Regioselective C-H chlorination: Towards the sequential difunctionalization of phenol derivatives and late-stage chlorination of bioactive compounds

Article abstract of DOI:10.1039/c7ra09939h

We have developed a protocol for the auxillary directed C-H chlorination of phenol derivatives using catalytic amounts of palladium acetate that is amenable to the late-stage chlorination of diflufenican and estrone. The 2-pyridine group allows for a highly efficient palladium-catalyzed chlorination and sequential ortho C-H functionalization reaction of phenol derivatives to produce a variety of symmetrical and unsymmetrical 2,4,6-trisubstituted phenols.

Full text of DOI:10.1039/c7ra09939h

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PAPER
Regioselective C–H chlorination: towards the
sequential difunctionalization of phenol derivatives
and late-stage chlorination of bioactive
compounds†
Cite this: RSC Adv., 2017, 7, 46636
b
Chao Gao,b Hongchen Li,b Miaochang Liu,b Jinchang Ding,b Xiaobo Huang,
b
ac
Huayue Wu, Wenxia Gaob and Ge Wu
*
*
We have developed a protocol for the auxillary directed C–H chlorination of phenol derivatives using
catalytic amounts of palladium acetate that is amenable to the late-stage chlorination of diflufenican and
Received 6th September 2017
Accepted 25th September 2017
estrone. The 2-pyridine group allows for
a highly efficient palladium-catalyzed chlorination and
DOI: 10.1039/c7ra09939h
sequential ortho C–H functionalization reaction of phenol derivatives to produce
a variety of
rsc.li/rsc-advances
symmetrical and unsymmetrical 2,4,6-trisubstituted phenols.
former was only effective for electron-decient phenols,
whereas, the later oen gave the undesired para-substituted
phenols. Moreover, palladium-catalyzed C–H chlorination of
phenyl carbamate was also reported.2j Up to now, the metal-
catalyzed double C–H functionalization of phenol and their
derivatives has not been explored and remains a great chal-
lenge. Therefore, an efficient and general methodology for the
synthesis of densely functionalized phenol and derivatives is
highly desired.
Introduction
Catalytic C–H activation/chlorination is one of the most effi-
cient pathways to prepare aryl chlorides.1,2 The resulting aryl
chlorides serve as synthetic handles that participate in transi-
tion metal catalyzed cross-coupling reactions,3 and they also
function as precursors of organometallic reagents utilized for
nucleophilic addition and substitution reactions.4 Currently,
their use in the development of site-selective chlorination of
phenol is highly attractive as these compounds are prevalent in
numerous pharmaceuticals and agrochemicals, such as Nitro-
fungin,5a Lofexidine,5b Chloroxynil5c and Sportak5d (Scheme 1a).
Currently, electrophilic aromatic substitution represents the
leading strategy to obtain chlorinated phenols (Scheme 1b), yet
producing a mixture of ortho and para substituted products. In
addition, many efforts have been devoted toward the develop-
ment of new routes to ortho-chlorinated phenols, including
dehalogenation,6 arene oxidation,7 or O-methoxymethyl
directed lithiation.8 However, these methods suffer from limi-
tations, such as requirement of harsh reaction condition and
limited substrate scope. Recently, efficient methods have been
developed. Snider demonstrated that bulky amine catalyzed
ortho-chlorination of phenols by sulfuryl chloride.9 Gustafson
reported the preparation of ortho-chlorinated phenols by
employing Nagasawa's bis-thiourea catalyst.10 However, the
2-Aryloxypyridines are ubiquitous motif found in numerous
biologically active molecules and pesticide.11 During the past
few years, palladium-catalyzed ortho mono-arylation,12 -nitra-
tion,13
-alkenylation,14
-acylation,15
-uorination,16
aSchool of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035,
People's Republic of China. E-mail: wuge@wmu.edu.cn
bCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou
325035, People's Republic of China. E-mail: huayuewu@wzu.edu.cn
cState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectral data. See DOI: 10.1039/c7ra09939h
Scheme
functionalization phenols.
1 Synthesis and application of chloro-containing multi-
46636 | RSC Adv., 2017, 7, 46636–46643
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-acetoxylation17 -alkoxylation,18 and sulfonylation19 of
2-aryloxypyridines have been developed. However, to the best of
our knowledge, selective chlorination, bromination, iodination
and borylation of 2-aryloxypyridines have not been reported.
Herein, we report a new protocol for double symmetrical and
unsymmetrical C–H functionalization of phenols, directed by
a removable 2-pyridine group, enabling the introduction of two
Cl or different functional groups (Cl/F, Br, I, NO2 and Bpin) into
ortho positions of phenols (Scheme 1c).
Results and discussion
At the onset of this project, we selected 2-phenoxypyridine (1a)
and NCS as a model substrates to examine the feasibility of
palladium-catalyzed C–H chlorination reaction. As shown in
Table 1, we observed that the choice of additive had a consid-
erable impact on the chlorination reactions. Further explora-
tion conrmed that TsOH was the most efficient promoter.
However, no signicant results could be achieved when K2S2O8
or Na2S2O8 used as the additive.2h It is worth noting that when
the reaction was conducted in a coordinating solvent, such as
Scheme 2 C–H chlorination of 2-aryloxylpyridine. aConditions: 1 (0.2
DMF and dioxane, the desired product was not observed, and mmol), NCS (3.0 equiv.), Pd(OAc)2 (10 mol%), TsOH (10 mol%), EtOAc
(2.0 mL), 110 ꢀC, under N2, 6 h, isolated yields. bNCS (2.0 equiv.), DMF
(2.0 mL), 100 ꢀC, under open air, 2 h, isolated yields.
the starting material was recoveried. Lowering the amount of
NCS decrease the yield of 3a to 58%, and 10% of the mono-
chlorinated product was isolated. Finally, the optimal yield of
dichlorinated product 3a was obtained when 2-phenoxypyridine
With the optimal conditions in hand, we next examined the
and NCS (molar ration 1.0 : 3.0) were stirred in EtOAc in the
presence of Pd(OAc)2 (10 mol%) and TsOH (10 mol%) at 100 ꢀC
for 6 h. The practical utilization of current method was
demonstrated by scaling up the reaction: when 1a was subjected
to dichlorination on 10 mmol scale, 3a was obtained in 69%
yield (entry 1). Interestingly, we found that when 2.0 equiv. of
NCS in DMF, only para-chlorination product (3a0) was obtained
(Scheme 2) in 90% yield without any trace of isomers.
scope of 2-aryloxypyridines. As shown in Scheme 2, both
electron-donating and -withdrawing groups at ortho-, meta-, or
para-position of phenyl groups were well tolerated and afforded
the corresponding chlorinated products in good to excellent
yields. It is worth mentioning that the degree of chlorination is
dependent on the substitutent on phenyl ring of 2-phenox-
ypyridine derivatives. When para-positions of 2-phenoxypyr-
idine were substituted by a methyl (3b), chloride (3c), bromide
(3d), ester (3e), nitro (3f), triuoromethyl (3g) and tri-
uoromethoxy (3h), the corresponding dichlorination products
were yields. In contrast, when 2-aryloxypyridine bearing
a phenyl (3i), aldehyde (3j), nitrile (3k), methoxy (3l) and uoro
(3m) in para-position, affording the monochlorination prod-
ucts. Notably, the chlorination reaction was highly steric
sensitive, in the cases of 1n–p, the less congested C–H bonds of
the meta-position of 2-phenoxypyridines (3n–p) were regiose-
lectively chlorinated. Furthermore, the ortho-substituted 2-ary-
Table 1 Optimization of double-chlorination reactiona
Equiv. of
NCS
Entry
Additive
Solvent
Yieldb% loxypyridines (3q–v) are also viable substrates in the current
reaction, giving the corresponding products in good yields.
The diversity of 2-phenoxypyridines for dichlorination was
examined. As shown in Scheme 3, we found that the dichlori-
0
1
2
3
4
5
6
7
8
9
TsOH
AcOH
K2S2O8
Na2S2O8
AgOAc
TsOH
TsOH
TsOH
TsOH
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DMF
Dioxane
Toluene
EtOAc
83 (69)c
22
nation of 2-phenoxypyridine derivatives bearing electron-rich
substitutents on pyridine rings reacted smoothly providing
the corresponding dichlorinated products in fair to excellent
yields (5a–i). The reactions of electron-decient substrates, gave
lower yields of products (5a, 5g). Probably containing the
electron-withdrawing substituents 2-phenoxypyridines weakens
their coordinating abilities and lowers their activities of
phenol's C–H bonds.
0
0
Trace
Trace
62
58
a
Conditions: 1 (0.2 mmol), NCS (3.0 equiv.), Pd(OAc)2 (10 mol%),
b
additive (10 mol%), solvent (2.0 mL), 110 ꢀC, under N2, 6 h. Isolated
yields. c 10 mmol gram-scalable reaction.
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Scheme 3 C–H chlorination of 2-phenoxypyridine derivatives.
Scheme 5 Sequential C–H functionalization of 2-phenoxypyridine.
aReaction conditions: (a) 3l (0.2 mmol), NFSI (3.0 equiv.), Pd(OAc)2
(10 mol%), EtOAc (2.0 mL), 110 ꢀC, under N2, 6 h, isolated yields. (b) 3l
(0.2 mmol), AgNO2 (2.0 equiv.), Pd(OAc)2 (10 mol%), K2S2O8 (2.0
equiv.), DCE (2.0 mL), 110 ꢀC, under N2, 48 h, isolated yields. (c) 3l
(0.2 mmol), B2pin2 (2.0 equiv.), [RhCp*Cl2]2 (5 mol%), PCy3 (30 mol%),
EtOAc (2.0 mL), 100 ꢀC, under N2, 24 h, isolated yields. (d) 3l
(0.2 mmol), NBS (3.0 equiv.), Pd(OAc)2 (10 mol%), TsOH (10 mol%),
EtOAc (2.0 mL), 110 ꢀC, under N2, 6 h, isolated yields. (e) 3l (0.2 mmol),
NIS (3.0 equiv.), Pd(OAc)2 (10 mol%), TsOH (10 mol%), EtOAc (2.0 mL),
110 ꢀC, under N2, 6 h, isolated yields.
The advantage of 2-pyridyl directing group lies in the possi-
bility of their removal to provide the structurally diversied 2,6-
dichlorinated and 2-chlorinated phenols (Scheme 4).12a Signi-
cantly, the current reaction offer opportunities to synthesis
ortho-chlorination phenols with electron-withdrawing groups
(6b–f, 6j) and electron-donating groups (6a, 6g–i), which nicely
complements the aforementioned approaches (Scheme 5).
With the palladium-catalyzed C–H chlorination protocol in
hand, we tried to achieve sequential C–H functionalization
access to a variety of polysubstituted phenols. We began using
our current monoselective C–H chlorination, which is compat-
ible with various substitutents (3i–m). Three grams of mono-
chlorinated 3l could be prepared in one pot via coupling of 1l
with NCS, further functionalizations of 3l were explored. Sub-
sequential C–H uorination (7a),17 nitration (7b),14 bromination
(7d) and iodination (7e) were quite successful, and the highly
polysubstituted phenols 7a–e were obtained in good yields. We
also developed the Cp*Rh(III)-catalyzed C–H bond borylation of
3l in the presence of PCy3 at 100 ꢀC in EtOAc within 12 h, and 7c
was afforded in 57% yield.
Next, we evaluated the utility of this work in the context of
late-stage functionalization of known bioactive molecular
(Scheme 6). Selective C–H functionalization of a phenyl ring is
always a ticklish problem. Diufenican acts as residual and
foliar herbicide, contains two potential directing groups,
a phenoxy pyridine and amide functionality. To our delight, its
chlorination under the optimized conditions selectively
occurred at the para position of aryloxy group gave the mono-
chlorinated product 8a in 94% yield. Meanwhile, to illustrate
the chemoselectivity, the current palladium-catalyzed chlori-
nation reaction and direct chlorination in DMF of estrone were
comparatively studied (Scheme 6 eqn (2) and eqn (3)), in the
presence of the palladium catalyst, the desired chlorinated
product 8b was isolated in 55% yield, in contrast, utilizing the
aforementioned DMF reaction condition, we didn't observe
appreciable chlorination.
A few control experiments were conducted to shed light on
the mechanism of dichlorination reaction. Kinetic isotope
effect (KIE) studies, between 2-phenoxypyridine and ve-
deuterated 2-phenoxypyridine showed a KIE of 1.8 (Scheme 7,
eqn (1)). It suggested that the C–H dichlorination of phenols
might proceeds the concerted metalation and deprotonation
mechanism.20 When complex A12a was used as the catalyst,
2-phenoxypyridine could be smoothly converted to 3a with NCS
(Scheme 7, eqn (2)), which suggesting that complex A is prob-
ably the catalytically active species.
On the basis of these results and previous literatures,
a plausible reaction mechanism was proposed in Scheme 8. The
reaction begins with the pyridine-assisted ortho C–H activation
of 2-aryloxypyridine to form cyclopalladate complex A, subse-
quently oxidative addition with NCS generated Pd(IV)
Scheme 4 Removal of pyridyl group.
46638 | RSC Adv., 2017, 7, 46636–46643
Scheme 6 Late-stage C–H chlorination of diflufenican and estrone.
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General procedure of palladium-catalyzed C–H chlorination of
2-aryloxylpyridine
A 25 mL Schlenk tube equipped with a stir bar was charged with
2-aryloxylpyridine (0.2 mmol), NCS (0.6 mmol), Pd(OAc)2
(10 mol%), TsOH (10 mol%). The tube was tted with a rubber
septum, and then it was evacuated and relled with nitrogen
three times. Under nitrogen, EtOAc (2 mL) were added in turn to
the Schlenk tube through the rubber septum using syringes,
and then the septum was replaced by a Teon screw cap under
nitrogen ow. The reaction mixture was stirred at 100 ꢀC for 6 h.
Aer cooling down, the reaction mixture was diluted with 10 mL
of ethyl ether, ltered through a pad of silica gel, concentrated
under reduced pressure. The residue was then puried by ash
chromatography on silica gel to provide the corresponding
product.
Scheme 7 Mechanistic studies.
General procedure of DMF promoted C–H chlorination of
2-aryloxylpyridine to afford the para-chlorination product
Scheme 8 Proposed reaction mechanism.
A 25 mL Schlenk tube equipped with a stir bar was charged with
2-aryloxylpyridine NCS (2.0 equiv.), DMF (2 mL) were added in
the Schlenk under open air, then obturated with Teon screw-
ꢀ
cap. The reaction mixture was stirred at 100 C for 2 h. Aer it
intermediate B. Finally, reductive elimination of B afforded the
chlorinated product and regenerates the catalyst. PTSA2f is
probably to play dual roles in the activation N–Cl bond by
protonating a carbonyl group of the NCS, and increasing the
was cooled, the reaction mixture was diluted with 10 mL of ethyl
ether, and ltered through a pad of silica gel, followed by
washing the pad of silica gel with the same solvent (20 mL). The
electrophilicity of the Pd(II) center by replacement of AcOꢁ ltrate was washed with water (3 ꢂ 15 mL). The organic phase
with TsOꢁ.
was dried over Na2SO4, ltered, and concentrated under
reduced pressure. The residue was then puried by ash chro-
matography on silica gel to provide the corresponding product.
Conclusions
In this work, we have described a convenient and straightfor-
ward strategy for C–H chlorination/sequential C–H functional-
ization of phenols, employing 2-pyridyl as the removable group.
A variety of 2,4,6-trisubstituted phenols could be readily
accessed through this step-by-step difunctionalization of both
ortho C–H bonds of phenols. The present protocol could be
applied to the late-stage of diufenican and estrone, to facilitate
drug development, especially for new herbicide agent.
General procedure of removal of pyridyl group
To a solution of 2-(2,6-dichloro-4-methylphenoxy)pyridine (3b)
(101 mg, 0.4 mmol) in dry toluene (10 mL), MeOTf (144 mg,
0.88 mmol) was added. The solution was stirred at 100 ꢀC under
N2 atmosphere for 2 h. The reaction mixture was cooled to
ambient temperature and the solvent was evaporated under
vacuum. The crude product was dissolved in dry methanol
(2.0 mL) and then added to a solution of Na (276 mg, 12 mmol)
in dry methanol (10 mL) under N2 atmosphere. The reaction
mixture was heated to reux for 30 min, cooled to room
temperature. Aer evaporating the solvent under vacuum, water
General information
1H NMR (500 MHz), 13C NMR (125 MHz) and 19F NMR (30 mL) was added, and the aqueous solution was extracted with
(470 MHz) spectra were recorded in CDCl3 solutions using EtOAc. The combined organic layer was dried over anhydrous
a 500 MHz spectrometer. Alternatively, 1H NMR (400 MHz), 13
C
Na2SO4. The solution was concentrated by vacuum and the
NMR (100 MHz) and 19F NMR (377 MHz) spectra were recorded residue was puried by column chromatography on silica gel
in CDCl3 solutions using a 400 MHz spectrometer. High- (hexane/EtOAc: 10/1) to give the corresponding product 6a.
resolution mass spectra were recorded on an ESI-Q-TOF mass
2-(2,6-Dichlorophenoxy)pyridine (3a). Following the general
spectrometer. All reactions were conducted using standard procedure, using 15 : 1 petroleum ether–EtOAc as the eluant
1
Schlenk techniques. Column chromatography was performed afforded yellow liquid (40 mg, 83% yield). H NMR (500 MHz,
1
using EM silica gel 60 (300–400 mesh). H NMR and 13C NMR CDCl3): d 8.10 (d, J ¼ 3.5 Hz, 1H), 7.33 (t, J ¼ 7.0 Hz, 1H), 7.39
spectra are provided as ESI.† 2-phenoxy pyridine derivatives21 (d, J ¼ 8.0 Hz, 2H), 7.14 (t, J ¼ 8.5 Hz, 1H), 7.05 (d, J ¼ 8.0 Hz,
were prepared according to the reported procedures. 1H and 13
spectra of known compounds were in accordance with those 147.4, 146.4, 139.6, 129.8, 128.8, 126.4, 118.7, 110.6; HRMS
C
1H), 7.00 (t, J ¼ 6.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 162.0,
described in the literature.
(TIC): calcd for C11H8Cl2NO [M + H]+ 239.9978, found 239.9976.
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2-(4-Chlorophenoxy)pyridine (3a0). Following the general
procedure, using 15 : 1 petroleum ether–EtOAc as the eluant
afforded yellow liquid (37 mg, 90% yield). H NMR (500 MHz,
CDCl3): d ꢁ62.6 (s, 1F); HRMS (TIC): calcd for C12H7Cl2F3NO
[M + H]+ 307.9852, found 307.9850.
1
2-(2,6-Dichloro-4-(triuoromethoxy)phenoxy)pyridine (3h).
Following the general procedure, using 15 : 1 petroleum ether–
EtOAc as the eluant afforded a light yellow liquid (59.3 mg, 92%
yield). 1H NMR (500 MHz, CDCl3): d 8.09 (d, J ¼ 6.5 Hz, 1H), 7.75
(t, J ¼ 7.0 Hz, 1H), 7.30 (s, 2H), 7.08 (d, J ¼ 8.5 Hz, 1H), 7.03 (t,
J ¼ 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 161.7, 147.3, 145.7
(q, JF ¼ 1.2 Hz), 145.5, 139.8, 130.6, 121.6, 120.3 (q, JF ¼ 256.2
Hz), 119.1, 110.7; 19F NMR (470 MHz, CDCl3): d ꢁ58.1 (s, 3F);
HRMS (TIC): calcd for C12H7Cl2F3NO2 [M + H]+ 323.9801, found
323.9800.
2-((3-Chloro-[1,10-biphenyl]-4-yl)oxy)pyridine (3i). Following
the general procedure, using 15 : 1 petroleum ether–EtOAc as
the eluant afforded yellow liquid (45.6 mg, 81% yield). 1H NMR
(500 MHz, CDCl3): d 8.13 (d, J ¼ 6.0 Hz, 1H), 7.75 (t, J ¼ 8.5 Hz,
1H), 7.60–7.54 (m, 4H), 7.46–7.37 (m, 4H), 7.10–7.01 (m, 2H);
13C NMR (125 MHz, CDCl3): d 172.2, 162.1, 147.4, 145.5, 140.0,
137.7, 138.3, 129.9, 129.0, 128.2, 127.4, 127.0, 121.5, 118.8,
110.7; HRMS (TIC): calcd for C17H13ClNO [M + H]+ 282.0680,
found 282.0684.
CDCl3): d 8.16–8.15 (m, 1H), 7.66 (t, J ¼ 7.3 Hz, 1H), 7.33 (d, J ¼
8.6 Hz, 2H), 7.06 (d, J ¼ 8.5 Hz, 2H), 6.97 (t, J ¼ 5.6 Hz, 1H), 6.90
(d, J ¼ 8.3 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 163.4, 152.7,
147.6, 139.6, 129.8, 129.6, 122.6, 118.8, 111.7; HRMS (TIC): calcd
for C11H8ClNO [M + H]+ 206.0367, found 206.0365.
2-(2,6-Dichloro-4-methylphenoxy)pyridine (3b). Following
the general procedure, using 15 : 1 petroleum ether–EtOAc as
the eluant afforded yellow liquid (35.1 mg, 69% yield). 1H NMR
(500 MHz, CDCl3): d 8.03 (d, J ¼ 4.5 Hz, 1H), 7.65 (t, J ¼ 7.0 Hz,
1H), 7.13 (s, 2H), 6.97–6.91 (m, 2H), 2.26 (s, 3H); 13C NMR (125
MHz, CDCl3): d 161.1, 146.4, 142.9, 138.5, 135.7, 128.3, 128.1,
117.6, 109.6, 19.7; HRMS (TIC): calcd for C12H10Cl2NO [M + H]+
254.0134, found 254.0131.
2-(2,4,6-Trichlorophenoxy)pyridine (3c). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded yellow liquid (35.1 mg, 69% yield). 1H NMR
(500 MHz, CDCl3): d 8.08 (d, J ¼ 4.5 Hz, 1H), 7.74 (t, J ¼ 6.5 Hz,
1H), 7.40 (s, 2H), 7.08–7.01 (m, 2H); 13C NMR (125 MHz, CDCl3):
d 161.7, 147.3, 145.4, 139.8, 131.0, 130.4, 128.7, 128.1, 121.7,
118.9, 110.7; HRMS (TIC): calcd for C11H7Cl3NO [M + H]+
273.9588 found 273.9591.
3-Chloro-4-(pyridin-2-yloxy)benzaldehyde (3j). Following the
general procedure, using 4 : 1 petroleum ether–EtOAc as the
1
eluant afforded a light yellow liquid (21.3 mg, 46% yield). H
NMR (500 MHz, CDCl3): d 9.96 (s, 1H), 8.16 (d, J ¼ 3.0 Hz, 1H),
8.01 (s, 1H), 7.84–7.76 (m, 2H), 7.36 (d, J ¼ 8.5 Hz, 1H), 7.09–7.06
(m, 2H); 13C NMR (125 MHz, CDCl3): d 189.8, 162.2, 154.9, 147.1,
140.4, 133.6, 131.4, 129.2, 128.3, 123.7, 119.5, 111.8; HRMS
(TIC): calcd for C12H9ClNO2 [M + H]+ 234.0317, found 234.0315.
3-Chloro-4-(pyridin-2-yloxy)benzonitrile (3k). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded white liquid (23.3 mg, 51% yield). 1H NMR
(500 MHz, CDCl3): d 8.14 (d, J ¼ 3.5 Hz, 1H), 7.79–7.76 (m, 2H),
7.61–7.59 (m, 1H), 7.32 (d, J ¼ 8.5 Hz, 1H), 7.09–7.07 (m, 2H);
13C NMR (125 MHz, CDCl3): d 162.0, 154.0, 147.4, 140.0, 134.3,
131.7, 128.3, 124.2, 119.6, 117.4, 111.8, 109.6; HRMS (TIC): calcd
for C12H8ClN2O [M + H]+ 231.0320, found 231.0321.
2-(4-Bromo-2,6-dichlorophenoxy)pyridine (3d). Following
the general procedure, using 15 : 1 petroleum ether–EtOAc as
the eluant afforded yellow liquid (59.6 mg, 94% yield). 1H NMR
(500 MHz, CDCl3): d 8.09 (d, J ¼ 4.5 Hz, 1H), 7.75 (t, J ¼ 7.5 Hz,
1H), 7.55 (s, 2H), 7.07 (d, J ¼ 8.0 Hz, 1H), 7.03 (t, J ¼ 5.5 Hz, 1H);
13C NMR (125 MHz, CDCl3): d 162.0, 147.4, 146.4, 139.6, 129.8,
128.8, 128.1, 16.4, 121.7, 118.7, 110.6; HRMS (TIC): calcd for
C
11H7BrCl2NO [M + H]+ 317.9083, found 317.9085.
Methyl 3,5-dichloro-4-(pyridin-2-yloxy)benzoate
(3e).
Following the general procedure, using 15 : 1 petroleum ether–
EtOAc as the eluant afforded a light yellow liquid (59.1 mg, 99%
yield). 1H NMR (500 MHz, CDCl3): d 8.07 (s, 3H), 7.76 (t, J ¼
8.0 Hz, 1H), 7.09 (d, J ¼ 8.0 Hz, 1H), 7.03 (t, J ¼ 5.0 Hz, 1H), 3.95
(s, 3H); 13C NMR (125 MHz, CDCl3): d 164.6, 161.7, 150.2, 147.3,
139.9, 130.1, 130.0, 128.6, 119.1, 110.8, 52.7; HRMS (TIC): calcd
for C13H10Cl2NO3 [M + H]+ 298.0032, found 298.0030.
2-(2-Chloro-4-methoxyphenoxy)pyridine (3l). Following the
general procedure, using 5 : 1 petroleum ether–EtOAc as the
1
eluant afforded a yellow liquid (29.4 mg, 63% yield). H NMR
(500 MHz, CDCl3): d 8.14 (d, J ¼ 5.5 Hz, 1H), 7.71–7.66 (m, 1H),
7.31–7.20 (m, 1H), 7.03–6.91 (m, 4H), 3.74 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 162.4, 156.8, 147.4, 140.0, 139.5, 129.8,
118.6, 114.5, 110.7, 110.5, 102.0, 55.9; HRMS (TIC): calcd for
2-(2,6-Dichloro-4-nitrophenoxy)pyridine (3f). Following the
general procedure, using 5 : 1 petroleum ether–EtOAc as the
eluant afforded a white liquid (56.2 mg, 99% yield). 1H NMR
(500 MHz, CDCl3): d 8.30 (s, 2H), 8.04 (d, J ¼ 6.0 Hz, 1H), 7.80 (t,
J ¼ 8.5 Hz, 1H), 7.14 (d, J ¼ 8.0 Hz, 1H), 7.07 (t, J ¼ 7.0 Hz, 1H);
13C NMR (125 MHz, CDCl3): d 161.4, 152.1, 147.2, 144.8, 140.1,
131.1, 124.2, 119.5, 110.8; HRMS (TIC): calcd for C11H7Cl2N2O3
[M + H]+ 284.9828, found 284.9825.
C
12H11ClNO2 [M + H]+ 236.0473, found 236.0470.
2-(2-Chloro-4-uorophenoxy)pyridine (3m). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
1
eluant afforded a yellow liquid (51.4 mg, 76% yield). H NMR
(500 MHz, CDCl3): d 8.18–8.12 (m, 1H), 7.72–7.66 (m, 1H), 7.23–
7.17 (m, 1H), 7.10–6.97 (m, 3H), 6.90 (d, J ¼ 8.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3): d 163.3 (d, JF ¼ 98.8 Hz), 160.4 (d, JF ¼
22.5 Hz), 158.5 (d, JF ¼ 26.2 Hz), 147.5 (d, JF ¼ 26.2 Hz), 139.5 (d,
JF ¼ 15.0 Hz), 124.7 (d, JF ¼ 10.0 Hz), 122.7 (d, JF ¼ 8.8 Hz), 118.6
(d, JF ¼ 20.0 Hz), 117.6 (d, JF ¼ 26.2 Hz), 116.2 (d, JF ¼ 22.5 Hz),
111.2 (d, JF ¼ 46.2 Hz); 19F NMR (470 MHz, CDCl3): d ꢁ118.5 (s,
1F); HRMS (TIC): calcd for C11H8ClFNO [M + H]+ 224.0273,
found 224.0275.
2-(2,6-Dichloro-4-(triuoromethyl)phenoxy)pyridine
(3g).
Following the general procedure, using 15 : 1 petroleum ether–
EtOAc as the eluant afforded a yellow liquid (56.2 mg, 92%
yield). 1H NMR (500 MHz, CDCl3): d 8.07 (d, J ¼ 5.0 Hz, 1H), 7.77
(t, J ¼ 6.5 Hz, 1H), 7.67 (s, 2H), 7.11 (d, J ¼ 8.0 Hz, 1H), 7.04 (t,
J ¼ 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 161.5, 149.5,
147.3, 140.0, 130.8, 128.9 (q, JF ¼ 33.8 Hz), 126.0 (q, JF ¼ 3.8 Hz),
122.7 (q, JF ¼ 271.2 Hz), 119.2, 110.8. 19F NMR (470 MHz,
46640 | RSC Adv., 2017, 7, 46636–46643
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2-(2,5-Dichlorophenoxy)pyridine (3n). Following the general
procedure, using 15 : 1 petroleum ether–EtOAc as the eluant
afforded yellow liquid (38.1 mg, 80% yield). 1H NMR (400 MHz,
CDCl3): d 8.26–8.21 (m, 1H), 7.73 (d, J ¼ 8.4 Hz, 1H), 7.54–7.26
(m, 3H), 7.04–6.95 (m, 2H); 13C NMR (125 MHz, CDCl3): d 162.5,
150.4, 147.5, 139.8, 133.0, 131.1, 128.3, 126.2, 124.2, 119.0,
111.3; HRMS (TIC): calcd for C11H8Cl2NO [M + H]+ 239.9978,
found 239.9976.
2-(5-Bromo-2-chlorophenoxy)pyridine (3o). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded yellow liquid (49.7 mg, 88% yield). 1H NMR
(400 MHz, CDCl3): d 8.19 (s, 1H), 7.77 (t, J ¼ 7.2 Hz, 1H), 7.42 (s,
1H), 7.39–7.34 (m, 2H), 7.06–7.04 (m, 2H); 13C NMR (100 MHz,
CDCl3): d 162.5, 150.3, 147.5, 139.8, 131.5, 129.1, 127.0, 126.6,
120.4, 119.1, 111.5; HRMS (TIC): calcd for C11H8BrClNO [M +
H]+ 283.9473, found 283.9474.
RSC Advances
(125 MHz, CDCl3): d 162.0, 147.1, 146.6, 143.7, 138.3, 128.0,
127.4, 124.9, 124.6, 116.9, 109.7, 34.3, 29.5, 28.2, 17.4; HRMS
(TIC): calcd for C15H17ClNO [M + H]+ 262.0993, found 262.0990.
Methyl-4,5-dichloro-3-(pyridin-2-yloxy)thiophene-2-carboxylate
(3u). Following the general procedure, using 8 : 1 petroleum
ether–EtOAc as the eluant afforded a brown liquid (42.3.3 mg,
70% yield). 1H NMR (500 MHz, CDCl3): d 8.01 (d, J ¼ 5.0 Hz, 1H),
7.66 (t, J ¼ 6.5 Hz, 1H), 7.33 (s, 1H), 7.00 (d, J ¼ 8.5 Hz, 1H), 6.93 (t,
J ¼ 7.0 Hz, 1H), 3.65 (s, 3H); 13C NMR (125 MHz, CDCl3): d 161.5,
159.4, 148.7, 146.2, 138.6, 123.5, 121.4, 118.6, 117.8, 109.8, 51.1;
HRMS (TIC): calcd for C11H8Cl2NO3S [M + H]+ 303.9597, found
303.9595.
2-(2,6-Dichloro-4-uorophenoxy)pyridine (3v). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
1
eluant afforded a light yellow liquid (48.4 mg, 92% yield). H
NMR (500 MHz, CDCl3): d 8.00 (d, J ¼ 4.0 Hz, 1H), 7.66 (t, J ¼
7.0 Hz, 1H), 7.08 (t, J ¼ 8.0 Hz, 2H), 6.99–6.92 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 160.8, 158.7, 156.7, 146.2, 142.1, 138.7,
2-(2-Chloro-5-methylphenoxy)pyridine (3p). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
129.3 (d, JF ¼ 12.5 Hz), 117.9, 115.2 (d, JF ¼ 25.0 Hz), 109.6; 19
F
1
eluant afforded a yellow liquid (34.8 mg, 79% yield). H NMR
NMR (470 MHz, CDCl3): d ꢁ113.9 (s, 1F); HRMS (TIC): calcd for
(400 MHz, CDCl3): d 8.27–8.22 (m, 1H), 7.73 (d, J ¼ 8.4 Hz, 1H),
7.41–7.32 (m, 1H), 7.09–7.02 (m, 3H), 6.95 (d, J ¼ 8.0 Hz, 1H),
2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): d 162.1, 148.4, 146.5,
138.4, 137.2, 129.1, 125.9, 123.3, 123.1, 117.4, 110.0, 20.0; HRMS
(TIC): calcd for C12H11ClNO [M + H]+ 220.0524, found 220.0523.
2-(2-Chloro-6-methylphenoxy)pyridine (3q). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded yellow liquid (35.5 mg, 81% yield). 1H NMR
(400 MHz, CDCl3): d 8.17 (s, 1H), 7.74 (t, J ¼ 8.0 Hz, 1H), 7.35 (d,
J ¼ 8.0 Hz, 1H), 7.30 (s, 1H), 7.16–7.12 (m, 1H), 7.01–6.99 (m,
2H), 2.23 (s, 3H); 13C NMR (125 MHz, CDCl3): d 161.5, 147.0,
146.5, 138.5, 132.7, 128.4, 126.9, 126.8, 124.9, 117.2, 109.2, 15.8;
HRMS (TIC): calcd for C12H11ClNO [M + H]+ 220.0524, found
220.0523.
2-(2-Bromo-6-chlorophenoxy)pyridine (3r). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded yellow liquid (40.1 mg, 71% yield). 1H NMR
(500 MHz, CDCl3): d 8.10 (d, J ¼ 4.5 Hz, 1H), 7.74 (t, J ¼ 7.0 Hz,
1H), 7.55 (d, J ¼ 8.5 Hz, 1H), 7.43 (d, J ¼ 8.0 Hz, 1H), 7.09–6.99
(m, 3H); 13C NMR (125 MHz, CDCl3): d 161.9, 147.5, 147.3, 139.6,
131.8, 129.7, 129.5, 126.9, 118.9, 118.7, 110.7; HRMS (TIC): calcd
for C11H8BrClNO [M + H]+ 283.9473, found 283.9474.
C
11H7Cl2FNO [M + H]+ 257.9883, found 257.9885.
2-(2,6-Dichlorophenoxy)-3-(triuoromethyl)pyridine
(5a).
Following the general procedure, using 15 : 1 petroleum ether–
EtOAc as the eluant afforded a yellow liquid (14.1 mg, 23%
yield). 1H NMR (500 MHz, CDCl3): d 8.25 (d, J ¼ 4.5 Hz, 1H), 8.01
(d, J ¼ 8.0 Hz, 1H), 7.49 (d, J ¼ 7.0 Hz, 1H), 7.42–7.33 (m, 1H),
7.25–7.22 (m, 1H), 7.11–7.09 (m, 1H); 13C NMR (125 MHz,
CDCl3): d 159.6, 150.7, 149.0, 137.1 (q, J F ¼ 5.0 Hz), 130.6, 128.1
(q, J F ¼ 108.8 Hz), 127.9, 126.7, 120.0 (q, J F ¼ 271.2 Hz), 117.9;
19F NMR (470 MHz, CDCl3): d ꢁ63.4 (s, 3F); HRMS (TIC): calcd
for C12H7Cl2F3NO [M + H]+ 307.9852, found 307.9850.
2-(2,6-Dichlorophenoxy)-3-methylpyridine (5b). Following
the general procedure, using 15 : 1 petroleum ether–EtOAc as
the eluant afforded a yellow liquid (41.1 mg, 81% yield). 1H
NMR (500 MHz, CDCl3): d 7.81 (d, J ¼ 5.0 Hz, 1H), 7.45 (d, J ¼
7.5 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.04 (t, J ¼ 8.0 Hz, 1H), 6.84–
6.82 (m, 1H), 2.35 (s, 3H); 13C NMR (125 MHz, CDCl3): d 159.3,
145.9, 143.4, 138.7, 128.7, 127.6, 125.1, 119.8, 117.8, 14.8; HRMS
(TIC): calcd for C12H10Cl2NO [M + H]+ 254.0134, found 254.0131.
2-(2,6-Dichlorophenoxy)-3-uoropyridine (5c). Following the
general procedure, using 10 : 1 petroleum ether–EtOAc as the
1
eluant afforded a light yellow liquid (40.8 mg, 79% yield). H
2-(2-Chloro-6-(triuoromethyl)phenoxy)pyridine (3s). Following
the general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded yellow liquid (25.7 mg, 47% yield). 1H NMR
(400 MHz, CDCl3): d 8.14 (s, 1H), 7.79 (t, J ¼ 7.2 Hz, 1H), 7.70 (t, J ¼
8.4 Hz, 2H), 7.38–7.32 (m, 2H), 7.12 (d, J ¼ 8.0 Hz, 1H), 7.06 (s, 1H);
13C NMR (125 MHz, CDCl3) d 163.1, 151.8, 147.5, 139.6, 138.4,
132.9, 127.1 (q, JF ¼ 5.0 Hz), 124.5, 123.6, 123.0 (q, JF ¼ 151.2 Hz),
119.0; 19F NMR (470 MHz, CDCl3): d ꢁ61.8 (s, 3F); HRMS (TIC):
calcd for C12H8ClF3NO [M + H]+ 274.0241, found 274.0240.
2-(2-(tert-Butyl)-6-chlorophenoxy)pyridine (3t). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
NMR (500 MHz, CDCl3): d 7.84 (s, 1H), 7.26–7.18 (m, 1H), 7.11 (t,
J ¼ 8.5 Hz, 3H), 7.00 (s, 1H); 13C NMR (125 MHz, CDCl3): d 155.7
(d, JF ¼ 6.2 Hz), 150.6 (d, JF ¼ 200.0 Hz), 144.0 (d, JF ¼ 75 Hz),
143.1, 129.9 (d, JF ¼ 45 Hz), 126.8 (d, JF ¼ 81.2 Hz), 124.4 (d, JF ¼
8.8 Hz), 123.4 (d, JF ¼ 31.2 Hz), 118.8 (d, JF ¼ 18.8 Hz); 19F NMR
(470 MHz, CDCl3): d ꢁ137.7 (s, 1F); HRMS (TIC): calcd for C11
-
H7Cl2FNO [M + H]+ 257.9883, found 257.9885.
3-Chloro-2-(2,6-dichlorophenoxy)pyridine (5d). Following
the general procedure, using 15 : 1 petroleum ether–EtOAc as
the eluant afforded a light yellow liquid (40.1 mg, 73% yield). 1H
NMR (500 MHz, CDCl3): d 7.96 (d, J ¼ 3.5 Hz, 1H), 7.79 (d, J ¼
9.0 Hz, 1H), 7.40 (d, J ¼ 8.0 Hz, 2H), 7.17 (t, J ¼ 8.0 Hz, 1H), 7.01–
6.98 (m, 1H); 13C NMR (125 MHz, CDCl3): d 157.3, 146.3, 144.9,
139.5, 129.6, 128.8, 126.7, 119.8, 118.3; HRMS (TIC): calcd for
1
eluant afforded a brown liquid (40.1 mg, 77% yield). H NMR
(500 MHz, DMSO-d6): d 8.17 (d, J ¼ 4.5 Hz, 1H), 7.85 (t, J ¼
7.5 Hz, 1H), 7.41 (d, J ¼ 7.5 Hz, 1H), 7.22 (d, J ¼ 7.5 Hz, 1H),
7.15–7.10 (m, 2H), 7.01–6.91 (m, 1H), 1.31 (s, 9H); 13C NMR
C
11H7Cl3NO [M + H]+ 273.9588, found 273.9591.
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equiv.), DCE (2.0 mL), 110 ꢀC, under N2, 48 h, using 5 : 1
6-(2,6-Dichlorophenoxy)nicotinonitrile (5e). Following the
general procedure, using 5 : 1 petroleum ether–EtOAc as the
eluant afforded a yellow liquid (40.4 mg, 76% yield). H NMR
petroleum ether–EtOAc as the eluant afforded a light yellow
1
1
liquid (35.3 mg, 68% yield). H NMR (500 MHz, CDCl3): d 8.06
(d, J ¼ 4.5 Hz, 1H), 7.60 (t, J ¼ 8.0 Hz, 1H), 7.05 (d, J ¼ 9.0 Hz,
1H), 6.93–6.87 (m, 2H), 6.78–6.76 (m, 1H), 3.72 (s, 3H); 13C NMR
(125 MHz, CDCl3): d 161.2, 155.8, 146.4, 138.9, 138.5, 128.8,
124.4, 117.6, 113.5, 112.5, 109.5, 54.9; HRMS (TIC): calcd for
(500 MHz, CDCl3): d 8.40 (d, J ¼ 2.0 Hz, 1H), 7.99 (d, J ¼ 6.5 Hz,
1H), 7.42 (d, J ¼ 8.0 Hz, 2H), 7.22–7.19 (m, 2H); 13C NMR (125
MHz, CDCl3): d 163.7, 151.9, 142.6, 129.4, 128.9, 127.2, 122.0,
120.9, 116.5, 111.5; HRMS (TIC): calcd for C12H7Cl2N2O [M + H]+
264.9930, found 264.9927.
C
12H10ClN2O4 [M + H]+ 281.0324, found 281.0323.
2-(2-Chloro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
5-Chloro-2-(2,6-dichlorophenoxy)pyridine (5f). Following the
general procedure, using 15 : 1 petroleum ether–EtOAc as the
eluant afforded a light yellow liquid (53.3 mg, 98% yield). H
2-yl)phenoxy)pyridine (7c). A 25 mL Schlenk tube equipped with
a stir bar was charged with 3l (0.2 mmol), B2pin2 (2.0 equiv.),
[RhCp*Cl2]2 (5 mol%), PCy3 (30 mol%), EtOAc (2.0 mL), 100 ꢀC,
under N2, 24 h, using 10 : 1 petroleum ether–EtOAc as the
1
NMR (500 MHz, CDCl3): d 8.03 (d, J ¼ 2.0 Hz, 1H), 7.71–7.68 (m,
1H), 7.39 (d, J ¼ 8.0 Hz, 2H), 7.16 (t, J ¼ 8.0 Hz, 1H), 7.03 (d, J ¼
9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d 160.3, 146.1, 145.7,
139.6, 129.7, 128.8, 126.7, 126.3, 111.7; HRMS (TIC): calcd for
1
eluant afforded a light yellow liquid (41.1 mg, 57% yield). H
NMR (500 MHz, CDCl3): d 8.05 (d, J ¼ 4.5 Hz, 1H), 7.66 (t, J ¼
8.5 Hz, 1H), 6.96–6.92 (m, 2H), 6.88 (s, 2H), 3.74 (s, 3H), 1.51 (s,
6H), 1.18 (s, 6H); 13C NMR (125 MHz, CDCl3): d 162.3, 156.8,
147.5, 140.0, 139.5, 129.8, 126.1, 125.4, 118.6, 114.5, 113.6,
110.6, 83.5, 65.6, 56.7, 55.9, 25.0, 24.6; HRMS (TIC): calcd for
C
11H7Cl3NO [M + H]+ 273.9588, found 273.9591.
2-(2,6-Dichlorophenoxy)-5-nitropyridine (5g). Following the
general procedure, using 5 : 1 petroleum ether–EtOAc as the
1
eluant afforded a light yellow liquid (18.7 mg, 33% yield). H
C
18H22BClNO4 [M + H]+ 362.1325, found 362.1323.
NMR (500 MHz, CDCl3): d 8.98 (d, J ¼ 2.5 Hz, 1H), 8.55 (d, J ¼
6.0 Hz, 1H), 7.43 (d, J ¼ 8.5 Hz, 2H), 7.24–7.21 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 164.8, 145.6, 144.8, 141.0, 135.3, 129.3,
128.9, 127.3, 111.0; HRMS (TIC): calcd for C11H7Cl2N2O3 [M +
H]+ 284.9828, found 284.9825.
2-(2-Bromo-6-chloro-4-methoxyphenoxy)pyridine (7d).
A
25 mL Schlenk tube equipped with a stir bar was charged with 3l
(0.2 mmol), NBS (3.0 equiv.), Pd(OAc)2 (10 mol%), TsOH
ꢀ
(10 mol%), EtOAc (2.0 mL), 110 C, under N2, 6 h using 10 : 1
petroleum ether–EtOAc as the eluant afforded a light yellow
liquid (32.3 mg, 52% yield). 1H NMR (500 MHz, CDCl3): d 8.11 (s,
1H), 7.71 (t, J ¼ 8.0 Hz, 1H), 7.04–6.98 (m, 2H), 6.94 (s, 2H), 3.80
(s, 3H); 13C NMR (125 MHz, CDCl3): d 162.3, 156.8, 147.4, 139.9,
139.5, 129.8, 125.4, 118.6, 114.5, 111.0, 110.6, 55.9; HRMS (TIC):
calcd for C12H10BrClNO2 [M + H]+ 313.9578, found 313.9580.
2-(2-Chloro-6-iodo-4-methoxyphenoxy)pyridine (7e). A 25 mL
Schlenk tube equipped with a stir bar was charged with 3l (0.2
mmol), NIS (3.0 equiv.), Pd(OAc)2 (10 mol%), TsOH (10 mol%),
2-(2,6-Dichlorophenoxy)-6-methoxypyridine (5h). Following
the general procedure, using 2 : 1 petroleum ether–EtOAc as the
eluant afforded a yellow liquid (35.0 mg, 65% yield). H NMR
1
(500 MHz, CDCl3): d 8.06 (d, J ¼ 3.5 Hz, 1H), 7.60 (t, J ¼ 7.5 Hz,
1H), 7.05 (d, J ¼ 9.0 Hz, 1H), 6.93 (d, J ¼ 3.0 Hz, 2H), 6.90–6.76
(m, 2H), 3.72 (s, 3H); 13C NMR (125 MHz, CDCl3) d 156.0, 154.9,
153.6, 140.7, 129.2, 124.8, 121.1, 110.6, 109.2, 54.6; HRMS (TIC):
calcd for C12H10Cl2NO2 [M + H]+ 270.0083, found 270.0084.
2-(2,6-Dichlorophenoxy)-6-methylpyridine (5i). Following the
general procedure, using 5 : 1 petroleum ether–EtOAc as the
ꢀ
EtOAc (2.0 mL), 110 C, under N2, 6 h, using 10 : 1 petroleum
1
ether–EtOAc as the eluant afforded a light yellow liquid
(25.3 mg, 35% yield). 1H NMR (500 MHz, CDCl3): d 8.05 (d, J ¼
5.0 Hz, 1H), 7.66 (t, J ¼ 7.5 Hz, 1H), 6.97–6.93 (m, 2H), 6.88 (s,
2H), 3.74 (s, 3H); 13C NMR (125 MHz, CDCl3): d 163.4, 157.2,
147.5, 143.3, 139.4, 127.8, 124.4, 118.3, 115.6, 113.7, 110.8, 55.8;
HRMS (TIC): calcd for C12H11ClINO2 [M + H]+ 361.9439, found
361.9437.
eluant afforded a yellow liquid (36.6 mg, 68% yield). H NMR
(400 MHz, CDCl3): d 7.56 (t, J ¼ 7.2 Hz, 1H), 7.41 (t, J ¼ 6.4 Hz,
2H), 7.22–7.15 (m, 3H), 6.90 (d, J ¼ 6.8 Hz, 1H), 6.60 (d, J ¼
8.0 Hz, 1H), 2.50 (s, 3H); 13C NMR (125 MHz, CDCl3): d 161.3,
154.4, 139.7, 129.7, 124.9, 124.6, 122.1, 120.2, 109.4, 22.4; HRMS
(TIC): calcd for C12H10Cl2NO [M + H]+ 254.0134, found 254.0131.
2-(2-Chloro-6-uoro-4-methoxyphenoxy)pyridine (7a).
A
2-(2-Chloro-5-(triuoromethyl)phenoxy)-N-(2,4-diuorophenyl)-
nicotinamide (8a). Following the general procedure, using 8 : 1
petroleum ether–EtOAc as the eluant afforded a light brown
liquid (80.7 mg, 94% yield). 1H NMR (500 MHz, CDCl3): d 9.82
(s, 1H), 8.71–8.69 (m, 1H), 8.52–8.47 (m, 1H), 8.24–8.22 (m,
1H), 7.68–7.55 (m, 3H), 7.29–7.26 (m, 1H), 6.95–6.87 (m, 2H);
13C NMR (125 MHz, CDCl3): d 161.0, 158.8 (dd, JF ¼ 245.0, 11.2
Hz), 158.6, 152.9 (dd, JF ¼ 246.2, 11.2 Hz), 150.4, 148.5, 142.9,
131.4, 131.2, 130.6 (q, JF ¼ 33.8 Hz), 124.2, 123.9 (q, JF ¼ 3.8
Hz), 123.1 (d, JF ¼ 7.5 Hz), 122.8 (dd, JF ¼ 10.0, 3.8 Hz), 122.0
(q, JF ¼ 3.8 Hz), 120.4, 116.6, 111.3 (dd, JF ¼ 21.2, 3.8 Hz), 103.6
(dd, JF ¼ 26.2, 23.8 Hz); 19F NMR (470 MHz, CDCl3): d ꢁ125.3
(s, 1F), ꢁ114.5 (s, 1F), ꢁ62.5 (s, 3F). HRMS (TIC): calcd for
25 mL Schlenk tube equipped with a stir bar was charged with 3l
(0.2 mmol), NFSI (3.0 equiv.), Pd(OAc)2 (10 mol%), EtOAc (2.0
mL), 110 ꢀC, under N2, 6 h, using 10 : 1 petroleum ether–EtOAc
as the eluant afforded a light yellow liquid (26.7 mg, 53% yield).
1H NMR (500 MHz, CDCl3): d 8.12 (d, J ¼ 4.5 Hz, 1H), 7.72 (t, J ¼
7.5 Hz, 1H), 7.05–7.00 (m, 2H), 6.95 (s, 1H), 6.82–6.68 (m, 1H),
3.80 (s, 3H); 13C NMR (125 MHz, CDCl3): d 163.2, 155.8, 146.3 (d,
JF ¼ 3.8 Hz), 138.6 (d, JF ¼ 7.5 Hz), 134.5, 128.7 (d, JF ¼ 23.8 Hz),
127.4, 117.7 (d, JF ¼ 15.0 Hz), 113.5, 109.6 (d, JF ¼ 27.5 Hz), 101.0
(d, JF ¼ 22.5 Hz), 54.9; 19F NMR (470 MHz, CDCl3): d ꢁ123.4 (s,
1F); HRMS (TIC): calcd for C12H10ClFNO2 [M + H]+ 254.0379,
found 254.0382.
2-(2-Chloro-4-methoxy-6-nitrophenoxy)pyridine
(7b).
A
C
19H11ClF5N2O2 [M + H]+ 429.0424, found 429.0423.
25 mL Schlenk tube equipped with a stir bar was charged with 3l
(8R,9S,13S,14S)-2-Chloro-8,9,13,14-tetramethyl-3-(pyridin-
(0.2 mmol), AgNO2 (2.0 equiv.), Pd(OAc)2 (10 mol%), K2S2O8 (2.0
2-yloxy)-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta
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H. R. Khavasi, Org. Biomol. Chem., 2017, 15, 6264; Copper-
catalyzed C-H chlorination, see: (p) X. Chen, X.-S. Hao,
C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128,
6790; Nickel-catalyzed C-H chlorination, (q) B.-B. Zhan,
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[a]phenanthren-17-one (8b). Following the general proce-
dure, using 10 : 1 petroleum ether–EtOAc as the eluant
afforded a yellow liquid (46.5 mg, 55% yield). H NMR (400
1
MHz, CDCl3): d 8.22 (s, 1H), 7.77 (t, J ¼ 6.8 Hz, 1H), 7.39 (s,
1H), 7.05–7.01 (m, 3H), 3.06–3.03 (m, 1H), 2.93 (s, 2H), 2.59–
2.52 (m, 1H), 2.46–2.41 (m, 2H), 2.19–2.09 (m, 2H), 1.94–1.90
(m, 2H), 1.74–1.52 (m, 4H), 1.30 (s, 1H), 1.17 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 205.6, 162.9, 147.4, 147.2, 139.9, 137.4,
136.3, 127.4, 124.3, 123.8, 118.5, 111.2, 82.9, 47.3, 45.8, 45.7,
43.8, 36.5, 32.3, 28.7, 26.2, 25.2, 15.8; HRMS (TIC): calcd for
¨
5294; (s) F. Lied, A. Lerchen, T. Muck-Lichtenfeld,
C. Knecht and F. Glorius, ACS Catal., 2016, 6, 7839. Iron-
catalyzed, see: (t) M. A. B. Mostafa, R. M. Bowley,
D. T. Racys, M. C. Henry and A. Sutherland, J. Org. Chem.,
2017, 82, 7529.
C
26H31ClNO2 [M + H]+ 424.2038, found 424.2039.
3 A. de Meijere and F. Diederich, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, Germany, 2004.
Conflicts of interest
The authors declare no competing nancial interest.
4 Handbook of Grignard Reagents, ed. G. S. Silverman and P. E.
Rakita, Marcel Dekker, New York, 1996.
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Financial support from the National Natural Science Founda-
tion of China (21602158, 21372177, and 21472140), State Key
Laboratory of Structural Chemistry (No. 20170037), Zhejiang
Provincial Natural Science Foundation (LY16B020011), Wenz-
hou Medical University start-up funding (QTJ15026) and Gran-
ted from the Opening Project of Zhejiang Provincial Top Key
Discipline of Pharmaceutical Sciences (201723) are greatly
appreciated.
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