Palladium-Catalyzed Regioselective C-H Functionalization of Arenes Substituted by Two N -Heterocycles and Application in Late-Stage Functionalization

Article abstract of DOI:10.1021/acs.joc.8b00322

Reported herein is a Pd-catalyzed regioselective C-H activation method that is used for C-H deuteration, carbonylation, halogenation, and oxidation of arene substrates substituted by two N-heterocycles. When conducted in acetic acid (AcOH), these reaction

Full text of DOI:10.1021/acs.joc.8b00322

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Palladium-Catalyzed Regioselective C-H Functionalization
of Arenes Substituted by Two N-Heterocycles
and Application in Late-Stage Functionalization
Da-Wei Yin, and Gang Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00322 • Publication Date (Web): 13 Mar 2018
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Palladium-Catalyzed Regioselective C-H Functionalization of
Arenes Substituted by Two N-Heterocycles and Application
in Late-Stage Functionalization
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Da-Wei Yin† and Gang Liu*, †, ‡
†Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Handian
Dist, Beijing 100084 (P.R. China)
‡School of Pharmaceutical Sciences, Tsinghua University, Handian Dist, Beijing 100084 (P. R. China)
*E-mail: gangliu27@tsinghua.edu.cn
Abstract
Reported herein is a Pd-catalyzed regioselective C-H activation method that is used for
C-H deuteration, carbonylation, halogenation, and oxidation of arene substrates
substituted by two N-heterocycles. When conducted in acetic acid (AcOH) these
reactions occur at the five-membered palladacycle sites, whereas they switch to the six-
membered palladacycle sites in trifluoroacetic acid (TFA). This controllable
regioselective C-H activation is applied for late-stage functionalization (LSF) of
bioactive molecules. A mechanism study indicated that the regioselectivity is achieved
by Brönsted acid-Lewis base interactions and electronic effects (in TFA) and the
different kinetic stabilities of palladacycle intermediates (in AcOH).
Introduction
Site-specifically deuterium-labelled compounds have been widely used in the
pharmaceutical industry because of their ability to improve the half-life time and
toxicity profiles of small molecules.1 For instance, replacement of the hydrogen with
deuterium at the chiral center of a thalidomide analogue (Fig.1a, 1) increases the
exposure for each enantiomer in vivo without changing their pharmacokinetics.1c
Another example, deutetrabenazine (Fig.1a, 2), has recently become the first deuterated
drug approved by the US FDA, which has deuterium incorporated at its methoxyl group
and exhibits a longer half-life time and lower toxicity than its parent compound.1d These
and other recent examples have highlighted that deuterium-incorporation is a practical
strategy for the development of new drug candidates, often generating new leads from
old drugs with improved metabolic stability and efficacy in vivo. e.g. 3 (Fig.1a,).2
Transition-metal catalyzed C-H activation has been a versatile method to
manipulate inert C-H bonds during the past decade.3 Many excellent studies have
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applied directed C-H activation for the ortho-deuteration of relatively simple
molecules.4 However, the application of directed C-H activation for late-stage
functionalization (LSF) of N-heterocycle-containing bioactive molecules has been
limited because of the strongly coordinating ability of Lewis basic heterocycles with
metals, which can result in catalyst arrest or the generation of undesired products.5 To
date, several creative methods have been developed to overcome these limitations
(Fig.1b).6 In 2014, Patterson and workers reported that a pyridine group was blocked
by a Lewis acid or an N-oxide to avoid Pd-catalyst arrest.6a Another report by Yu et al.
in 2014 demonstrated that a simple N-methoxy amide group could serve as both a
directing group and an anionic ligand that overrode the conventional positional
selectivity patterns.6b In 2016, Ackermann and his colleagues developed cobalt-
catalyzed C-H amidation that tolerated strongly coordinating nitrogen heterocycles.6c
Very recently, Yu and co-workers used an oxazoline-based directing group to override
the poisoning effect of a wide range of heterocycle substrates in LSF of N-heterocycle-
containing molecules.6d Because the structures of many druggable molecules or other
biological probes contain multiple similar N-hetrocycles (e.g., pyridine groups),7 the
metal-catalyzed regioselective C-H functionalization of such molecules are still
challenging, and the regioselective LSF of molecules with multiple N-hetrocycles is
even more difficult.
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Figure 1. a: D-incorporation in drug molecules; b: C-H activations overcoming the limitations of
heterocycles.
Generally, N-heterocycles act as directing groups in Pd-catalysed ortho-C-H
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activation through the formation of five-membered or six-membered palladacycles via
concerted metalation deprotonation.8 These two types of intermediate exhibit
characteristic differences in their reactivities in subsequent transformation reactions.9
We envisioned that this differential reactivity could be utilized to achieve regioselective
C-H functionalization in substrates that contain multiple N-heterocycles, particularly in
druggable molecules or natural products. Due to the emerging importance of deuterium
at specific positions in drug molecules, we initially intended to explore this speculation
in Pd-catalyzed C-H deuteration of arenes. This regioselective reaction was
successfully applied for the late stage functionalization of drug candidates and extended
to the regioselective Carbon-Carbon, Carbon-halegon and Carbon-Oxygen bond
formation reactions.
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Results and Discussion
The arene 2-(3-methyl-4-(pyridin-2-yl)phenoxy)pyridine 1a, with its two pyridine
directing groups, was chosen as a model substrate. In this molecule, one pyridine group
(PG-6) is connected with the phenyl core via an O-atom, which can form a six-
membered palladacycle intermediate; the other pyridine group (PG-5) is directly linked
to the phenyl core that alternatively gives a five-membered palladacycle intermediate
(Table 1). When treating 1a with 10 mol% Pd(OAc)2 in d4-AcOH at 120 °C, deuterated
product 2a was obtained with 81% D-incorporation at the five-membered palladacycle
site (x site) and 11% D-incorporation at the six-membered palladacycle sites (y and y’
sites) after 48 h reaction (Table 1, entry 1). Several base additives were then examined.
All the buffer-liked reaction systerms gave lower rate of D-incorporation (Table 1,
entry 2, 5-10). Further screening revealed that the amount of base (Table 1, entry 3-4),
amount of solvent or reaction time (Table 1, entry 11) couldn’t improve the rate of D-
incorporation or selectvity in d4-AcOH. Interestingly, when d-TFA was chosen as the
deuterium source without additives, C-H deuteration mainly occurred at the y and y’
sites at 120 °C for 24 h (Table 1, entry 12). This observation indicated contrary
regioselective C-H activation process controlled by an acid. The addition of D2O
yielded poorer regioselectivity in d-TFA indicating that in situ generated water by base
and acid neutralization in entry 2 (the optimal regioselective condition) did not
contribute to the regioselectivity (Table 1, entry 13). Increasing the reaction temperature
to 140 °C (Table 1, entry 15, 17) resulted in poorer regioselectivity in both d4-AcOH
and d-TFA, however, decreasing the reaction temperature to 100 °C significanty
reduced the rate of D-incorporation at either x site in d4-AcOH (Table 1, entry 14) or y
and y’ sites in d-TFA (Table 1, entry 16).
We further examined a variety of substituents of the phenyl core (Table 2). All of
the tested substrates gave excellent regioselectivity at x sites in d4-AcOH. Among them,
1a (3-methyl) and 1j (4-methylphenyl) showed the best reactivity, with 81% and 75%
D-incorporation (2a and 2j), respectively. Other substrates (1b-1i, 1k-1l), and
especially those with electron-withdrawing groups (1d, 1f, 1i), showed worse reactivity,
with 20%-52% D-incorporation (2b-2i, 2k-2l). Compared to d4-AcOH, using d-TFA as
the deuterium source resulted in moderate to excellent D-incorporatio-
Table 1. Conditions optimizationa
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Entry
Base
solvent
Deuterium incorporation[%]b
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x
y
y’
11
0
1
None
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOH
d4-AcOHe
d-TFAf
81
70
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68
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76
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79
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0
11
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2
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
Li2CO3
K3PO4
KF
c
3
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27
0
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0
d
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0
0
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0
0
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0
0
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NaOAc
None
10
90
91
0
10
90
91
0
None
None
d-TFAg
None
d4-AcOHh
d4-AcOHi
d-TFAj
None
14
75
90
14
75
90
None
None
d-TFAk
35
a Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 10 mol %, base 2.0 equiv., solvent 1.0 mL, 120 °C, 48
b
1
c
d
h in sealed tube. Deuterium incorporation was determined by H-NMR. Base: 0.5 equiv. Base: 1.0
equiv. e Solvent: 3.0 mL, reaction time: 72 h. f Reaction time: 24 h in d-TFA. g 0.1 mmol D2O was added.
h, j Reaction temperature: 100 °C. i, k Reaction temperature: 140 °C.
1
n (40%-95%), and good selectivity at y sites. H-NMR analysis detected no D-
incorporation at the x sites of 1c, 1f, and 1k in d-TFA giving products of 2c’, 2f’, and
2k’ with their lower rate of D-incorporation, probably because of the existence of strong
electron-withdrawing groups. As for other substrates, C-H deuteration occurred mainly
at y sites (from 53% of 2g’ to 97% of 2d’), with much less D-incorporation at x sites.
Substrates with other N-heterocycles were also studied (Table 3). Replacing the
pyridine group with pyrimidine afforded products with good D-incorporation (2m: 72%)
and excellent regioselectivity in d4-AcOH, or excellent D-incorporation (2m’: 90%)
and good regioselectivity in d-TFA. Although substrates substituted by benzoglioxaline
(1n), benzothiazole (1o), thiazole (1p), or benzoxazole (1q) decomposed in d4-AcOH;
with d-TFA, the corresponding deuterated products (2n’-q’) of each of these were
obtained, and gave moderate to good D-incorporation (32%-85%) and excellent
regioselectivity. We also tested substrates bearing N atom instead of the O atom in 1a.
Unfrotunately, the corresponding substrates did not show the above regioselectivity
(data not shown).
Next, we wanted to test whether the regioselectivity of other different C-H
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functionalization reactions were controllable in AcOH and TFA. Owing to the
prevalence of carbonyl group in organic molecules, we first explored the regioselective
C-H carbonylation reaction. To our delight, such acid-controlled regioselectivity could
be accomplished successfully for the tested substrates (Scheme 1).
Table 2. Scope of the substrates for C-H deuterationa
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aReaction conditions: 1 (0.1 mmol), Pd(OAc)2 10 mol %, solvent 1.0 mL, 120 °C, 48 h (d4-AcOH) or 24
h (d-TFA) in sealed tube, yield > 99%. b Deuterium incorporation: Determined by 1H-NMR.
We also applied our acid-controlled strategy to the regioselective C-H iodination,
bromination, and oxidation (Scheme 2).
We further explored the possibility for the late-stage functionalization of bioactive
molecules using this Pd-catalyzed regioselective C-H activation (Scheme 3).
Compound 7a is an intermediate of a known voltage-gated sodium channel blocker
analogue 7.7a 7a could be regioselectively deuterated by this method (with 95% D-
incorporation) following a one-step transformation to the anticipated D-labelled
compound d-7. Another ACC2 inhibitor analogue 87b was regioselectively deuterated
and iodinated in a single step with acceptable yields as well. It is worth to note that this
LSF method does not involve the installation or removal of directing groups.10
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Table 3. Scope of the directing groups for C-H deuterationa
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a Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 10 mol %, solvent 1.0 mL, 120 °C, 48 h (d4-AcOH) or 24
h (d-TFA) in sealed tube. Yield > 99% if not mentioned. b Deuterium incorporation: Determined by 1H-
NMR. c Determined by ES-HRMS. d Product without directing group was obtained.
Scheme 1. Regioselective C-H Carbonylation a
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a Reaction conditions: With TFA (See SI for the details): 1 (0.1 mmol), Pd(OAc)2 10 mol %, TFA 0.9
mL/DCE 0.1 mL, Peroxy acid 1.5 equiv., K2S2O8 2.0 equiv, 120 °C, 24 h in sealed tube; With AcOH
(reported conditions): 1 (0.1 mmol), Pd(OAc)2 10 mol %, Dioxane 0.75 mL/AcOH 0.15 mL/DMSO 0.1
mL, Peroxy acid 1.5 equiv., K2S2O8 1.0 equiv, Ag2CO3 2.0 equiv, 120 °C, 24 h in sealed tube.
Scheme 2. Different C-H functionalization reactions with controllable regioselectivity.
1) Regioselective C-H Iodinationa
a Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 20 mol %, solvent 1.0 mL, NIS 1.5 equiv., 120 °C, 6-8 h
in sealed tube. b 10 mol% Pd(OAc)2 was used. c 2 h at 80 °C.
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2) Regioselective C-H Brominationd
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d Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 20 mol %, solvent 1.0 mL, NBS 1.5 equiv., 120 °C, 6-8
h in sealed tube. e Mixture was obtained, but there was no 5a’ isolated determined by NMR. f 10 mol%
Pd(OAc)2 was used.
3) Regioselective C-H Oxidationg
g Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 20 mol %, solvent 1.0 mL, Oxidant 2.0 equiv., 120 °C,
12 h.h 10 mol% Pd(OAc)2 was used. i Mixture was obtained due to the similar polarities, but there was
no 6a or 6c isolated determined by NMR.
Scheme 3. LSF of bioactive molecules’ analogues
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We finally conducted additional experiments to gain insight into the mechanism
for the controllable regioselectivity in this C-H functionalization. The treatment of 1b
with d-TFA afforded 1b·TFA (9b) after solvent evaporation (Scheme 4, eq 1). 1H-NMR
analysis showed apparent chemical shift variation of the hydrogens on PG-5 (Figure 2,
Ha’-d’) of 9b compared to those (Figure 2, Ha-d) of 1b. Subsequent reaction of 9b with
Pd(OAc)2 in d4-AcOH afforded 2b-1 with poorer regioselectivity and lower rate of D-
incorporation. These observations indicated that the nitrogen atom of PG-5 was
protonated. Theoretical calculation supported that the protonated PG-5 is with a lower
energy. Therefore it is much easier to be protonated that resulted in losing affinity to
Pd catalyst (See SI, Scheme S1). We then evaluated the reactivity of 2-(4-
hydroxypenyl)-pyridine 1q’ in the deuteration reaction with d-TFA. Surprisingly, D-
incorporation was only observed at the ortho-site of the hydroxyl group (Scheme 4, eq
2). When Pd(CF3COO)2 was used as the catalyst, C-H deuteration occurred mainly at
the y and y’ sites in d-TFA (Scheme 4, eq 3). Additionally, upon stoichiometric reaction
of 1b with Pd(OAc)2 in AcOH or TFA, two metal-ligand complexes (I and ІІ)
1
exhibiting distinct H-NMR signals were obtained (See SI). Further protonolysis of
complex І in d-TFA afforded 2b’-1 with more than 90% D-incorporation at the x, x’, y
and y’ sites (Scheme 4, eq 4). Protonolysis of complex ІІ in d-TFA afforded 2b’-2 with
99% D-incorporation at the y and y’ sites, but only 30% D-incorporation at the x and x’
sites (Scheme 4, eq 5).
Based on these results, we propose a mechanism for this Pd-catalyzed
regioselective C-H activation (Figure 3). In AcOH, complexation of the substrate and
Pd(OAc)2 forms complex І with kinetically favoured five-membered palladacycle
(Figure 3A). In TFA, on the one hand, the directly connected pyridine group is firstly
protonated, which blocks the formation of the five-membered palladacycle intermediate.
On the other hand, the Pd(OAc)2 precatalyst is converted to the [Pd(TFA)]+ species,
which is significantly more electrophilic,11 it inserts into the electron-rich C-H bond
specifically to form complex ІІ with the six-membered palladacycle (Figure 3B).
Following the formation of complex I and II in AcOH and TFA, respectively, we
speculate that each undergoes a nucleophilic reaction to form the C-D bonds and C-
halogen bonds with D+, Br+ or I+ as the electrophile9a. Alternatively, complexes I and II
can also undergo oxidative addition/reductive elimination to form C-C or C-O bonds
with similar pathway to the literatures.8e, 12
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Scheme 4. Mechanism experiments
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Figure 2. 1H-NMR of 1b (up) and 9b (down)
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Figure 3. Proposed mechanism
Conclusion
In summary, we have developed a new Brönsted acid-controlled strategy to
achieve regioselectivity in Pd-catalyzed C-H deuteration, carbonylation, iodination,
bromination and oxidation of substrates containing two pyridine groups in a single
molecule. Our mechanism study showed that this regioselectivity is controlled by
Brönsted acid-Lewis base interactions and electronic effects (in TFA) and the different
kinetic stabilities of palladacycle intermediates (in AcOH). This Brönsted acid-Lewis
base interaction can selectively overcome the strongly coordinating ability of Lewis
basic heterocycles to metals and achieve the regioselectivity of C-H activation. This
method is further applied for the late-stage C-H deuteration and iodination of bioactive
molecules.
Experimental Section
General information
Unless otherwise stated, all reagents were purchased from commercial suppliers
and were used without further purification. The substrate 1 was synthesized by coupling
reactions (See Supporting Information). The reactions were heated on an oil bath. If the
rate of D-incorporation was under 40%, the molecular formula given by ES-HRMS will
not contain the corresponding deuterium atom. Proton nuclear magnetic resonance (1H
NMR) and carbon nuclear magnetic resonance (13C NMR) spectroscopy were
performed on Bruker Advance 400, spectrometer. Chemical shifts of 1H NMR spectra
are reported as in units of parts per million (ppm). Multiplicities were given as: s
(singlet); d (doublet); t (triplet); q (quartet); dd (doublet of doublets); m (multiplets),
etc. The number of protons (n) for a given resonance is indicated by nH. Carbon nuclear
magnetic resonance spectra (13C NMR) are reported as in units of parts per million
(ppm). High-resolution LC-MS was carried out by Agilent LC/MSD TOF using a
column of Agilent ZORBAX SB-C18 (rapid resolution, 3.5 μm, 2.1 × 30 mm) at a flow
of 0.40 mL/min. The solvent was MeOH/water (75:25 (v/v)), containing 5 mmol/L
ammonium formate. The ion source is electrospray ionization (ESI).
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The substrate 1 (0.1 mmol), Pd(OAc)2 (0.01 mmol) was dissolved in d4-AcOH or
d-TFA(1.0 mL), and the tube was sealed with a PTFE stopcock. The mixture was stirred
at 120 °C for 48 h (reaction in d4-AcOH) or 24 h (reaction in d-TFA). After cooled to
room temperature, the solvent was evaporated in vacuo. The residue was dissolved in
DCM (20 mL) and washed with saturated NaHCO3 aqueous three times. The organic
layer was dried by Na2SO4, filtered and concentrated in vacuo. The residue was purified
by Combiflash column chromatography (PE:EA=1:1) to give the deuterated products.
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2-(3-Methyl-4-(pyridin-2-yl)phenoxy)pyridine (1a) Colorless oil; H NMR (400
MHz, DMSO-d6): δ 8.67 (d, J = 4.4 Hz, 1H), 8.19 (dd, J = 4.8, 1.4 Hz, 1H), 7.89 (m,
2H), 7.55 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 7.2, 5.1 Hz, 1H),
7.15 (dd, J = 6.9, 5.2 Hz, 1H), 7.05 (m, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, DMSO-
d6): δ 163.4, 159.0, 154.1, 149.5, 147.9, 140.6, 137.8, 137.0, 136.9, 131.4, 124.4, 123.4,
122.4, 119.5, 118.9, 112.1, 20.7. ES-HRMS: Calcd for C17H15ON2 [M+H]+, 263.1173,
Found 263.1178.
2-(3-Methyl-4-(pyridin-2-yl)phenoxy-2,5,6-d3)pyridine (2a) (26.3 mg, >99% yield)
D-incorporation was determined against integral at δ 7.55; 1H NMR (400 MHz, DMSO-
d6): δ 8.67 (d, J = 4.4 Hz, 1H), 8.19 (dd, J = 4.8, 1.4 Hz, 1H), 7.89 (m, 2H), 7.55 (d, J
= 7.8 Hz, 1H), 7.43 (d, J = 8.3 Hz, 0.19H), 7.37 (dd, J = 7.2, 5.1 Hz, 1H), 7.15 (dd, J
= 6.9, 5.2 Hz, 1H), 7.05 (m, 2.78H), 2.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ
163.4, 158.9, 154.1, 149.4, 147.9, 140.6, 137.7, 137.0, 136.8, 131.4 (labelled), 124.4,
123.4, 122.4, 119.5, 118.8, 112.1, 20.6. ES-HRMS: Calcd for C17H14DON2 [M+H]+,
264.1226, Found 264.1235.
2-(3-Methyl-4-(pyridin-2-yl)phenoxy-2,5,6-d3)pyridine (2a’) (26.3 mg, >99%
yield) D-incorporation was determined against integral at δ 7.55; 1H NMR (400 MHz,
DMSO-d6): δ 8.67 (d, J = 4.4 Hz, 1H), 8.19 (dd, J = 4.8, 1.4 Hz, 1H), 7.89 (m, 2H),
7.55 (d, J = 7.8 Hz, 1H), 7.43 (s, 0.86H), 7.37 (dd, J = 7.2, 5.1 Hz, 1H), 7.15 (dd, J =
6.9, 5.2 Hz, 1H), 7.05 (m, 1.20H), 2.33 (s, 3H). ES-HRMS: Calcd for C17H13D2ON2
[M+H]+, 265.1304, Found 265.1295.
2-(4-(Pyridin-2-yl)phenoxy)pyridine (1b) While solid; m.p. 102-105C; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (dd, J = 7.0, 6.4 Hz, 1H), 8.19 (dd, J = 4.9, 1.5 Hz, 1H),
8.14 (d, J = 8.7 Hz, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.35 (m, 1H), 7.24 (d,
J = 8.7 Hz, 2H), 7.16 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 163.3, 155.9, 155.3, 149.9, 147.9, 140.7, 137.6, 135.4, 128.4, 122.8, 121.6, 120.4,
119.7, 112.3. ES-HRMS: Calcd for C16H13ON2 [M+H]+, 249.1018, Found 249.1022.
2-(4-(Pyridin-2-yl)phenoxy-3,5-d2)pyridine (2b) (24.9 mg, >99% yield) D-
incorporation was determined against integral at δ 7.09; 1H NMR (400 MHz, DMSO-
d6): δ 8.68 (dd, J = 7.0, 6.4 Hz, 1H), 8.19 (dd, J = 4.9, 1.5 Hz, 1H), 8.14 (d, J = 8.7 Hz,
1.00H), 7.95 (d, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.35 (m, 1H), 7.24 (m, 2H), 7.16 (m,
1H), 7.09 (d, J = 8.3 Hz, 1H). ES-HRMS: Calcd for C16H11D2ON2 [M+H]+, 251.1147,
Found 251.1138.
2-(4-(Pyridin-2-yl)phenoxy-2,3,5,6-d4)pyridine (2b’) (25.0 mg, >99% yield) D-
incorporation was determined against integral at δ 7.09; 1H NMR (400 MHz, DMSO-
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d6): δ 8.68 (dd, J = 7.0, 6.4 Hz, 1H), 8.19 (dd, J = 4.9, 1.5 Hz, 1H), 8.14 (m, 1.80H),
7.95 (d, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.35 (m, 1H), 7.24 (m, 0.10H), 7.16 (m, 1H),
7.09 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.2, 155.8, 155.2, 149.8,
147.9, 140.7, 137.9, 135.1, 128.3, 122.8, 121.6 (labelled), 120.5, 119.8, 112.3. ES-
HRMS: Calcd for C16H11D2ON2 [M+H]+, 251.1147, Found 251.1138.
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2-(2-Methyl-4-(pyridin-2-yl)phenoxy)pyridine (1c) Colorless oil; H NMR (400
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MHz, DMSO-d6): δ 8.66 (m, 1H), 8.13 (m, 1H), 8.05 (m, 1H), 7.95 (m, 2H), 7.87 (m,
2H), 7.34 (dd, J = 6.2, 5.4 Hz, 1H), 7.13 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 2.17 (s, 3H).
13C NMR (100 MHz, DMSO-d6): δ 163.3, 156.0, 153.4, 149.9, 147.9, 140.6, 137.6,
135.8, 130.9, 129.8, 125.8, 122.8, 122.6, 120.5, 119.2, 111.4, 16.6. ES-HRMS: Calcd
for C17H15ON2 [M+H]+, 263.1173, Found 263.1175.
2-(2-Methyl-4-(pyridin-2-yl)phenoxy-5-d)pyridine (2c) (26.4 mg, >99% yield) D-
incorporation was determined against integral at δ 7.34; 1H NMR (400 MHz, DMSO-
d6): δ 8.66 (m, 1H), 8.13 (m, 1H), 8.05 (m, 1H), 7.95 (m, 1.52H), 7.87 (m, 2H), 7.34
(dd, J = 6.2, 5.4 Hz, 1H), 7.13 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 2.17 (s, 3H). ES-
HRMS: Calcd for C17H14DON2 [M+H]+, 264.1226, Found 264.1230.
2-(2-Methyl-4-(pyridin-2-yl)phenoxy-6-d)pyridine (2c’) (26.3 mg, >99% yield) D-
incorporation was determined against integral at δ 7.34; 1H NMR (400 MHz, DMSO-
d6): δ 8.66 (m, 1H), 8.13 (m, 1H), 8.05 (m, 1H), 7.95 (m, 2H), 7.87 (m, 2H), 7.34 (dd,
J = 6.2, 5.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 0.44H), 7.13 (m, 1H), 7.08 (d, J = 8.3 Hz,
1H), 2.17 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 163.2, 155.4, 153.6, 148.9, 147.8,
140.7, 138.9, 134.8, 131.0, 130.1, 126.1, 123.2, 122.6, 121.2, 119.3, 111.4, 16.6. ES-
HRMS: Calcd for C17H14DON2 [M+H]+, 264.1226, Found 264.1226.
2-(3-Fluoro-4-(pyridin-2-yl)phenoxy)pyridine (1d) Brown oil; 1H NMR (400 MHz,
DMSO-d6): δ 8.60 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 3.8 Hz, 1H), 7.90 (dd, J = 8.4, 7.2
Hz, 1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.24 (m, 2H), 7.13 (dd,
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J = 9.8, 2.3 Hz, 1H), 7.08 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H). C NMR (100 MHz,
DMSO-d6): δ 162.9, 162.8 (d, 1JC-F = 245 Hz), 154.2, 152.5 (d, 3JC-F = 11 Hz), 149.9,
147.8, 140.7, 136.8, 132.9 (d, 3JC-F = 10 Hz), 129.8 (d, 4JC-F = 3.4 Hz), 124.1, 122.8,
119.7, 112.7 (d, 2JC-F = 21 Hz), 112.0, 110.8 (d, 2JC-F = 23 Hz). ES-HRMS: Calcd for
C16H12FON2 [M+H]+, 267.0946, Found 267.0951.
2-(3-Fluoro-4-(pyridin-2-yl)phenoxy-5-d)pyridine (2d) (26.5 mg, >99% yield) D-
incorporation was determined against integral at δ 7.66; 1H NMR (400 MHz, DMSO-
d6): δ 8.60 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 3.8 Hz, 1H), 7.90 (dd, J = 8.4, 7.2 Hz,
0.72H), 7.81 (m, 1H), 7.73 (m, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.24 (m, 2H), 7.13 (dd, J
= 9.8, 2.3 Hz, 1H), 7.08 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H). ES-HRMS: Calcd for
C16H12FON2 [M+H]+, 267.0946, Found 267.0953.
2-(3-Fluoro-4-(pyridin-2-yl)phenoxy-5,6-d2)pyridine (2d’) (26.6 mg, >99% yield)
D-incorporation was determined against integral at δ 7.66; 1H NMR (400 MHz, DMSO-
d6): δ 8.60 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 3.8 Hz, 1H), 7.90 (dd, J = 8.4, 7.2 Hz,
0.70H), 7.81 (m, 1H), 7.73 (m, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.24 (m, 2H), 7.13 (m,
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0.03H), 7.08 (m, 1H), 7.04 (d, J = 8.3 Hz, 1H). C NMR (100 MHz, DMSO-d6): δ
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162.9, 162.8 (d, 1JC-F = 245 Hz), 154.2, 152.5 (d, JC-F = 11 Hz), 149.9, 147.8, 140.7,
136.8, 132.9 (d, 3JC-F = 10 Hz), 129.8 (d, 4JC-F = 3.4 Hz), 124.1, 122.8, 119.7, 112.7 (d,
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2JC-F = 21 Hz, labelled), 112.0, 110.8 (labelled). ES-HRMS: Calcd for C16H11DFON2
[M+H]+, 268.0996, Found 268.0990.
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2-(3-Chloro-4-(pyridin-2-yl)phenoxy)pyridine (1e) Colorless oil; H NMR (400
MHz, DMSO-d6): δ 8.71 (m, 1H), 8.21 (dd, J = 4.8, 1.6 Hz, 1H), 7.91 (td, J = 7.8, 1.9
Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.42 (m, 2H), 7.24 (dd, J =
8.5, 2.3 Hz, 1H), 7.19 (dd, J = 6.9, 5.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H). 13C NMR (100
MHz, DMSO-d6): δ 162.9, 156.1, 154.8, 149.9, 147.9, 140.9, 136.9, 135.6, 132.9, 132.0,
125.0, 123.2, 122.9, 120.7, 120.1, 112.4. ES-HRMS: Calcd for C16H12ON2Cl [M+H]+,
283.0631 (35Cl), Found 283.0632 (35Cl).
2-(3-Chloro-4-(pyridin-2-yl)phenoxy-5-d)pyridine (2e) (28.2 mg, >99% yield) D-
incorporation was determined against integral at δ 7.69; 1H NMR (400 MHz, DMSO-
d6): δ 8.71 (m, 1H), 8.21 (dd, J = 4.8, 1.6 Hz, 1H), 7.91 (td, J = 7.8, 1.9 Hz, 2H), 7.69
(d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.5 Hz, 0.48H), 7.42 (m, 2H), 7.24 (dd, J = 8.5, 2.3
Hz, 1H), 7.19 (dd, J = 6.9, 5.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H). ES-HRMS: Calcd for
C16H11DON2Cl [M+H]+, 284.0695 (35Cl), Found 284.0683 (35Cl).
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2-(3-Chloro-4-(pyridin-2-yl)phenoxy-2,5,6-d3)pyridine (2e’) (28.1 mg, >99%
yield) D-incorporation was determined against integral at δ 7.69; 1H NMR (400 MHz,
DMSO-d6): δ 8.71 (m, 1H), 8.21 (dd, J = 4.8, 1.6 Hz, 1H), 7.91 (td, J = 7.8, 1.9 Hz,
2H), 7.69 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.5 Hz, 0.90H), 7.42 (m, 1.68H), 7.24 (dd,
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J = 8.5, 2.3 Hz, 0.60H), 7.19 (dd, J = 6.9, 5.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H). C
NMR (100 MHz, DMSO-d6): 162.8, 156.0, 154.8, 149.8, 147.9, 140.9, 136.8, 135.6,
132.9, 132.0, 125.0, 123.2, 122.8, 120.7, 120.1, 112.4. ES-HRMS: Calcd for
C16H11DON2Cl [M+H]+, 284.0695 (35Cl), Found 284.0682 (35Cl).
2-(3-Nitro-4-(pyridin-2-yl)phenoxy)pyridine (1f) Yellow solid; m.p. 104-106C;
1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 4.2 Hz, 1H), 8.22 (d, J = 4.6 Hz, 1H),
7.96 (q, J = 7.7 Hz, 2H), 7.83 (m, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.4 Hz,
1H), 7.43 (m, 1H), 7.22 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 162.6, 154.5,
154.4, 150.0, 149.7, 147.8, 141.1, 137.9, 132.6, 130.5, 125.6, 123.6, 123.1, 120.4, 117.8,
112.5. ES-HRMS: Calcd for C16H12O3N3 [M+H]+, 294.0867, Found 294.0873.
2-(3-Nitro-4-(pyridin-2-yl)phenoxy-5-d)pyridine (2f) (29.0 mg, >99% yield) D-
incorporation was determined against integral at δ 7.43; 1H NMR (400 MHz, DMSO-
d6): δ 8.59 (d, J = 4.2 Hz, 1H), 8.22 (d, J = 4.6 Hz, 1H), 7.96 (q, J = 7.7 Hz, 2H), 7.83
(m, 1.80H), 7.77 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 (m, 1H), 7.22 (m,
2H). 13C NMR (100 MHz, DMSO-d6): δ 162.5, 154.5, 154.4, 150.0, 149.7, 147.8, 141.1,
138.0, 132.6, 130.4, 125.6, 123.6, 123.1, 120.4, 117.7, 112.5. ES-HRMS: Calcd for
C16H12O3N3 [M+H]+, 294.0867, Found 294.0868.
2-(3-Nitro-4-(pyridin-2-yl)phenoxy-6-d)pyridine (2f’) (29.2 mg, >99% yield) D-
incorporation was determined against integral at δ 7.43; 1H NMR (400 MHz, DMSO-
d6): δ 8.59 (d, J = 4.2 Hz, 1H), 8.22 (d, J = 4.6 Hz, 1H), 7.96 (q, J = 7.7 Hz, 2H), 7.83
(m, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 0.83H), 7.43 (m, 1H), 7.22 (m,
2H). ES-HRMS: Calcd for C16H12O3N3 [M+H]+, 294.0867, Found 294.0869.
2-((5-(Pyridin-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyridine (1g) Yellow solid; m.p.
129-130C; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (m, 1H), 8.19 (d, J = 2.2 Hz, 1H),
8.12 (m, 2H), 8.06 (d, J = 8.0 Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.78 (m, 1H), 7.52
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(m, 2H), 7.37 (m, 3H), 7.31 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 6.8, 5.2 Hz,
1H), 6.97 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.5, 155.7, 152.0,
150.0, 147.8, 140.5, 137.7, 136.1, 134.6, 129.5, 129.2, 128.7, 127.8, 127.3, 123.7, 123.0,
120.7, 119.3, 111.8. ES-HRMS: Calcd for C22H17ON2 [M+H]+, 325.1330, Found
325.1335.
2-((5-(Pyridin-2-yl)-[1,1'-biphenyl]-2-yl-4-d)oxy)pyridine (2g) (32.4 mg, >99%
yield) D-incorporation was determined against integral at δ 7.89; 1H NMR (400 MHz,
DMSO-d6): δ 8.69 (m, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.12 (m, 1.48H), 8.06 (d, J = 8.0
Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.78 (m, 1H), 7.52 (m, 2H), 7.37 (m, 3H), 7.31
(m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 6.8, 5.2 Hz, 1H), 6.97 (d, J = 8.3 Hz,
1H). ES-HRMS: Calcd for C22H16DON2 [M+H]+, 326.1398, Found 326.1379.
2-((5-(Pyridin-2-yl)-[1,1'-biphenyl]-2-yl-3,4-d2)oxy)pyridine (2g’) (32.2 mg, >99%
yield) D-incorporation was determined against integral at δ 8.06; 1H NMR (400 MHz,
DMSO-d6): δ 8.69 (m, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.12 (m, 1.84H), 8.06 (d, J = 8.0
Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.78 (m, 1H), 7.52 (m, 2H), 7.37 (m, 3H), 7.31
(m, 1H), 7.27 (d, J = 8.5 Hz, 0.47H), 7.06 (dd, J = 6.8, 5.2 Hz, 1H), 6.97 (d, J = 8.3
Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.5, 155.7, 152.0, 149.9, 147.8, 140.5,
137.7, 136.1, 134.6, 129.4, 129.2, 128.7, 127.9, 127.3, 123.7, 123.0, 120.7, 119.3, 111.8.
ES-HRMS: Calcd for C22H16DON2 [M+H]+, 326.1398, Found 326.1382.
2-((4'-Chloro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyridine (1h) White solid;
m.p. 105-107C; 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.3 Hz, 1H), 8.19 (d,
J = 1.9 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 8.09 (d, J = 3.5 Hz, 1H), 8.05 (d, J =
8.0 Hz, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz,
2H), 7.36 (dd, J = 7.2, 5.0 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 6.7, 5.4 Hz,
1H), 6.98 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.4, 155.6, 151.9,
150.0, 147.8, 140.5, 137.7, 136.5, 136.2, 133.4, 132.7, 131.0, 129.3, 128.7, 127.7, 123.7,
123.0, 120.7, 119.4, 111.9. C22H16ON2Cl [M+H]+, 359.0945 (35Cl), Found 359.0948
(35Cl).
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2-((4'-Chloro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-4,6-d2)oxy)pyridine (2h) (35.6
mg, >99% yield) D-incorporation was determined against integral at δ 7.80; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (d, J = 4.3 Hz, 1H), 8.19 (m, 0.91H), 8.14 (m, 0.64H),
8.09 (d, J = 3.5 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.55 (d,
J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 7.2, 5.0 Hz, 1H), 7.28 (m, 1H),
7.06 (dd, J = 6.7, 5.4 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H). ES-HRMS: Calcd for
C22H16ON2Cl [M+H]+, 359.0945 (35Cl), Found 359.0943 (35Cl).
2-((4'-Chloro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-3,4-d2)oxy)pyridine
(2h’)
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(35.7 mg, >99% yield) D-incorporation was determined against integral at δ 7.80; H
NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.3 Hz, 1H), 8.19 (m, 1H), 8.14 (m, 0.83H),
8.09 (d, J = 3.5 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.55 (d,
J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.36 (dd, J = 7.2, 5.0 Hz, 1H), 7.28 (m, 0.18H),
7.06 (dd, J = 6.7, 5.4 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 163.3, 155.6, 151.9, 150.0, 147.8, 140.5, 137.7, 136.5, 136.2, 133.4, 132.7, 131.0,
129.3, 128.7, 127.7, 123.7 (labelled), 123.0, 120.7, 119.4, 111.9. ES-HRMS: Calcd for
C22H15DON2Cl [M+H]+, 360.1000 (35Cl), Found 360.1008 (35Cl).
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2-((4'-Nitro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyridine (1i) Yellow solid;
m.p. 105-106C; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.0 Hz, 1H), 8.26 (d, J
= 2.1 Hz, 1H), 8.21 (m, 3H), 8.09 (m, 2H), 7.90 (td, J = 7.8, 1.6 Hz, 1H), 7.81 (m, 3H),
7.37 (dd, J = 7.2, 4.9 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 6.8, 5.3 Hz, 1H),
7.02 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.2, 155.4, 152.1, 150.0,
147.8, 147.0, 144.5, 140.7, 137.7, 136.3, 132.5, 130.6, 129.3, 128.7, 123.8, 123.7, 123.1,
120.8, 119.6, 112.1. ES-HRMS: Calcd for C22H16O3N3 [M+H]+, 370.1182, Found
370.1186.
2-((4'-Nitro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-4-d)oxy)pyridine (2i) (36.6
mg, >99% yield) D-incorporation was determined against integral at δ 7.08; 1H NMR
(400 MHz, DMSO-d6): δ 8.69 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.21 (m,
2.74H), 8.09 (m, 2H), 7.90 (td, J = 7.8, 1.6 Hz, 1H), 7.81 (m, 3H), 7.37 (m, 1H), 7.32
(m, 1H), 7.08 (dd, J = 6.8, 5.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H). ES-HRMS: Calcd for
C22H16O3N3 [M+H]+, 370.1182, Found 370.1186.
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2-((4'-Nitro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-3,4-d2)oxy)pyridine (2i’) (36.7
mg, >99% yield) D-incorporation was determined against integral at δ 7.08; 1H NMR
(400 MHz, DMSO-d6): δ 8.69 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.21 (m,
2.83H), 8.09 (m, 2H), 7.90 (td, J = 7.8, 1.6 Hz, 1H), 7.81 (m, 3H), 7.37 (m, 1H), 7.32
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(m, 0.30H), 7.08 (dd, J = 6.8, 5.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H). C NMR (100
MHz, DMSO-d6): δ 163.1, 155.3, 152.1, 149.9, 147.8, 147.0, 144.5, 140.7, 137.8, 136.2,
132.5, 130.6, 129.3, 128.7, 123.8, 123.7, 123.2, 120.8, 119.6, 112.0. ES-HRMS: Calcd
for C22H15DO3N3 [M+H]+, 371.1248, Found 371.1232.
2-((4'-Methyl-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyridine (1j) Yellow oil;
1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H),
8.09 (m, 2H), 8.04 (d, J = 7.4 Hz, 1H), 7.88 (td, J = 7.8, 1.6 Hz, 1H), 7.78 (m, 1H), 7.42
(d, J = 8.0 Hz, 2H), 7.35 (dd, J = 7.1, 5.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (d, J
= 7.9 Hz, 2H), 7.06 (dd, J = 6.7, 5.2 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.28 (s, 3H). 13C
NMR (100 MHz, DMSO-d6): δ 163.6, 155.8, 151.9, 150.0, 147.8, 140.5, 137.7, 137.1,
136.1, 134.8, 134.6, 129.4, 129.3, 129.0, 127.1, 123.7, 122.9, 120.7, 119.2, 111.8, 21.1.
ES-HRMS: Calcd for C23H19ON2 [M+H]+, 339.1485, Found 339.1491.
2-((4'-Methyl-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-4-d)oxy)pyridine (2j) (33.6
mg, >99% yield) D-incorporation was determined against integral at δ 7.78; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (d, J = 4.1 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 8.09 (m,
1.25H), 8.04 (d, J = 7.4 Hz, 2H), 7.88 (td, J = 7.8, 1.6 Hz, 1H), 7.78 (m, 1H), 7.42 (d,
J = 8.0 Hz, 2H), 7.35 (dd, J = 7.1, 5.0 Hz, 1H), 7.25 (m, 1H), 7.17 (d, J = 7.9 Hz, 2H),
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7.06 (dd, J = 6.7, 5.2 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.28 (s, 3H). C NMR (100
MHz, DMSO-d6): δ 163.5, 155.7, 151.9, 149.9, 147.7, 140.5, 137.8, 137.2, 136.0, 134.6,
129.4, 129.3, 129.0, 127.1 (labelled), 123.6, 123.0, 120.7, 119.3, 111.7, 21.0. ES-
HRMS: Calcd for C23H18DON2 [M+H]+, 340.1554, Found 340.1541.
2-((4'-Methyl-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-3,4,6-d3)oxy)pyridine
(2j’)
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(33.8 mg, >99% yield) D-incorporation was determined against integral at δ 7.78; H
NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.1 Hz, 1H), 8.17 (s, 0.74H), 8.09 (m,
1.65H), 8.04 (d, J = 7.4 Hz, 2H), 7.88 (td, J = 7.8, 1.6 Hz, 1H), 7.78 (m, 1H), 7.42 (d,
J = 8.0 Hz, 2H), 7.35 (dd, J = 7.1, 5.0 Hz, 1H), 7.25 (m, 0.10H), 7.17 (d, J = 7.9 Hz,
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2H), 7.06 (dd, J = 6.7, 5.2 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.28 (s, 3H). ES-HRMS:
Calcd for C23H18DON2 [M+H]+, 340.1554, Found 340.1551.
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2-((3'-Methyl-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyridine (1k) Yellow oil;
1H NMR (400 MHz, DMSO-d6): δ 8.68 (m, 1H), 8.18 (m, 1H), 8.10 (m, 2H), 8.05 (m,
1H), 7.90 (m, 1H), 7.77 (m, 1H), 7.34 (m, 3H), 7.25 (m, 2H), 7.11 (m, 1H), 7.05 (m,
1H), 6.97 (m, 1H), 2.28 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 163.6, 155.8, 152.0,
149.9, 147.8, 140.4, 137.8, 137.7, 137.6, 136.1, 134.7, 129.8, 129.4, 128.4, 127.2, 126.3,
123.7, 122.9, 120.7, 119.2, 111.8, 21.4. ES-HRMS: Calcd for C23H19ON2 [M+H]+,
339.1485, Found 339.1489.
2-((3'-Methyl-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-4-d)oxy)pyridine (2k) (33.6
mg, >99% yield) D-incorporation was determined against integral at δ 7.05; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (m, 1H), 8.18 (m, 1H), 8.10 (m, 1.52H), 8.05 (m, 1H),
7.90 (m, 1H), 7.77 (m, 1H), 7.34 (m, 3H), 7.25 (m, 2H), 7.11 (m, 1H), 7.05 (m, 1H),
6.97 (m, 1H), 2.28 (s, 3H). ES-HRMS: Calcd for C23H18DON2 [M+H]+, 340.1554,
Found 340.1549.
2-((3'-Methyl-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-3-d)oxy)pyridine (2k’) (33.6
mg, >99% yield) D-incorporation was determined against integral at δ 7.05; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (m, 1H), 8.18 (m, 1H), 8.10 (m, 2H), 8.05 (m, 1H), 7.90
(m, 1H), 7.77 (m, 1H), 7.34 (m, 3H), 7.25 (m, 1.46H), 7.11 (m, 1H), 7.05 (m, 1H), 6.97
(m, 1H), 2.28 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 163.6, 155.7, 152.0, 149.9,
147.8, 140.4, 137.8, 137.7, 137.6, 136.1, 134.7, 129.8, 129.4, 128.5, 127.2, 126.3, 123.7,
122.9, 120.7, 119.2, 111.8, 21.4. ES-HRMS: Calcd for C23H18DON2 [M+H]+, 340.1554,
Found 340.1540.
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2-((4'-Fluoro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyridine (1l) Yellow solid;
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m.p. 99-100C; H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 3.8 Hz, 1H), 8.17 (s,
1H), 8.11 (m, 2H), 8.06 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.3 Hz, 1H), 7.79 (t, J = 7.1 Hz,
1H), 7.56 (dd, J = 7.7, 5.9 Hz, 2H), 7.37 (m, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.20 (t, J =
8.7 Hz, 2H), 7.06 (m, 1H), 6.98 (d, J = 8.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 163.4, 162.0 (d, J = 243 Hz), 155.7, 152.0, 149.9, 147.8, 140.5, 137.7, 136.2, 134.0
(d, J = 3 Hz), 133.6, 131.2 (d, J = 8 Hz), 129.4, 127.5, 123.6, 123.0, 120.7, 119.3, 115.5
(d, J = 21 Hz), 111.9. ES-HRMS: Calcd for C22H16FON2 [M+H]+, 343.1239, Found
343.1241.
2-((4'-Fluoro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-4-d)oxy)pyridine (2l) (34.0
mg, >99% yield) D-incorporation was determined against integral at δ 7.37; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (d, J = 3.8 Hz, 1H), 8.17 (s, 1H), 8.11 (m, 1.65H), 8.06
(d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.3 Hz, 1H), 7.79 (t, J = 7.1 Hz, 1H), 7.56 (dd, J = 7.7,
5.9 Hz, 2H), 7.37 (m, 1H), 7.27 (m, 1H), 7.20 (t, J = 8.7 Hz, 2H), 7.06 (m, 1H), 6.98
(d, J = 8.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.4, 162.0 (d, J = 243 Hz),
155.6, 152.0, 149.9, 147.8, 140.5, 137.7, 136.2, 134.0 (d, J = 3 Hz), 133.6, 131.2 (d, J
= 8 Hz), 129.4, 127.5, 123.6, 123.0, 120.7, 119.3, 115.5 (d, J = 21 Hz), 111.8. ES-
HRMS: Calcd for C22H16FON2 [M+H]+, 343.1239, Found 343.1241.
2-((4'-Fluoro-5-(pyridin-2-yl)-[1,1'-biphenyl]-2-yl-3,4-d2)oxy)pyridine (2l’) (34.1
mg, >99% yield) D-incorporation was determined against integral at δ 7.37; 1H NMR
(400 MHz, DMSO-d6): δ 8.68 (d, J = 3.8 Hz, 1H), 8.17 (s, 1H), 8.11 (m, 1.87H), 8.06
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(d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.3 Hz, 1H), 7.79 (t, J = 7.1 Hz, 1H), 7.56 (dd, J = 7.7,
5.9 Hz, 2H), 7.37 (m, 1H), 7.27 (m, 0.20H), 7.20 (t, J = 8.7 Hz, 2H), 7.06 (m, 1H), 6.98
(d, J = 8.2 Hz, 1H). ES-HRMS: Calcd for C22H15DFON2 [M+H]+, 344.1301, Found
344.1297.
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2-(4-(Pyridin-2-yl)phenoxy)pyrimidine (1m) While solid; m.p. 114-115C; H
NMR (400 MHz, DMSO-d6): δ 8.67 (m, 3H), 8.16 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 7.9
Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.31 (m, 4H). C NMR (100 MHz, DMSO-d6): δ
165.1, 160.5, 155.8, 154.0, 150.0, 137.7, 136.1, 128.3, 122.9, 122.3, 120.5, 117.5. ES-
HRMS: Calcd for C15H12ON3 [M+H]+, 250.0971, Found 250.0974.
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2-(4-(Pyridin-2-yl)phenoxy-3,5-d2)pyrimidine (2m) (25.0 mg, >99% yield) D-
incorporation was determined against integral at δ 7.97; 1H NMR (400 MHz, DMSO-
d6): δ 8.67 (m, 3H), 8.16 (m, 0.56H), 7.97 (d, J = 7.9 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H),
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7.31 (m, 4H). C NMR (100 MHz, DMSO-d6): δ 165.0, 160.5, 155.7, 154.0, 150.0,
137.7, 136.1 (labelled), 128.3 (labelled), 122.9, 122.3, 120.6, 117.5. ES-HRMS: Calcd
for C15H10D2ON3 [M+H]+, 252.1100, Found 252.1085.
2-(4-(Pyridin-2-yl)phenoxy-2,3,5,6-d4)pyrimidine (2m’) (25.1 mg, >99% yield) D-
incorporation was determined against integral at δ 7.97; 1H NMR (400 MHz, DMSO-
d6): δ 8.67 (m, 3H), 8.16 (m, 1.70H), 7.97 (d, J = 7.9 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H),
7.31 (m, 2.70H). ES-HRMS: Calcd for C15H11DON3 [M+H]+, 251.1037, Found
251.1035.
1-Methyl-2-(4-(pyridin-2-yl)phenoxy)-1H-benzo[d]imidazole (1n) While solid;
m.p. 163-165C; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.5 Hz, 1H), 8.20 (d,
J = 8.8 Hz, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.90 (td, J = 7.8, 1.7 Hz, 1H), 7.56 (d, J = 8.7
Hz, 2H), 7.46 (m, 2H), 7.37 (dd, J = 6.9, 5.1 Hz, 1H), 7.17 (m, 2H), 3.75 (s, 3H). 13C
NMR (100 MHz, DMSO-d6): δ 155.7, 155.6, 154.7, 150.0, 139.6, 137.7, 136.2, 134.4,
128.4, 123.0, 121.9, 121.7, 120.8, 120.6, 118.1, 109.8, 28.9. Calcd for C19H16ON3
[M+H]+, 302.1282, Found 302.1287.
1-Methyl-2-(4-(pyridin-2-yl)phenoxy-2,3,5,6-d4)-1H-benzo[d]imidazole
(2n’)
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(29.9 mg, >99% yield) D-incorporation was determined against integral at δ 8.00; H
NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.5 Hz, 1H), 8.20 (m, 1.90H), 8.00 (d, J =
8.0 Hz, 1H), 7.90 (td, J = 7.8, 1.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1.36H), 7.46 (m, 2H),
7.37 (dd, J = 6.9, 5.1 Hz, 1H), 7.17 (m, 2H), 3.75 (s, 3H). 13C NMR (100 MHz, DMSO-
d6): δ 155.7, 155.6, 154.7, 150.0, 139.6, 137.7, 136.2, 134.4, 128.4, 123.0, 121.9, 121.7,
120.8, 120.6, 118.1, 109.8, 28.9. ES-HRMS: Calcd for C19H16ON3 [M+H]+, 302.1282,
Found 302.1284.
2-(4-(Pyridin-2-yl)phenoxy)benzo[d]thiazole (1o) While solid; m.p. 105-106C;
1H NMR (400 MHz, DMSO-d6): δ 8.70 (d, J = 3.9 Hz, 1H), 8.23 (d, J = 8.4 Hz, 2H),
8.01 (d, J = 7.9 Hz, 1H), 7.93 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.4 Hz,
2H), 7.44 (t, J = 7.6 Hz, 1H), 7.36 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 171.9,
155.4, 155.3, 150.0, 148.9, 137.8, 137.3, 132.3, 128.8, 127.0, 124.7, 123.2, 122.7, 121.7,
121.5, 120.7. C18H13ON2S [M+H]+, 305.0740, Found 305.0743.
2-(4-(Pyridin-2-yl)phenoxy-2,3,5,6-d4)benzo[d]thiazole (2o’) (26.1 mg, 85%
yield) D-incorporation was determined against integral at δ 8.01; 1H NMR (400 MHz,
DMSO-d6): δ 8.70 (d, J = 3.9 Hz, 1H), 8.23 (m, 1.80H), 8.01 (d, J = 7.9 Hz, 1H), 7.93
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(m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 (m, 0.30H), 7.44 (t, J = 7.6 Hz, 1H), 7.36 (m,
2H). 13C NMR (100 MHz, DMSO-d6): δ 171.9, 155.4, 155.3, 150.0, 148.9, 137.8, 137.3,
132.3, 128.8, 127.0, 124.8, 123.2, 122.7, 121.7, 121.5, 120.7. ES-HRMS: Calcd for
C18H11D2ON2S [M+H]+, 307.0868, Found 307.0859.
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2-(4-(Pyridin-2-yl)phenoxy)thiazole (1p) While solid; m.p. 104-105C; H NMR
(400 MHz, DMSO-d6): δ 8.68 (d, J = 3.9 Hz, 1H), 8.19 (d, J = 8.3 Hz, 2H), 7.98 (d, J
= 7.8 Hz, 1H), 7.89 (m, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.35 (m, 2H), 7.28 (m, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 172.9, 156.2, 155.4, 150.0, 138.0, 137.7, 136.7, 128.7,
123.1, 120.6, 120.6, 115.4. ES-HRMS: Calcd for C14H11ON2S [M+H]+, 255.0582,
Found 255.0586.
d-2-(4-(Pyridin-2-yl)phenoxy)thiazole (2p’) (25.6 mg, >99% yield) D-
incorporation was determined against integral at δ 7.98; 1H NMR (400 MHz, DMSO-
d6): δ 8.68 (d, J = 3.9 Hz, 1H), 8.19 (m, 2H), 7.98 (d, J = 7.8 Hz, 1H), 7.89 (m, 1H),
7.45 (m, 0.48H), 7.35 (m, 1.74H), 7.28 (m, 0.06H). 13C NMR (100 MHz, DMSO-d6):
δ 172.9, 156.2, 155.4, 150.0, 137.9, 137.7, 136.7, 128.6, 123.1, 120.7, 120.6, 115.4
(labelled). ES-HRMS: Calcd for C14H8D3ON2S [M+H]+, 258.0583, Found 258.0574.
4-(Pyridin-2-yl)phenol (1q’) White solid; m.p. 145-1149C; 1H NMR (400 MHz,
DMSO-d6): δ 9.74 (s, 1H), 8.59 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.82 (m,
2H), 7.23 (t, J = 5.2 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, DMSO-
d6): δ 158.9, 156.5, 149.7, 137.3, 130.0, 128.3, 121.8, 119.4, 115.9. ES-HRMS: Calcd
for C11H10ON [M+H]+, 172.0754, Found 172.0756.
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4-(pyridin-2-yl)phen-2,6-d2-ol (2q’) (11.2 mg, 65% yield) D-incorporation was
determined against integral at δ 7.23; 1H NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H),
8.59 (d, J = 4.4 Hz, 1H), 7.94 (m, 2H), 7.82 (m, 2H), 7.23 (t, J = 5.2 Hz, 1H), 6.87 (m,
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1.00H). C NMR (100 MHz, DMSO-d6): δ 159.3, 156.0, 148.7, 138.6, 129.0, 128.6,
122.2, 120.2, 116.0. ES-HRMS: Calcd for C11H9DON [M+H]+, 173.0819, Found
173.0814.
2-(3-Methyl-4-(pyridin-2-yl)phenoxy-2,5,6-d3)pyridine (2a’-1) (26.3 mg, >99%
yield) D-incorporation was determined against integral at δ 7.55; 1H NMR (400 MHz,
DMSO-d6): δ 8.67 (d, J = 4.4 Hz, 1H), 8.19 (dd, J = 4.8, 1.4 Hz, 1H), 7.89 (m, 2H),
7.55 (d, J = 7.8 Hz, 1H), 7.43 (s, 0.71H), 7.37 (dd, J = 7.2, 5.1 Hz, 1H), 7.15 (dd, J =
6.9, 5.2 Hz, 1H), 7.05 (m, 1.24H), 2.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ
163.4, 158.9, 154.1, 149.4, 147.9, 140.6, 137.6, 137.0, 136.8, 131.3, 124.4, 123.4, 122.4,
119.5, 118.8 (labelled), 112.1, 20.6.
2-(4-(Pyridin-2-yl)phenoxy-2,3,5,6-d4)pyridine (2b-1) (20.3 mg, 82% yield) D-
incorporation was determined against integral at δ 7.09; 1H NMR (400 MHz, DMSO-
d6): δ 8.68 (m, 1H), 8.19 (m, 1H), 8.14 (m, 1.60H), 7.95 (m, 1H), 7.87 (m, 2H), 7.35
(m, 1H), 7.24 (m, 1.80H), 7.16 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 163.2, 155.9, 155.3, 149.9, 147.9, 140.7, 137.7, 135.3, 128.3, 122.8,
121.6, 120.4, 119.7, 112.2.
2-(4-(Pyridin-2-yl)phenoxy-2,3,5,6-d4)pyridine (2b’-1) (22.6 mg, 90% yield) D-
incorporation was determined against integral at δ 7.35; 1H NMR (400 MHz, DMSO-
d6): δ 8.68 (dd, J = 7.0, 6.4 Hz, 1H), 8.19 (dd, J = 4.9, 1.5 Hz, 1H), 8.14 (0.20H), 7.95
(d, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.35 (m, 1H), 7.24 (0.12H), 7.16 (m, 1H), 7.09 (d, J
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= 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.2, 155.8, 155.2, 149.9, 147.9,
140.7, 137.7, 135.2, 128.2 (labelled), 122.8, 121.5 (labelled), 120.4, 119.8, 112.2.
2-(4-(Pyridin-2-yl)phenoxy-2,3,5,6-d4)pyridine (2b’-2) (25.0 mg, >99% yield) D-
incorporation was determined against integral at δ 7.35; 1H NMR (400 MHz, DMSO-
d6): δ 8.68 (dd, J = 7.0, 6.4 Hz, 1H), 8.19 (dd, J = 4.9, 1.5 Hz, 1H), 8.14 (m, 1.40H),
7.95 (d, J = 8.0 Hz, 1H), 7.87 (m, 2H), 7.35 (m, 1H), 7.24 (0H), 7.16 (m, 1H), 7.09 (d,
J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.3, 155.9, 155.3, 150.0, 147.9,
140.7, 137.8, 135.3, 128.3, 122.8, 121.6 (labelled), 120.4, 119.8, 112.3.
4-(pyridin-2-yl)phen-2,6-d2-ol (2q’-1) (17.0 mg, >99% yield) D-incorporation was
determined against integral at δ 7.23; 1H NMR (400 MHz, DMSO-d6): δ 9.74 (s, 1H),
8.59 (d, J = 4.4 Hz, 1H), 7.94 (m, 2H), 7.82 (m, 2H), 7.23 (t, J = 5.2 Hz, 1H), 6.87 (m,
1.60H). 13C NMR (100 MHz, DMSO-d6): 158.9, 156.6, 149.7, 137.4, 130.1, 128.3,
121.8, 119.4, 115.9.
Ethyl (E)-3-(6-(3-methyl-4-(pyridin-2-yl)phenoxy)pyridin-3-yl)acrylate (8) White
solid; m.p. 93-95C; 1H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 4.2 Hz, 1H), 8.48
(m, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H),
7.56 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.36 (m, 1H), 7.12 (d, J = 8.2 Hz,
2H), 7.08 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 14.1 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 2.33
(s, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): δ 166.5, 164.5, 158.9,
153.5, 149.4, 149.1, 140.9, 139.0, 137.8, 137.3, 137.0, 131.4, 126.0, 124.4, 123.6, 122.4,
119.2, 118.7, 112.1, 60.5, 20.6, 14.6. ES-HRMS: Calcd for C22H21O3N2 [M+H]+,
361.1543, Found 361.1546.
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d-Ethyl (E)-3-(6-(3-methyl-4-(pyridin-2-yl)phenoxy-5-d)pyridin-3-yl)acrylate (8a)
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(35.9 mg, >99% yield) D-incorporation was determined against integral at δ 8.67; H
NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 4.2 Hz, 1H), 8.48 (m, 1H), 8.30 (d, J = 8.6
Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H),
7.44 (d, J = 8.2 Hz, 0.20H), 7.36 (m, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.08 (m, 1H), 6.68
(d, J = 14.1 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6): δ 166.5, 164.5, 158.8, 153.5, 149.4, 149.1, 141.0, 139.0,
137.8, 137.3, 137.1, 131.4 (labelled), 126.0, 124.5, 123.7, 122.4, 119.2, 118.6, 112.1,
60.5, 20.6, 14.6. ES-HRMS: Calcd for C22H20DO3N2 [M+H]+, 362.1609, Found
362.1597.
d-Ethyl (E)-3-(6-(3-methyl-4-(pyridin-2-yl)phenoxy-2,6-d2)pyridin-3-yl)acrylate
(8a’) (36.0 mg, >99% yield) D-incorporation was determined against integral at δ 8.67;
1H NMR (400 MHz, DMSO-d6): δ 8.67 (d, J = 4.2 Hz, 1H), 8.48 (m, 1H), 8.30 (d, J =
8.6 Hz, 1H), 7.88 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 16.1 Hz, 1H), 7.56 (d, J = 7.8 Hz,
1H), 7.44 (s, 1H), 7.36 (m, 1H), 7.12 (m, 1.76H), 7.08 (m, 0.18H), 6.68 (d, J = 14.1
Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, DMSO-d6): δ 166.5, 164.5, 158.7, 153.5, 149.4, 149.0, 140.8, 138.9, 137.8, 137.3,
137.1, 131.3, 126.0, 124.4, 123.5, 122.5, 119.1 (labelled), 118.6, 112.2, 60.6, 20.5, 14.5.
ES-HRMS: Calcd for C22H20DO3N2 [M+H]+, 362.1609, Found 362.1595.
General procedure for the C-H carbonylation reaction
1) The substrate 1 (0.1 mmol), Pd(OAc)2 (0.01 mmol), peroxy acid (0.15 mmol),
K2S2O8 (0.2 mmol) was dissolved in TFA (0.9 mL) and DCE (0.1 mL), and the tube
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was charged with Ar and sealed with a PTFE stopcock. The mixture was stirred at
120 °C for 24 h. After cooled to room temperature, the solvent was evaporated in vacuo.
The residue was dissolved in DCM (20 mL) and washed with saturated NaHCO3
aqueous three times. The organic layer was dried by Na2SO4, filtered and concentrated
in vacuo. The residue was purified by column chromatography on silica gel
(PE:EA=4:1) to give the desired products.
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2) The substrate 1 (0.1 mmol), Pd(OAc)2 (0.01 mmol), peroxy acid (0.15 mmol),
K2S2O8 (0.1 mmol), Ag2CO3 (0.2mmol) was dissolved in Dioxane (0.75mL), AcOH
(0.15 mL) and DMSO (0.1 mL), and the tube was charged with Ar and sealed with a
PTFE stopcock. The mixture was stirred at 120 °C for 24 h. After cooled to room
temperature, the solvent was evaporated in vacuo. The residue was dissolved in DCM
(20 mL) and washed with saturated NaHCO3 aqueous three times. The organic layer
was dried by Na2SO4, filtered and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (PE:EA=4:1) to give the desired products
(3-Methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)(phenyl)methanone
(3a)
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(33.6 mg, 92% yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.39 (m, 1H),
8.22 (d, J = 3.1, 1H), 7.89 (m, 1H), 7.67 (m, 1H), 7.55 (d, J = 7.6, 2H), 7.50 (t, J = 7.4,
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1H), 7.36 (m, 4H), 7.16 (m, 3H), 7.06 (d, J = 2.0, 1H), 2.26 (s, 3H). C NMR (100
MHz, DMSO-d6): δ 196.8, 163.2, 156.7, 153.3, 149.4, 147.9, 141.5, 140.8, 138.7, 137.3,
136.3, 135.9, 133.3, 129.7, 128.7, 125.8, 125.1, 122.4, 119.9, 119.0, 112.3, 20.4. ES-
HRMS: Calcd for C24H19O2N2 [M+H]+, 367.1441, Found 367.1441.
(4-Methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (3a’)
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(32.5 mg, 89% yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.69 (m, 1H),
8.00 (m, 1H), 7.90 (td, J = 7.7, 1.8, 1H), 7.68 (m, 3H), 7.63 (dt, J = 7.9, 1.0, 1H), 7.57
(m, 1H), 7.54 (s, 1H), 7.41 (m, 3H), 7.26 (s, 1H), 7.02 (m, 1H), 6.71 (d, J = 8.3, 1H),
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2.43 (s, 3H). C NMR (100 MHz, DMSO-d6): δ 194.3, 162.8, 157.9, 151.2, 149.6,
147.2, 141.1, 140.4, 137.5, 137.2, 137.1, 133.5, 131.6, 129.9, 129.7, 128.7, 125.2, 124.5,
122.7, 119.4, 111.5, 20.7. ES-HRMS: Calcd for C24H19O2N2 [M+H]+, 367.1441, Found
367.1441.
(3-Methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)(p-tolyl)methanone (3a-1)
(34.5 mg, 91% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 4.3
Hz, 1H), 8.22 (dd, J = 4.9, 1.5 Hz, 1H), 7.89 (td, J = 8.4, 2.0 Hz, 1H), 7.68 (td, J = 7.7,
1.7 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H),
7.16 (m, 5H), 7.02 (d, J = 2.3 Hz, 1H), 2.30 (s, 3H), 2.25 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 196.2, 163.1, 156.8, 153.2, 149.3, 147.9, 143.8, 141.6, 140.8, 138.7,
136.2, 135.8, 134.7, 130.0, 129.2, 125.7, 124.8, 122.4, 119.8, 118.8, 112.2, 21.5, 20.4.
ES-HRMS: Calcd for C25H21O2N2 [M+H]+, 381.1598, Found 381.1591.
(4-Methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)(p-tolyl)methanone (3a’-1)
(20.1 mg, 53% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.7
Hz, 1H), 8.01 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (td, J = 7.7, 1.5 Hz, 1H), 7.71 (m, 1H),
7.61 (dd, J = 11.9, 8.0 Hz, 3H), 7.49 (s, 1H), 7.40 (m, 1H), 7.24 (m, 3H), 7.03 (dd, J =
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7.0, 5.1 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H). C NMR (100
MHz, DMSO-d6): δ 193.9, 162.9, 157.9, 151.1, 149.6, 147.3, 144.0, 140.8, 140.4, 137.2,
136.9, 134.8, 131.4, 130.2, 129.9, 129.3, 125.1, 124.5, 122.7, 119.4, 111.6, 21.6, 20.7.
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ES-HRMS: Calcd for C25H21O2N2 [M+H]+, 381.1598, Found 381.1590.
(4-Fluorophenyl)(3-methyl-2-(pyridin-2-yl)-5-(pyridin-2-
yloxy)phenyl)methanone (3a-2) (32.2 mg, 84% yield) colorless oil; 1H NMR (400 MHz,
DMSO-d6): δ 8.39 (d, J = 4.3 Hz, 1H), 8.22 (dd, J = 4.9, 1.3 Hz, 1H), 7.90 (m, 1H),
7.69 (m, 1H), 7.62 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.16 (m,
5H), 7.09 (d, J = 2.3 Hz, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 195.3,
165.0 (d, 1JC-F = 250 Hz), 163.1, 156.5, 153.4, 149.4, 147.9, 141.3, 140.8, 138.6, 136.3,
135.8, 134.1 (d, 4JC-F = 3 Hz), 132.6 (d, 3JC-F = 11 Hz), 125.8, 125.1, 122.5, 119.8, 119.0,
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115.7 (d, JC-F = 22 Hz), 112.2, 20.4. ES-HRMS: Calcd for C24H18O2N2F [M+H]+,
385.1347, Found 385.1335.
(4-Fluorophenyl)(4-methyl-5-(pyridin-2-yl)-2-(pyridin-2-
yloxy)phenyl)methanone (3a’-2) (23.8 mg, 62% yield) colorless oil; H NMR (400
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MHz, DMSO-d6): δ 8.69 (d, J = 4.7 Hz, 1H), 8.00 (m, 1H), 7.91 (t, J = 7.6 Hz, 1H),
7.73 (m, 3H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.41 (m, 1H), 7.24 (m, 3H), 7.03
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(m, 1H), 6.74 (d, J = 8.2 Hz, 1H), 2.43 (s, 3H). C NMR (100 MHz, DMSO-d6): δ
192.9, 165.3 (d, 1JC-F = 250 Hz), 162.8, 157.9, 151.1, 149.6, 147.3, 141.3, 140.5, 137.2,
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137.1, 134.1 (d, JC-F = 3 Hz), 132.6 (d, JC-F = 10 Hz), 131.5, 129.7, 125.2, 124.6,
122.8, 119.5, 115.8 (d, 2JC-F = 22 Hz), 111.5, 20.4. ES-HRMS: Calcd for C24H18O2N2F
[M+H]+, 385.1347, Found 385.1329.
Mesityl(3-methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)methanone (3a-3)
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(33.4 mg, 82% yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.51 (m, 1H),
8.16 (m, 1H), 7.87 (m, 1H), 7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.30
(d, J = 7.8 Hz, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.00 (d, J =
2.4 Hz, 1H), 6.75 (s, 2H), 2.18 (s, 3H), 2.03 (m, 9H). 13C NMR (100 MHz, DMSO-d6):
δ 199.5, 163.0, 158.1, 153.4, 149.3, 147.7, 140.8, 140.0, 139.5, 138.9, 137.2, 136.9,
136.0, 135.0, 128.8, 127.1, 124.6, 122.2, 120.8, 119.8, 112.1, 21.0, 20.1, 20.1. ES-
HRMS: Calcd for C27H25O2N2 [M+H]+, 409.1911, Found 409.1900.
Mesityl(4-methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)methanone (3a’-3)
(19.5 mg, 48% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.1
Hz, 1H), 7.99 (dd, J = 5.0, 1.6 Hz, 1H), 7.91 (td, J = 7.7, 1.8 Hz, 1H), 7.74 (s, 1H), 7.70
(m, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.41 (m, 1H), 7.22 (s, 1H), 7.02 (dd, J = 6.6, 5.1 Hz,
1H), 6.70 (s, 2H), 6.62 (d, J = 8.3 Hz, 1H), 2.40 (s, 3H), 2.15 (s, 3H), 1.95 (s, 6H). 13C
NMR (100 MHz, DMSO-d6): δ 197.5, 163.2, 157.7, 152.7, 149.7, 146.8, 143.8, 139.8,
138.6, 138.1, 138.0, 137.3, 133.6, 132.7, 129.1, 128.3, 127.2, 124.5, 122.9, 118.8, 111.2,
21.0, 20.7, 19.4. ES-HRMS: Calcd for C27H25O2N2 [M+H]+, 409.1911, Found 409.1896.
Cyclohexyl(3-methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)methanone (3a-
4) (26.7 mg, 72% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.65 (m, 1H),
8.20 (m, 1H), 7.90 (m, 2H), 7.43 (m, 2H), 7.24 (m, 1H), 7.13 (m, 3H), 2.18 (m, 4H),
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1.55 (m, 4H), 1.03 (m, 6H). C NMR (100 MHz, DMSO-d6): δ 208.0, 163.2, 157.4,
153.5, 149.6, 147.9, 142.8, 140.8, 138.5, 136.7, 135.1, 125.6, 125.0, 122.7, 119.8, 118.1,
112.2, 49.1, 28.8, 25.7, 25.5, 20.3. ES-HRMS: Calcd for C24H25O2N2 [M+H]+,
373.1911, Found 373.1904.
Cyclohexyl(4-methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)methanone (3a’-
4) (24.1 mg, 65% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.70 (d, J =
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4.7 Hz, 1H), 8.15 (d, J = 4.2 Hz, 1H), 7.91 (m, 2H), 7.67 (s, 1H), 7.62 (d, J = 7.8 Hz,
1H), 7.41 (dd, J = 7.2, 5.2 Hz, 1H), 7.16 (m, 3H), 3.07 (m, 1H), 2.36 (s, 3H), 1.61 (m,
4H), 1.13 (m, 6H). 13C NMR (100 MHz, DMSO-d6): δ 204.1, 163.2, 158.0, 151.5, 149.6,
147.7, 141.5, 140.8, 137.4, 137.2, 131.2, 129.9, 125.7, 124.5, 122.7, 119.6, 111.9, 48.8,
28.9, 25.8, 25.6, 20.6. ES-HRMS: Calcd for C24H25O2N2 [M+H]+, 373.1911, Found
373.1895.
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3-Methyl-1-(3-methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)butan-1-one
(3a-5) (16.6 mg, 48% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.61 (m,
1H), 8.20 (dd, J = 4.9, 1.9 Hz, 1H), 7.88 (m, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.38 (m,
1H), 7.24 (m, 1H), 7.19 (m, 2H), 7.13 (d, J = 8.3 Hz, 1H), 2.28 (d, J = 6.6 Hz, 2H), 2.15
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(s, 3H), 1.88 (m, 1H), 0.71 (d, J = 6.5 Hz, 6H). C NMR (100 MHz, DMSO-d6): δ
204.6, 163.3, 157.6, 153.5, 149.6, 147.9, 143.3, 140.8, 138.6, 136.5, 135.2, 125.6, 125.1,
122.7, 119.7, 118.1, 112.1, 50.9, 24.3, 22.6, 20.3. ES-HRMS: Calcd for C22H23O2N2
[M+H]+, 347.1754, Found 347.1745.
3-Methyl-1-(4-methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)butan-1-one
(3a’-5) (17.6 mg, 51% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.70 (m,
1H), 8.14 (dd, J = 5.3, 1.9 Hz, 1H), 7.91 (m, 2H), 7.76 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H),
7.41 (m, 1H), 7.15 (m, 3H), 2.72 (d, J = 6.8 Hz, 2H), 2.36 (s, 3H), 2.01 (m, 1H), 0.76
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(d, J = 6.7 Hz, 6H). C NMR (100 MHz, DMSO-d6): δ 200.2, 163.3, 158.0, 151.6,
149.6, 147.8, 142.0, 140.8, 137.4, 137.2, 131.2, 130.4, 125.7, 124.5, 122.8, 119.5, 112.0,
51.0, 24.6, 22.6, 20.6. ES-HRMS: Calcd for C22H23O2N2 [M+H]+, 347.1754, Found
347.1743.
Phenyl(2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)methanone (3b) (30.3 mg, 86%
1
yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.22 (m, 2H), 7.95 (d, J = 8.5
Hz, 1H), 7.91 (m, 1H), 7.77 (m, 2H), 7.60 (m, 2H), 7.45 (m, 2H), 7.34 (t, J = 7.6 Hz,
2H), 7.22 (d, J = 2.5 Hz, 1H), 7.15 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ 196.3,
162.9, 155.7, 154.6, 148.9, 147.9, 140.9, 140.9, 137.8, 137.5, 135.4, 132.8, 130.5, 129.0,
128.7, 123.0, 122.5, 122.5, 121.5, 120.0, 112.5. ES-HRMS: Calcd for C23H17O2N2
[M+H]+, 353.1285, Found 353.1270.
Phenyl(5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)methanone (3b’) (29.2 mg, 83%
yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.6 Hz, 1H), 8.35
(dd, J = 8.6, 1.8 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.03 (m, 2H), 7.91 (t, J = 7.7 Hz,
1H), 7.72 (d, J = 7.3 Hz, 3H), 7.61 (t, J = 7.4 Hz, 1H), 7.42 (m, 4H), 7.04 (m, 1H), 6.76
13
(d, J = 8.3 Hz, 1H). C NMR (100 MHz, DMSO-d6): δ 194.7, 162.7, 154.9, 152.2,
150.1, 147.3, 140.6, 137.9, 137.1, 135.5, 133.8, 132.6, 130.5, 129.8, 128.8, 128.1, 123.5,
123.3, 120.7, 119.6, 111.7. ES-HRMS: Calcd for C23H17O2N2 [M+H]+, 353.1285,
Found 353.1273.
3-Methyl-1-(2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)butan-1-one (3b-1) (15.9
mg, 48% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ8.55 (m, 1H), 8.18 (m,
1H), 7.93 (m, 2H), 7.78 (m, 2H), 7.34 (m, 2H), 7.18 (m, 3H), 2.43 (m, 2H), 2.00 (m,
1H), 0.83 (m, 6H). 13C NMR (100 MHz, DMSO-d6): δ 204.8, 163.0, 156.6, 154.4, 149.2,
147.9, 143.7, 140.8, 137.8, 134.6, 131.0, 122.8, 122.6, 120.2, 119.9, 115.9, 112.3, 51.2,
24.5, 22.8. ES-HRMS: Calcd for C21H21O2N2 [M+H]+, 333.1598, Found 333.1583.
3-Methyl-1-(5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)butan-1-one (3b’-1) (14.6
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mg, 44% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.71 (m, 1H), 8.40 (d,
J = 2.3 Hz, 1H), 8.28 (dd, J = 8.5, 2.3 Hz, 1H), 8.14 (m, 1H), 8.05 (d, J = 8.0 Hz, 1H),
7.91 (m, 2H), 7.40 (m, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.16 (m, 2H), 2.78 (d, J = 6.8 Hz,
2H), 2.05 (m, 1H), 0.79 (d, J = 6.7 Hz, 6H). 13C NMR (100 MHz, DMSO-d6): δ 201.3,
163.0, 155.0, 152.5, 150.0, 147.8, 140.8, 137.8, 135.8, 133.3, 131.1, 127.7, 124.0, 123.2,
120.7, 119.7, 112.1, 51.2, 24.6, 22.6. ES-HRMS: Calcd for C21H21O2N2 [M+H]+,
333.1598, Found 333.1584.
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(4-Methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)(phenyl)methanone
(3c)
(29.0 mg, 79% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J = 4.7
Hz, 1H), 8.16 (m, 1H), 7.97 (m, 2H), 7.76 (m, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.44 (t, J
= 7.3 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.13 (m, 4H), 2.26 (s, 2H). 13C NMR (100 MHz,
DMSO-d6): δ 196.2, 163.1, 156.0, 152.6, 148.9, 147.8, 140.8, 138.4, 138.0, 137.3,
136.1, 133.0, 132.7, 132.0, 129.1, 128.6, 122.7, 122.6, 122.5, 119.5, 111.6, 16.5. ES-
HRMS: Calcd for C24H19O2N2 [M+H]+, 367.1441, Found 367.1437.
(3-Methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)(phenyl)methanone (3c’)
(30.7 mg, 84% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 4.0,
1H), 8.27 (d, J = 1.7, 1H), 8.05 (m, 2H), 7.94 (dd, J = 4.9, 1.4, 1H), 7.90 (td, J = 7.8,
1.7, 1H), 7.74 (m, 3H), 7.60 (t, J = 7.4, 1H), 7.45 (t, J = 7.7, 2H), 7.37 (dd, J = 7.1, 5.1,
1H), 6.98 (dd, J = 6.8, 5.3, 1H), 6.72 (d, J = 8.3, 1H), 2.22 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 194.9, 162.7, 155.1, 150.1, 150.0, 147.2, 140.4, 137.8, 137.2, 135.7,
133.7, 133.6, 132.9, 131.9, 129.9, 128.8, 125.7, 123.2, 120.7, 119.0, 110.8, 16.9. ES-
HRMS: Calcd for C24H19O2N2 [M+H]+, 367.1441, Found 367.1441.
Cyclohexyl(4-methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl)methanone (3c-1)
(29.7 mg, 80% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ8.60 (d, J = 4.2
Hz, 1H), 8.13 (dd, J = 4.9, 1.3 Hz, 1H), 7.95 (t, J = 7.3 Hz, 1H), 7.94 (m, 2H), 7.77 (s,
1H), 7.38 (m, 1H), 7.12 (m, 2H), 7.03 (s, 1H), 2.17 (m, 4H), 1.63 (m, 4H), 1.24 (m, 2H),
13
0.94 (m, 4H). C NMR (100 MHz, DMSO-d6): δ 208.1, 163.1, 156.3, 152.5, 149.3,
147.8, 140.8, 140.2, 137.8, 134.8, 132.6, 132.1, 122.8, 122.4, 121.8, 119.4, 111.5, 50.1,
29.1, 25.9, 25.6, 16.4. ES-HRMS: Calcd for C24H25O2N2 [M+H]+, 373.1911, Found
373.1895.
Cyclohexyl(3-methyl-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)methanone (3c’-1)
(23.8 mg, 64% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ8.69 (d, J = 4.6
Hz, 1H), 8.19 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.06 (m, 2H), 7.88 (m, 2H),
7.38 (m, 1H), 7.12 (m, 2H), 3.01 (m, 1H), 2.13 (s, 3H), 1.62 (m, 4H), 1.13 (m, 6H). 13C
NMR (100 MHz, DMSO-d6): δ 205.6, 163.0, 155.2, 150.1, 150.0, 147.6, 140.8, 137.7,
136.1, 134.3, 133.0, 132.1, 125.2, 123.2, 120.8, 119.1, 110.9, 48.9, 28.8, 25.8, 25.5,
16.9. ES-HRMS: Calcd for C24H25O2N2 [M+H]+, 373.1911, Found 373.1905.
1-(4-Fluoro-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)phenyl)-3-methylbutan-1-one (3d’)
(15.0 mg, 43% yield) yellow oil; 1H NMR (400 MHz, DMSO-d6): δ8.54 (d, J = 4.2 Hz,
1H), 7.93 (m, 2H), 7.71 (m, 2H), 7.60 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 8.9 Hz, 1H), 7.23
(m, 1H), 6.98 (dd, J = 6.7, 5.1 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 2.65 (d, J = 6.7 Hz,
2H), 1.98 (m, 1H), 0.76 (d, J = 6.7 Hz, 6H). 13C NMR (100 MHz, DMSO-d6): δ 199.6,
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3
162.5, 158.9 (d, JC-F = 248 Hz), 153.8, 149.9, 148.2 (d, JC-F = 7 Hz), 147.3, 140.6,
136.8, 133.7 (d, 3JC-F = 10 Hz), 131.3 (d, 4JC-F = 3 Hz), 125.0 (d, 2JC-F = 20 Hz), 124.1,
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123.0, 119.4, 113.8 (d, JC-F = 23 Hz), 111.3, 53.0, 24.0, 22.4. ES-HRMS: Calcd for
C21H20O2N2F [M+H]+, 351.1503, Found 351.1487.
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3-Methyl-1-(5-(pyridin-2-yl)-2-(pyridin-2-yloxy)-[1,1'-biphenyl]-4-yl)butan-1-one
(3g) (24.4 mg, 60% yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.57 (m,
1
1H), 8.09 (m, 1H), 7.94 (m, 2H), 7.79 (m, 2H), 7.57 (m, 2H), 7.37 (m, 4H), 7.29 (s, 1H),
7.08 (m, 1H), 7.01 (d, J = 8.3 Hz, 1H), 2.47 (d, J = 6.6 Hz, 2H), 2.03 (m, 1H), 0.85 (d,
J = 6.7 Hz, 6H). 13C NMR (100 MHz, DMSO-d6): δ 204.5, 163.4, 156.6, 151.1, 149.2,
147.7, 142.5, 140.6, 137.7, 136.8, 135.7, 135.6, 132.1, 129.2, 128.7, 128.2, 123.0, 122.4,
119.4, 111.9, 51.2, 24.6, 22.8. ES-HRMS: Calcd for C27H25O2N2 [M+H]+, 409.1911,
Found 409.1893.
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3-Methyl-1-(5-(pyridin-2-yl)-2-(pyridin-2-yloxy)-[1,1'-biphenyl]-3-yl)butan-1-one
1
(3g’) (22.0 mg, 54% yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.72 (m,
1H), 8.37 (d, J = 2.3 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.94
(m, 2H), 7.71 (m, 1H), 7.43 (m, 3H), 7.30 (m, 3H), 6.97 (m, 1H), 6.88 (d, J = 8.3 Hz,
1H), 2.78 (d, J = 6.8 Hz, 2H), 2.01 (m, 1H), 0.75 (d, J = 6.7 Hz, 6H). 13C NMR (100
MHz, DMSO-d6): δ 201.7, 163.0, 154.9, 150.1, 148.5, 147.3, 140.4, 137.8, 137.3, 136.8,
136.4, 135.5, 132.0, 129.3, 128.6, 128.0, 126.6, 123.4, 121.0, 118.9, 111.4, 50.9, 24.3,
22.5. ES-HRMS: Calcd for C27H25O2N2 [M+H]+, 409.1911, Found 409.1897.
1-(4'-Fluoro-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)-[1,1'-biphenyl]-4-yl)-3-
methylbutan-1-one (3l) (25.9 mg, 61% yield) yellow oil; 1H NMR (400 MHz, DMSO-
d6): δ 8.56 (m, 1H), 8.09 (dd, J = 4.9, 1.3 Hz, 1H), 7.92 (m, 2H), 7.81 (m, 2H), 7.61 (m,
2H), 7.39 (m, 1H), 7.29 (s, 1H), 7.21 (m, 2H), 7.13 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H),
2.46 (d, J = 6.6 Hz, 2H), 2.03 (m, 1H), 0.85 (d, J = 6.7 Hz, 6H). 13C NMR (100 MHz,
DMSO-d6): δ 204.5, 163.2, 162.2 (d, 1JC-F = 244 Hz), 156.5, 151.1, 149.2, 147.7, 142.6,
140.6, 137.7, 135.6, 134.7, 133.1 (d, 4JC-F = 3 Hz), 132.1, 131.3 (d, 3JC-F = 8 Hz), 123.0,
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122.4, 119.5, 115.6 (d, JC-F = 21 Hz), 111.9, 51.2, 24.6, 22.8. ES-HRMS: Calcd for
C27H24O2N2F [M+H]+, 427.1816, Found 427.1796.
1-(4'-Fluoro-5-(pyridin-2-yl)-2-(pyridin-2-yloxy)-[1,1'-biphenyl]-3-yl)-3-
methylbutan-1-one (3l’) (24.3 mg, 57% yield) yellow oil; 1H NMR (400 MHz, DMSO-
d6): δ 8.72 (m, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 8.0
Hz, 1H), 7.94 (m, 2H), 7.73 (m, 1H), 7.50 (m, 2H), 7.42 (m, 1H), 7.17 (m, 2H), 6.98
(m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 2.78 (d, J = 6.8 Hz, 2H), 2.00 (m, 1H), 0.75 (d, J =
6.7 Hz, 6H). 13C NMR (100 MHz, DMSO-d6): δ 201.7, 162.9, 162.0 (d, 1JC-F = 243 Hz),
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154.8, 150.0, 148.5, 147.3, 140.5, 137.8, 136.4, 135.8, 135.5, 133.6 (d, JC-F = 3 Hz),
132.0, 131.4 (d, 3JC-F = 8 Hz), 126.7, 123.4, 121.0, 119.0, 115.5 (d, 2JC-F = 21 Hz), 111.4,
51.2, 24.3, 22.5. ES-HRMS: Calcd for C27H24O2N2F [M+H]+, 427.1816, Found
427.1805.
General procedure for the C-H Bromination and Iodination reaction
The substrate 1 (0.1 mmol), Pd(OAc)2 (0.01 or 0.02 mmol), NIS or NBS (0.15
mmol) was dissolved in AcOH or TFA (1.0 mL), and the tube was sealed with a PTFE
stopcock. The mixture was stirred at 120 °C for 6-8 h. After cooled to room temperature,
the solvent was evaporated in vacuo. The residue was dissolved in DCM (20 mL) and
washed with saturated NaHCO3 aqueous three times. The organic layer was dried by
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Na2SO4, filtered and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (PE:EA=4:1) to give the desired products.
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2-(3-Iodo-5-methyl-4-(pyridin-2-yl)phenoxy)pyridine (4a) (31.0 mg, 80% yield)
colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.70 (d, J = 4.2 Hz, 1H), 8.21 (dd, J =
4.9, 1.3 Hz, 1H), 7.91 (m, 2H), 7.54 (d, J = 2.1 Hz, 1H), 7.43 (m, 1H), 7.35 (d, J = 7.7
Hz, 1H), 7.17 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 2.01 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): δ 163.2, 161.0, 153.9, 149.8, 147.9, 141.7, 140.8, 138.8, 137.2, 128.9,
125.1, 123.2, 123.1, 119.8, 112.1, 99.1, 21.4. ES-HRMS: Calcd for C17H14ON2I
[M+H]+, 389.0145, Found 389.0134.
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2-(5-Iodo-2-methyl-4-(pyridin-2-yloxy)phenyl)pyridine (4a’) (29.1 mg, 75% yield)
colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.7 Hz, 1H), 8.14 (d, J =
4.8 Hz, 1H), 7.90 (t, J = 7.7 Hz, 2H), 7.86 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.41 (m,
1H), 7.14 (m, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 162.9, 157.3, 153.8,
149.6, 147.7, 140.7, 140.2, 139.3, 138.1, 137.1, 125.6, 124.5, 122.8, 119.4, 111.7, 88.5,
20.3. ES-HRMS: Calcd for C17H14ON2I [M+H]+, 389.0145, Found 389.0138.
2-(3,5-Diiodo-4-(pyridin-2-yl)phenoxy)pyridine (4b) (26.5 mg, 53% yield)
1
colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.71 (m, 1H), 8.22 (dd, J = 4.9, 1.9,
1H), 7.93 (m, 2H), 7.79 (s, 2H), 7.44 (dd, J = 7.4, 4.9, 1H), 7.33 (d, J = 7.8, 1H), 7.21
(dd, J = 7.2, 5.0, 1H), 7.15 (d, J = 8.3, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.9,
162.8, 154.1, 149.5, 147.8, 145.2, 141.0, 137.2, 131.6, 124.6, 123.8, 120.2, 112.3, 97.6.
ES-HRMS: Calcd for C16H11ON2I2 [M+H]+, 500.8955, Found 500.8959.
2-(2,6-Diiodo-4-(pyridin-2-yl)phenoxy)pyridine (4b’-1) (22.5 mg, 45% yield)
1
colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.70 (m, 1H), 8.59 (s, 2H), 8.09 (m,
13
2H), 7.92 (m, 2H), 7.42 (m, 1H), 7.16 (m, 2H). C NMR (100 MHz, DMSO-d6): δ
161.7, 154.3, 152.9, 150.1, 147.5, 140.9, 139.4, 137.9, 137.6, 123.7, 121.2, 119.5, 111.7,
93.8. ES-HRMS: Calcd for C16H11ON2I2 [M+H]+, 500.8955, Found 500.8959.
2-(2-Iodo-4-(pyridin-2-yl)phenoxy)pyridine (4b’-2) (14.2 mg, 38% yield)
colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.68 (dd, J = 4.8, 0.8, 1H), 8.61 (d, J =
2.1, 1H), 8.14 (m, 2H), 8.02 (d, J = 8.0, 1H), 7.91 (td, J = 7.8, 1.9, 2H), 7.39 (m, 1H),
7.29 (d, J = 8.5, 1H), 7.16 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 162.8, 154.8,
154.3, 150.0, 147.7, 140.8, 137.8, 137.6, 137.6, 128.2, 123.7, 123.3, 120.8, 119.6, 111.9,
92.7. ES-HRMS: Calcd for C16H12ON2I [M+H]+, 374.9988, Found 374.9990
2-(5-Iodo-2-methyl-4-(pyridin-2-yl)phenoxy)pyridine (4c) (26.4 mg, 68% yield)
1
colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.68 (m, 1H), 8.15 (dd, J = 4.9, 1.8,
1H), 7.90 (m, 2H), 7.63 (s, 1H), 7.58 (d, J = 7.8, 1H), 7.42 (m, 2H), 7.13 (m, 2H), 2.08
(s, 3H).13C NMR (100 MHz, DMSO-d6): δ 163.0, 160.1, 152.5, 149.4, 147.8, 141.9,
140.8, 136.7, 132.9, 132.7, 131.1, 124.6, 123.1, 119.4, 111.5, 93.5, 16.1. ES-HRMS:
Calcd for C17H14ON2I [M+H]+, 389.0145, Found 389.0145.
2-(3-Iodo-5-methyl-4-(pyridin-2-yloxy)phenyl)pyridine (4c’) (32.6 mg, 84% yield)
colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, J = 4.7, 1H), 8.42 (d, J = 1.8,
1H), 8.08 (dd, J = 5.4, 1.6, 1H), 8.04 (d, J = 1.3, 1H), 8.01 (d, J = 8.0, 1H), 7.90 (td, J
= 8.0, 1.5, 2H), 7.38 (dd, J = 7.4, 4.8, 1H), 7.12 (m, 2H), 2.16 (s, 3H).13C NMR (100
MHz, DMSO-d6): δ 162.2, 154.5, 152.9, 150.0, 147.6, 140.8, 137.8, 137.8, 135.2, 133.2,
129.7, 123.3, 120.8, 119.2, 111.2, 94.0, 17.7. ES-HRMS: Calcd for C17H14ON2I
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[M+H]+, 389.0145, Found 389.0145.
2-(5-Bromo-2-methyl-4-(pyridin-2-yloxy)phenyl)pyridine (5a’) (30.6 mg, 90%
yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 4.2 Hz, 1H), 8.14
(m, 1H), 7.88 (m, 2H), 7.70 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.41 (m, 1H), 7.25 (s, 1H),
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7.15 (m, 2H), 2.30 (s, 3H). C NMR (100 MHz, DMSO-d6): δ 162.9, 157.4, 150.6,
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149.6, 147.7, 140.8, 139.1, 137.4, 137.2, 134.3, 126.5, 124.5, 122.9, 119.5, 113.3, 111.5,
20.2. ES-HRMS: Calcd for C17H14ON2Br [M+H]+, 341.0284 (79Br), Found 341.0280
(79Br).
2-(3,5-Dibromo-4-(pyridin-2-yl)phenoxy)pyridine (5b) (33.2 mg, 82% yield)
colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.71 (d, J = 3.0, 1H), 8.23 (d, J = 2.7,
1H), 7.94 (m, 2H), 7.64 (m, 2H), 7.45 (m, 2H), 7.24 (m, 1H), 7.18 (d, J = 8.2, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 162.7, 158.2, 154.6, 149.8, 147.8, 141.0, 138.4, 137.3,
125.3, 125.1, 123.8, 123.5, 120.3, 112.4. ES-HRMS: Calcd for C16H11ON2Br2 [M+H]+,
404.9232 (79Br) Found 404.9234, 406.9212, 408.9189.
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2-(2,6-Dibromo-4-(pyridin-2-yl)phenoxy)pyridine (5b’-1) (20.2 mg, 50% yield)
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colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.71 (d, J = 4.1, 1H), 8.44 (m, 2H),
8.13 (d, J = 8.0, 1H), 8.10 (m, 1H), 7.94 (t, J = 7.8, 2H), 7.44 (dd, J = 7.3, 4.9, 1H),
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7.23 (d, J = 8.3, 1H), 7.17 (dd, J = 6.7, 5.4, 1H). C NMR (100 MHz, DMSO-d6): δ
161.7, 153.0, 150.1, 148.7, 147.5, 141.1, 139.0, 138.0, 130.8, 124.0, 121.3, 119.8, 119.2,
111.1. ES-HRMS: Calcd for C16H11ON2Br2 [M+H]+, 404.9232 (79Br) Found 404.9234,
406.9212, 408.9189.
2-(2-Bromo-4-(pyridin-2-yl)phenoxy)pyridine (5b’-2) (11.4 mg, 35% yield)
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colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.70 (d, J = 4.6, 1H), 8.43 (m, 1H),
8.14 (m, 2H), 8.05 (d, J = 7.9, 1H), 7.93 (m, 2H), 7.39 (m, 2H), 7.17 (m, 2H). 13C NMR
(100 MHz, DMSO-d6): δ 162.7, 154.3, 151.7, 150.1, 147.7, 140.9, 137.9, 137.6, 131.5,
127.5, 124.8, 123.4, 120.8, 119.7, 116.9, 111.6. ES-HRMS: Calcd for C16H12ON2Br
[M+H]+, 327.0127 (79Br) Found 327.0129 (79Br).
2-(5-Bromo-2-methyl-4-(pyridin-2-yl)phenoxy)pyridine (5c) (27.8 mg, 82% yield)
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colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.69 (m, 1H), 8.16 (dd, J = 4.6, 1.5,
1H), 7.90 (m, 2H), 7.65 (d, J = 7.8, 1H), 7.50 (s, 1H), 7.43 (m, 2H), 7.5 (m, 2H), 2.10
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(s, 3H). C NMR (100 MHz, DMSO-d6): δ 163.0, 157.6, 152.8, 149.6, 147.8, 140.8,
138.0, 136.7, 134.1, 130.7, 126.6, 124.9, 123.2, 119.5, 118.3, 111.5, 16.0. ES-HRMS:
Calcd for C17H14ON2Br [M+H]+, 341.0284 (79Br), Found 341.0280 (79Br).
2-(3-Bromo-5-methyl-4-(pyridin-2-yloxy)phenyl)pyridine (5c’) (31.6 mg, 93%
yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.67 (m, 1H), 8.23 (d, J = 2.0,
1H), 8.08 (dd, J = 4.9, 1.4, 1H), 8.06 (d, J = 1.6, 1H), 8.03 (d, J = 8.0,1H), 7.91 (m,
2H), 7.38 (m, 1H), 7.13 (m, 2H), 2.18 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 162.2,
154.5, 150.0, 149.9, 147.6, 140.8, 137.8, 137.5, 134.2, 129.0, 128.9, 123.4, 120.8, 119.3,
117.9, 110.9, 17.3. ES-HRMS: Calcd for C17H14ON2Br [M+H]+, 341.0284 (79Br),
Found 341.0280 (79Br).
Ethyl (E)-3-(6-(2-iodo-5-methyl-4-(pyridin-2-yl)phenoxy)pyridin-3-yl)acrylate
(8-I’) (43.8 mg, 90% yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J
= 4.4 Hz, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.32 (dd, J = 8.6, 2.1 Hz, 1H), 7.89 (m, 2H),
7.64 (dd, J = 20.4, 12.0 Hz, 2H), 7.40 (dd, J = 7.0, 5.3 Hz, 1H), 7.19 (m, 2H), 6.69 (d,
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J = 16.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6): δ 166.5, 163.9, 157.3, 153.5, 149.6, 148.9, 140.9, 140.2,
139.7, 139.2, 138.2, 137.1, 126.1, 125.7, 124.5, 122.8, 118.7, 112.0, 88.4, 60.5, 20.3,
14.6. ES-HRMS: Calcd for C22H20O3N2I [M+H]+, 487.0513, Found 487.0498.
General procedure for the C-H oxidation reaction
a) The substrate 1 (0.1 mmol), Pd(OAc)2 (0.01 or 0.02 mmol), PhI(OAc)2 (0.2 mmol)
was dissolved in AcOH (0.5 mL) and Ac2O (0.5 mL), and the tube was sealed with
a PTFE stopcock. The mixture was stirred at 120 °C for 12 h. After cooled to room
temperature, the solvent was evaporated in vacuo. The residue was dissolved in
DCM (20 mL) and washed with saturated NaHCO3 aqueous three times. The
organic layer was dried by Na2SO4, filtered and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (PE:EA=2:1) to give the
desired products.
b) The substrate 1 (0.1 mmol), Pd(OAc)2 (0.01 or 0.02 mmol), K2S2O8 (0.2 mmol) was
dissolved in TFA (0.9 mL) and (CF3CO)2O (0.1 mL), and the tube was sealed with
a PTFE stopcock. The mixture was stirred at 120 °C for 12 h. After cooled to room
temperature, the solvent was evaporated in vacuo. The residue was dissolved in
DCM (20 mL) and washed with saturated NaHCO3 aqueous three times. The
organic layer was dried by Na2SO4, filtered and concentrated in vacuo. The residue
was dissolved in DCM (5 mL). Ac2O (0.02 mL) and triethylamine (0.02 mL) were
added to the solution. The mixture was stirred at room temperature for 2 h. The
solvent was evaporated in vacuo. The residue was dissolved in DCM (20 mL) and
washed with saturated NaHCO3 aqueous three times. The organic layer was dried
by Na2SO4, filtered and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (PE:EA=2:1) to give the mixed products.
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3-Methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl acetate (6a) (28.9 mg, 90%
yield) colorless oil; 1H NMR (400 MHz, DMSO-d6): δ8.69 (d, J = 4.8, 1H), 8.21 (dd,
J = 4.9, 1.3, 1H), 7.90 (m, 2H), 7.41 (dd, J = 7.0, 5.4, 1H), 7.34 (d, J = 7.8, 1H), 7.18
(dd, J = 6.8, 5.4, 1H), 7.11 (d, J = 8.3, 1H), 7.03 (d, J = 1.8, 1H), 6.90 (d, J = 2.0, 1H),
2.11 (s, 3H), 1.91 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 169.0, 163.0, 154.8, 154.0,
149.6, 149.3, 148.0, 140.8, 139.2, 137.1, 130.1, 125.4, 123.0, 120.6, 119.9, 113.7, 112.2,
20.7, 20.1. ES-HRMS: Calcd for C19H16O3N2 [M+H]+, 321.1233, Found 321.1230.
4-Methyl-2-(pyridin-2-yl)-5-(pyridin-2-yloxy)phenyl acetate (6c) (26.6 mg, 83%
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yield) colorless oil; H NMR (400 MHz, DMSO-d6): δ 8.68 (m, 1H), 8.16 (m, 1H),
7.88 (m, 2H), 7.71 (s, 1H), 7.65 (d, J = 7.9, 1H), 7.36 (m, 1H), 7.13 (m, 3H), 6.98 (s,
1H), 2.14 (m, 6H). 13C NMR (100 MHz, DMSO-d6): δ 169.4, 163.0, 154.8, 152.9, 149.9,
147.9, 146.8, 140.8, 137.2, 132.9, 129.6, 128.6, 123.6, 122.8, 119.5, 117.4, 111.5, 21.1,
16.0. ES-HRMS: Calcd for C19H16O3N2 [M+H]+, 321.1233, Found 321.1230.
Procedure for the reductive amination
To the solution of compound d-7a (0.1 mmol) in methanol (3 mL) was added the
corresponding amine (0.15 mmol). The mixture was stirred at room temperature for 1h.
Then Pd/C (5%, 35 mg) was added and the solution was stirred under hydrogen (1atm)
for another 3 h. The Pd/C was removed by filtration and the filtrated was purified by
Combiflash C18 column to give the desired product d-7.
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1-(2-(((6-(2-Methyl-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2-
yl)methyl)amino)ethyl)imidazolidin-2-one (7) Colorless oil; H NMR (400 MHz,
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DMSO-d6): δ 8.60 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.47 (d, J
= 8.2 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 1H), 7.16 (s, 1H), 7.12 (d,
J = 8.4 Hz, 1H), 6.26 (s, 1H), 3.87 (s , 2H), 3.33 (t, J = 7.7 Hz, 2H), 3.17 (dd, J = 13.2,
6.9 Hz, 4H), 2.67 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ
166.1, 162.8, 160.1, 158.0, 153.0, 145.8 (q, 4JC-F = 4.4 Hz), 138.0, 137.8, 137.4, 131.5,
124.3 (q, 1JC-F = 270 Hz), 123.8, 122.3, 121.0, 120.7, 120.4, 119.4, 112.2, 54.7, 47.2,
45.3, 43.5, 37.9, 20.7. ES-HRMS: Calcd for C24H25O2N5F3 [M+H]+, 472.1939, Found
472.1954.
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d-1-(2-(((6-(2-Methyl-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl-3,5,6-
d3)pyridin-2-yl)methyl)amino)ethyl)imidazolidin-2-one (d-7) (30.8 mg, 65% yield) D-
incorporation was determined against integral at δ 8.25; 1H NMR (400 MHz, DMSO-
d6): δ 8.60 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.47 (s, 0.95H),
7.41 (t, J = 7.7 Hz, 2H), 7.28 (d, J = 8.7 Hz, 1H), 7.16 (s, 0.60H), 7.12 (m, 0.05H), 6.26
(s, 1H), 3.87 (s, 2H), 3.33 (t, J = 7.7 Hz, 2H), 3.17 (dd, J = 13.2, 6.9 Hz, 4H), 2.67 (t, J
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= 6.3 Hz, 2H), 2.34 (s, 3H). C NMR (100 MHz, DMSO-d6): δ 166.0, 162.8, 159.8,
158.0, 153.0, 145.8 (q, 4JC-F = 4.4 Hz), 138.0, 137.8, 137.4, 131.4, 124.3 (d, 1JC-F = 270
Hz), 123.8, 122.4, 121.0, 120.7, 120.5, 119.4 (labelled), 112.2, 54.5, 47.1, 45.3, 43.4,
37.9, 20.6 ES-HRMS: Calcd for C24H23D2O2N5F3 [M+H]+, 474.2069, Found 474.2065.
Procedure for the synthesis of complex I and II
1b (0.5 mmol), Pd(OAc)2 (0.5 mmol) was dissolved in AcOH or TFA (5 mL). The
mixture was stirred at 50 °C for 10 h. The solvent was removed in vacuo. The residue
was washed with MeOH or ethyl acetate to give the complex I or II.
Complex I 1H NMR (400 MHz, DMSO-d6): δ1H NMR (400 MHz, DMSO) δ 8.31
(m, 1H), 7.89 (m, 2H), 7.66 (m, 1H), 7.46 (m, 1H), 7.18 (m, 3H), 6.82 (m, 1H), 6.64
(m, 1H), 6.32 (m, 1H), 1.86 (s, 3H).
Complex II 1H NMR (400 MHz, CD2Cl2): δ 8.82 (dd, J = 6.0, 1.5 Hz, 1H), 8.36
(dd, J = 5.6, 1.2 Hz, 1H), 8.00 (m, 2H), 7.42 (m, 1H), 7.13 (m, 3H), 6.87 (td, J = 7.8,
1.6 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 4.86 (m, 1H).
Acknowledgments
We thank Dr. Yi Dong for his kind suggestions on this paper. We thank Dr.
Yongshuai Chai for his work on the theoretical calculation. We gratefully acknowledge
the funding support from the National Natural Science Foundation of China (Grants:
81273364, 91213303).
Supporting informationt
The synthesis of substrate 1 and copies of 1H and 13C NMR spectra of substrate 1 and
the products or intermediates
Reference
(1) a) Katsnelson, A. Nature Med. 2013, 19, 656. b) Meanwell, N. A. J. Med. Chem.
2011, 54, 2529-2591. c) Jacques, V.; Czarnik, A. W.; Judge, T. M.; Van der Ploeg, L. H.
T.; DeWitt, S. H. Proc. Natl. Acad. Sci. 2015, 112, E1471-1479. d) Elmore, C. S. Annu.
Rep. Med. Chem. 2009, 44, 515-534.
(2) a) Chen, Y. PCT Int. Appl. 2013, WO 2013087004. b) Faming Zhuanli Shenqing,
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