω-C-Cl bond can be easily transformed to a C-C or C-heteroatom bond, increasing the use of 2-alkoxylated pyridine products in organic synthesis. The electronic property of the substituent linked on the pyridine ring did not influence the reactivity of the 2-picolinic acid substrates.

Full text of DOI:10.1021/acs.orglett.8b02896

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metal-Free Decarboxylative Alkoxylation of 2‑Picolinic Acid and Its
Derivatives with Cyclic Ethers: One Step Construction of C−O and
C−Cl Bonds
Xiaoqiang Yu,† Min He, Jianglin Wu, Chuancheng Zhou, Xiujuan Feng, Yoshinori Yamamoto,
and Ming Bao*
†
†
†
†
†,‡,§
,
†
†
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023 Liaoning, China
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
‡
§
*
S Supporting Information
ABSTRACT: A new strategy for the metal-free decarboxylative
alkoxylation of 2-picolinic acid and its derivatives is described.
The three-component reaction of 2-picolinic acid or its
t
derivatives, cyclic ethers, and BuOCl proceeded smoothly in
the presence of a catalytic amount of p-chloranil to produce 2-
alkoxylated pyridines with an ω-chlorine atom in satisfactory to excellent yields. New C−O and C−Cl bonds were generated in
one step. The ω-C−Cl bond can be easily transformed to a C−C or C−heteroatom bond, increasing the use of 2-alkoxylated
pyridine products in organic synthesis. The electronic property of the substituent linked on the pyridine ring did not influence
the reactivity of the 2-picolinic acid substrates.
he 2-substituted pyridine structural motifs have fre-
Scheme 1. Synthesis of 2-Alkoxylated Pyridines
T
quently been found in the frameworks of various natural
1
products, pharmaceuticals, materials, and ligands. As a
member of this family, 2-pyridyl ethers have attracted
considerable attention due to their fungicidal, insecticidal/
2
acaricidal, and herbicidal activities. For example, 2-pyridyl
ethers constitute the core structures of commercial drugs and
pesticides, such as pre-emergence herbicide, picoxystrobin, and
3
imaging agents (Figure 1). Therefore, the development of
Figure 1. Bioactive compounds containing pyridine structural motifs.
new methods for the synthesis of 2-pyridyl ether derivatives
9
4
bonds. The advantages of using carboxylates as leaving groups
has attracted considerable attention. The Ullmann, Chan−
5
6
for regiospecific coupling is that aromatic carboxylic acids show
good stability, low cost, and high commercial availability.
However, 2-pyridyl ethers are difficult to obtain through the
transition-metal-catalyzed decarboxylative cross-coupling reac-
tion of 2-picolinic acids with alcohols (Scheme 1, eq 2). We
also failed to obtain 2-pyridyl ether by the palladium-catalyzed
decarboxylative cross-coupling reaction of 2-picolinic acid with
hexan-1-ol. The reason could be the generally harsh
conditions required by decarboxylative carbometalation to
Lam−Evans, and Buchwald−Hartwig reactions are tradi-
10
tional methods for the synthesis of 2-pyridyl ether derivatives
(Scheme 1, eq 1). In these transition-metal-catalyzed reactions,
specific ligands or Lewis acids are generally required because
the ligating ability of the nitrogen atom can lead to catalyst
deactivation and the electronic properties of specific ring
11
7
positions can be unfavorable for elementary reactions. In
1
2
addition, the use of organoboronic acids and organohalides as
the starting materials causes increasing production cost owing
8
extrude CO and the fast protodemetalation of the resulting
2
to their tedious and sluggish preparation.
In the past decade, a rapidly growing number of
decarboxylative reactions have been discovered for the
regioselective construction of C−C and C−heteroatom
Received: September 10, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02896
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carbometallic species under such conditions before a C−O
Table 2. Decarboxylative Alkoxylation of Picolinic Acid and
Its Derivatives with 1,4-Dioxane
9c,11
a
bond coupling reaction.
Conducting research on new strategies of metal-free
1
3
amidation of quinoline N-oxides, we found that the
t
decarboxylation of 2-picolinic acids with BuOCl and cyclic
ethers in the presence of a catalytic amount of p-chloranil
proceeds smoothyl to produce 2-alkoxylated pyridine deriva-
tives with an ω-chlorine atom (Scheme 1, eq 3). The results
are reported in the current work.
In our initial studies, the reaction of picolinic acid (1a) with
,4-dioxane was chosen as a model reaction to optimize the
1
reaction conditions. The results are shown in Table 1. Several
a
Table 1. Optimization of the Reaction Conditions
b
entry
oxidant
BQ
Cl source
yield (%)
1
2
3
4
5
6
7
8
9
tBuOCl
tBuOCl
tBuOCl
tBuOCl
tBuOCl
tBuOCl
tBuOCl
KCl
11
5
DDQ
9,10-PQ
8
c
m-CPBA
p-bromanil
p-chloranil
none
NR
52
63
c
NR
c
p-chloranil
p-chloranil
p-chloranil
p-chloranil
p-chloranil
p-chloranil
NR
NR
NR
NR
c
NaCl
NCS
c
1
1
1
1
0
1
2
c
DDQ
d
t
BuOCl
90
55
3 ,
de
tBuOCl
a
Reaction conditions: 2-picolinic acid (1a, 0.3 mmol), Cl source (0.3
mmol), oxidant (0.03 mmol, 10 mol %), and 1,4-dioxane (3.0 mL, 33
b
c
equiv) under N atmosphere at 110 °C for 12 h. Isolated yield. No
2
d
reaction; starting material 1a was recovered. Using 0.5 mmol
t
e
BuOCl. Using 10.0 equiv of 1,4-dioxane (0.26 mL).
oxidants, including benzoquinone (BQ), 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ), 9,10-phenanthrenequi-
none (9,10-PQ), m-chloroperoxybenzoic acid (m-CPBA), p-
bromanil, and p-chloranil, were initially examined using
t
BuOCl as the chlorine source in dioxane at 110 °C for 12 h
(
entries 1−6). The use of p-chloranil as an oxidant led to the
formation of the desired product 2-(2-(2-chloroethoxy)-
ethoxy)-pyridine (2a) in relatively high yield (entry 6 vs
entries 1−5). No reaction was observed when the mixture of
t
1
a, BuOCl, and 1,4-dioxane was treated in the absence of an
oxidant (entry 7). The chlorine source was subsequently
screened using p-chloranil as the oxidant. No reaction was
observed when KCl, NaCl, N-chlorosuccinimide (NCS), and
DDQ were examined as chlorine sources. To improve the yield
t
of product 2a, we increased the amount of BuOCl from 0.3 to
0
.5 mmol. Gratifyingly, a yield of 90% was attained (entry 12).
The yield of 2a was decreased along with the decreased
amount of dioxane (entry 13). Therefore, the subsequent
reactions of picolinic acid substrates 1 with 1,4-dioxane were
t
performed using chloranil and BuOCl as the oxidant and
chlorine source, respectively, at 110 °C for 12 h.
The reactions of the picolinic acid substrates 1a−1r were
allowed to proceed under optimal conditions. The results are
summarized in Table 2. As described in Table 1, desired
B
DOI: 10.1021/acs.orglett.8b02896
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. continued
Table 3. Decarboxylative Alkoxylation of Picolinic Acid and
Its Derivatives with Cyclic Ethers
a
a
t
Reaction conditions: 2-picolinic acid (1, 0.3 mmol), BuOCl (0.5
mmol), p-chloranil (10 mol %), and 1,4-dioxane (3.0 mL) under N
2
b
c
atmosphere at 110 °C for 12 h. Isolated yield. Reaction performed
d
e
for 20 h. Reaction performed for 30 h. No reaction was observed,
f
t
and 1k was recovered completely. Using 0.6 mmol BuOCl (2.0
equiv) and 20 mol % p-chloranil with the reaction mixture treated for
48 h.
product 2a was obtained in 90% yield (entry 1). Reactions of
1
b−1d having a methyl group on the pyridine ring at the 3-, 4-,
and 5-positions, respectively, afforded the corresponding
products in high yields (83−88%, entries 2−4). The reactions
of substrates 1e−1g bearing electron-withdrawing groups
(
CO Me, NO , and CF ) on the pyridine ring at the 5-
2 2 3
position afforded the desired products 2e−2g in 81−90%
yields (entries 5−7). These results indicate that the electronic
property of the substituent linked on the pyridine ring did not
influence the reactivity of 2-picolinic acid substrates.
Interestingly, the decarboxylative alkoxylation reaction selec-
tively occurred at the 2-position when the substrates 1h−1j
bearing two carboxyl (CO H) groups on the pyridine ring
2
were treated under optimum conditions (entries 8−10).
However, the substrate 1k having two CO H groups at the
2
2
1
- and 6-positions did not produce desired product 2k (entry
1); this result can be attributed to the formation of a stable
intramolecular hydrogen bond between nitrogen atom and two
CO H groups. The chlorine atom linked on the pyridine ring
2
was tolerated in this type of decarboxylative alkoxylation
reaction; the desired products 2l−2o were obtained in
moderate to good yields (62−86%, entries 12−15). Product
a
t
Reaction conditions: 2-picolinic acid (1, 0.3 mmol), BuOCl (0.6
mmol), p-chloranil (20 mol %), and cyclic ether (3.0 mL) under a N
atmosphere at 110 °C for 48 h. Isolated yield.
2
b
2
o is a type of pre-emergence herbicide. The reactions of
substrates 1p−1r having quinoline, isoquinoline, and quinoxa-
line motifs, respectively, were finally performed. Desired
products 2p−2r were obtained in 80−95% yields (entries
Scheme 2. Control Experiments
1
6−18).
We then examined the reaction with various cyclic ethers
under the optimized reaction conditions. The results are
summarized in Table 3. The reaction of 2-picolinic acid 1a
with tetrahydrofuran produced 2s in only 35% yield (entry 1).
Low yields were also observed in the reactions of 1b and 1q
with tetrahydrofuran under the optimized reaction conditions
(
entries 2 and 3). The low yields observed may be attributed to
the low boiling point of tetrahydrofuran. The six-membered
cyclic ether tetrahydro-2H-pyran afforded the corresponding
product 2v in 63% yield (entry 4). The reaction of 1a with
oxepane proceeded smoothly in the presence of p-chloranil and
t
BuOCl to afford the desired product 2w in 80% yield (entry
5
).
Control experiments were conducted to gain insight into the
recovered [Scheme 2, eq (3)]. This phenomenon indicates
that the carboxyl group must be linked on the position near the
nitrogen atom.
mechanism of this type of decarboxylative alkoxylation
reaction. Only a trace amount of 2a was observed when the
reaction of 1a was performed under the optimized reaction
conditions in the presence of 1.5 equiv of 2,2,6,6-tetramethyl-
A plausible reaction mechanism is depicted in Scheme 3 on
the basis of the mechanistic studies described above. Initially,
t
the reaction of p-chloranil with BuOCl may form the mixture
t
1
-piperidinyloxy (TEMPO) [Scheme 2, eq (1)]. This result
of the BuO· radical and semiquinone radical A. Semiquinone
suggests that the target reaction may involve a radical process.
radical A subsequently reacts with 1a to produce semiquinone
t
No decarboxylation reaction occurred when 1a was treated
with di-t-butylperoxide instead of BuOCl; 1a was recovered
completely [Scheme 2, eq (2)]. This indicates that the BuOCl
radical B and zwitterionic intermediate C. The BuO· radical
t
t
derived from BuOCl reacts with semiquinone radical B to
t
t
14
form BuOH and regenerate p-chloranil. Meanwhile,
is required for the reaction to proceed. No reaction was
observed when nicotinic acid (1s) was treated under the
optimized reaction conditions; starting material 1s was
zwitterionic intermediate C releases CO , resulting in a ylide,
2
15
N-chloro pyridinium D. A resonance possibly exists between
16
ylide D and N-chloro carbene E. Subsequently, E undergoes
C
DOI: 10.1021/acs.orglett.8b02896
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Plausible Mechanism
standing Young Scholars Development Growth Plan of
Universities in Liaoning Province (LJQ2015027).
REFERENCES
■
(
1) (a) Arena, C. G.; Arico, G. Curr. Org. Chem. 2010, 14, 546−580.
(
b) Schlosser, M.; Mongin, F. Chem. Soc. Rev. 2007, 36, 1161−1172.
(
c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627−646. (d) Henry, G.
D. Tetrahedron 2004, 60, 6043−6061.
(
2) (a) Li, J. J.; Johnson, D. S. Modern Drug Synthesis; Wiley:
Hoboken, NJ, 2010. (b) Li, J. J.; Johnson, D. S.; Sliskovic, D. R.; Roth,
B. D. Contemporary Drug Synthesis; Wiley-Interscience: Hoboken, NJ,
2
(
004.
3) (a) Zha, Z. H.; Choi, S. R.; Ploessl, K.; Lieberman, B. P.; Qu, W.
C.; Hefti, F.; Mintun, M.; Skovronsky, D.; Kung, H. F. J. Med. Chem.
011, 54, 8085−8098. (b) Ran, Z. J.; Yuan, H. Z.; Cao, A. C. Z.; Qin,
2
H. Chin. J. Pestic. Sci. 2010, 12, 458−462. (c) Ran, Z. J.; Ni, H. W.;
Duan, H. X.; Li, N.; Dong, Y. H.; Fu, B.; Xiao, Y. M.; Qin, Z. H. Chin.
J. Pestic. Sci. 2009, 22, 41−46. (d) Whitaker, R. L.; Smith, H. Q.;
Wash, T.; Pa, M. 3,5-dichloro-2-pyridoxyethyl ethers as herbicide. US
3
(
,894,862[P].
4) March, J. Advanced Organic Chemistry; Wiley-Interscience:
Hoboken, NJ, 1992.
5) For reviews on this topic, see: (a) Monnier, F.; Taillefer, M.
Angew. Chem., Int. Ed. 2009, 48, 6954−6971. (b) Hartwig, J. F. Nature
008, 455, 314−322. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400−5449. (d) Hartwig, J. F. Angew. Chem., Int. Ed.
998, 37, 2046−2067.
6) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
(
2
a C−O and C−Cl coupling reaction with 1,4-dioxane to form
product 2a.
1
(
In conclusion, we have developed a new and efficient
method to synthesize 2-alkoxylated pyridines under metal-free
conditions. The decarboxylative alkoxylation of 2-picolinic acid
Tetrahedron Lett. 1998, 39, 2933−2936. (b) Evans, D. A.; Katz, J. L.;
West, T. R. Tetrahedron Lett. 1998, 39, 2937−2940. (c) Lam, P. Y. S.;
Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941−2067.
t
and its derivatives with BuOCl and cyclic ethers proceeded
(
7) Shen, Q. L.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734−
735.
8) Katritzky, A. R.; Taylor, R. J. K. Comprehensive Organic
smoothly in the presence of a catalytic amount of p-chloranil
via a carbene intermediate to afford 2-pyridyl ethers with ω-
chlorine atom in satisfactory to excellent yields. Further
manipulation of a ω-C−Cl bond may produce other useful
compounds. The new strategy for generation of a carbene
intermediates from 2-picolinic acids was established in the
current paper. Further investigations into the synthetic
applications of the carbene intermediates are ongoing.
7
(
Functional Group Transformations II; Elsevier, Dordrecht, 2004;
Chapter 2, p 561.
(9) For selected examples, see: (a) Liu, C.; Wang, X. Q.; Li, Z. D.;
Cui, L.; Li, C. Z. J. Am. Chem. Soc. 2015, 137, 9820−9823. (b) Zhou,
M. X.; Chen, M.; Zhou, Y.; Yang, K.; Su, J. H.; Du, J. F.; Song, Q. L.
Org. Lett. 2015, 17, 1786−1789. (c) Hu, G. B.; Gao, Y. X.; Zhao, Y. F.
Org. Lett. 2014, 16, 4464−4467. (d) Wang, P. F.; Wang, X. Q.; Dai, J.
J.; Feng, Y. S.; Xu, H. Org. Lett. 2014, 16, 4586−4589. (e) Zhang, Y.;
Patel, S.; Mainolfi, N. Chemical Science 2012, 3, 3196−3199. (f) Ranjit,
S.; Duan, Z. Y.; Zhang, P. F.; Liu, X. G. Org. Lett. 2010, 12, 4134−
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02896.
4
(
136.
10) For reviews on this topic, see: (a) Rodriguez, N.; Goossen, K.
Chem. Soc. Rev. 2011, 40, 5030−5048. (b) Shang, R.; Liu, L. Sci.
China: Chem. 2011, 54, 1670−1687. (c) Goossen, L. J.; Rodriguez,
N.; Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100−3120.
Experimental procedures and characterization data
(PDF)
(11) For selected examples, see: (a) Goossen, L. J.; Manjolinho, F.;
Khan, B. A.; Rodríguez, N. J. J. Org. Chem. 2009, 74, 2620−2623.
b) Goossen, L. J.; Linder, C.; Rodríguez, N.; Lange, P. P.; Fromm, A.
Chem. Commun. 2009, 46, 7173−7175.
12) The Pd- and Cu-catalyzed decarboxylative cross-coupling
reactions of 2-picolinic acid with hexan-1-ol were examined. In these
reactions, the protonation reaction occurred to afford pyridine as
major product, and the alkoxylation product was not detected at all.
For details, see the Supporting Information.
AUTHOR INFORMATION
Corresponding Author
E-mail: mingbao@dlut.edu.cn.
(
■
(
*
ORCID
Xiaoqiang Yu: 0000-0001-9396-3882
Ming Bao: 0000-0002-5179-3499
Notes
(13) Yu, X. Q.; Yang, S. N.; Zhang, Y.; Guo, M. J.; Yamamoto, Y.;
Bao, M. Org. Lett. 2017, 19, 6088−6091.
t
(
14) The BuOH is determined by GCMS, and its spectrum is
available in the Supporting Information.
15) (a) Haake, P.; Mantecon, J. J. Am. Chem. Soc. 1964, 86, 5230−
234. (b) Brown, B. R.; Hammick, D. L. J. Chem. Soc. 1949, 659−663.
c) Ashworth, M. R. F.; Daffern, R. P.; Hammick, D. L. J. Chem. Soc.
939, 0, 809−812.
(16) (a) Rosello-Merino, M.; Díez, J.; Conejero, S. Chem. Commun.
2010, 46, 9247−9249. (b) Cabeza, J. A.; Del Río, I.; Perez-Carreno,
The authors declare no competing financial interest.
(
5
́
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21572028 and 21573032) for their financial
support. This work was also supported by the Liaoning Natural
Science Foundation of China (201602181) and the Out-
(
1
́
́
̃
D
DOI: 10.1021/acs.orglett.8b02896
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
E.; Sanchez-Vega, M. G.; Vazquez-García, D. Angew. Chem., Int. Ed.
́ ́
2
009, 48, 555−558. (c) Conejero, S.; Lara, P.; Paneque, J. M.;
Petronilho, M.; Poveda, L.; Serrano, O.; Vattier, F.; Alvarez, E.; Maya,
C.; Salazar, V.; Carmona, E. Angew. Chem., Int. Ed. 2008, 47, 4380−
4
383. (d) Song, G. Y.; Zhang, Y.; Su, Y.; Deng, W. Q.; Han, K. L.; Li,
́
X. W. Organometallics 2008, 27, 6195−6201. (e) Alvarez, E.;
Conejero, S.; Lara, P.; Lopez, J. A.; Paneque, M.; Petronilho, A.;
Poveda, M. L.; del Río, D.; Serrano, O.; Carmona, E. J. Am. Chem. Soc.
́
́
007, 129, 14130−14131. (f) Alvarez, E.; Conejero, S.; Paneque, M.;
2
Petronilho, A.; Poveda, M. L.; Serrano, O.; Carmona, E. J. Am. Chem.
Soc. 2006, 128, 13060−13061. (g) Owen, J. S.; Labinger, J. A.;
Bercaw, J. E. J. Am. Chem. Soc. 2004, 126, 8247−8255.
E
DOI: 10.1021/acs.orglett.8b02896
Org. Lett. XXXX, XXX, XXX−XXX