Fully regiocontrolled polyarylation of pyridine

Article abstract of DOI:10.1021/jo402200q

Starting from commercially available 2-chloro-3-hydroxypyridine, a new route leading to the first protypical pentaarylpyridine bearing five different substituents is reported. This strategy involves a set of five sequential but fully regiocontrolled Suzuki-Miyaura reactions and highlights the 2-OBn pyridine protecting group as a key intermediate. The 2-OBn group played a double role: (i) it allowed additional bromination at position 5 and (ii) it could afford the reactive OTf species for the last C-arylation step at the less hindered 2 position of the tetraarylpyridine. The photophysical properties of the novel compounds are also described. The synthesized pentaarylpyridine derivative exhibit a large Stokes shift, strong solvatochromism, and quantum yield values up to 0.47; thus, they constitute promising building blocks for the design of environment-sensitive probes.

Full text of DOI:10.1021/jo402200q

Article
pubs.acs.org/joc
Fully Regiocontrolled Polyarylation of Pyridine
Christelle Doebelin,† Patrick Wagner,† Frederic Bihel,† Nicolas Humbert,‡ Cyril Assongo Kenfack,§
́
́
Yves Mely,‡ Jean-Jacques Bourguignon,†,∥ and Martine Schmitt*,†,∥
†Laboratoire d’Innovation Ther
France
́ ́
apeutique, UMR7200 CNRS-Universite de Strasbourg, 74 route du Rhin, BP 60024, 67401 Illkirch,
‡Laboratoire de Biophotonique et Pharmacologie, UMR7213 CNRS-Universite
Illkirch, France
́
de Strasbourg, 74 route du Rhin, BP 60024, 67401
§Laboratoire d’Optique et Applications, Centre de Physique Atomique Molec
Universite de Douala, BP 8580 Douala, Cameroon
́
́
ulaire et Optique Quantique, Faculte des Sciences,
́
S
* Supporting Information
ABSTRACT: Starting from commercially available 2-chloro-3-hydroxypyridine, a new route leading to the first protypical
pentaarylpyridine bearing five different substituents is reported. This strategy involves a set of five sequential but fully
regiocontrolled Suzuki−Miyaura reactions and highlights the 2-OBn pyridine protecting group as a key intermediate. The 2-OBn
group played a double role: (i) it allowed additional bromination at position 5 and (ii) it could afford the reactive OTf species for
the last C-arylation step at the less hindered 2 position of the tetraarylpyridine. The photophysical properties of the novel
compounds are also described. The synthesized pentaarylpyridine derivative exhibit a large Stokes shift, strong solvatochromism,
and quantum yield values up to 0.47; thus, they constitute promising building blocks for the design of environment-sensitive
probes.
multicomponent reactions24 combining Michael acceptors
INTRODUCTION
■
with malonitrile afforded numerous polyfunctionalized pyr-
idines. However, the products contained specific functional
groups resulting from the use of specific reagents in these
methodologies (i.e., CN, CO2Et, or CF3 residues). Pd- or Cu-
catalyzed cross-coupling reactions offer novel perspectives in
organic synthesis. Although initially these reactions were
conducted with halobenzenes, they have now been extended
to heteroaromatic halides such as halopyridines.
By combining various Pd-catalyzed reactions (such as
Suzuki−Miyaura, Buchwald−Hartwig, and Sonogashira reac-
tions), di- or trisubstituted pyridines have been prepared
starting from commercially available starting materials such as
2,6-dichloro-4-iodopyridine or 3,4,5-triiodopyridine.25−28 How-
ever, the regioselective monosubstitution of symmetrical
halogens in positions 2/6 or 3/5, using Pd-catalyzed reactions
generally results in complex mixtures of mono- and
disubstituted aryl pyridines.25,28,29 A better regiocontrolled
Pyridine derivatives represent an important class of six-
membered heterocycles prevalent in a number of biologically
active natural products1−7 and pharmaceutical drugs.8−12 They
have significant applications in many fields of chemistry.13 In
particular, they are useful building blocks for the preparation of
chiral ligands14−16 and new materials with important photo- or
electrochemical properties.17−20 Several strategies have been
developed to control the polysubstitution of a pyridine
ring.21−24 However, these methods suffer from limited chemical
diversity and either sometimes fail because of steric hindrance,
particularly for tetra- or pentasubstituted pyridines, or afforded
low yields. Herein, we describe a versatile strategy based on a
set of sequential Suzuki−Miyaura Pd-catalyzed cross-coupling
reactions that allow for regiocontrolled aryl substitutions at the
five positions of a pyridine ring, resulting in a large amount of
chemical diversity in good yields.
Among the various strategies developed to control the
polysubstitution of pyridine, simple condensation reactions
based on the classical Hantzsch reaction, various cyclo-
additions,21,22 thermal rearrangements of triazines,23 and
Received: October 3, 2013
Published: January 13, 2014
© 2014 American Chemical Society
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substitution was observed when 2-chloro-3,4-diiodopyridine
was used, which resulted in differently substituted 2,3,4-
triarylpyridine derivatives30 owing to the different chemical
reactivities of both iodine atoms.
RESULTS AND DISCUSSION
■
Commercially available 2-chloro-3-hydroxypyridine 1 was first
treated with iodine in basic medium to afford 6-iododerivative 2
in satisfactory yield after precipitation in water at pH 6
(Scheme 2). This first step could be scaled up on a multigram
However, it became significantly more challenging to
increase the number of substitutions (more than three or
four) at the pyridine nucleus, and very few studies have
reported the synthesis of pentasubstituted pyridine derivatives.
Recently, Langer et al. reported multiple Sonogashira reactions
on pentachloropyridine to afford the corresponding pentaalky-
nylpyridine (compound I).31 Reissig and co-workers attempted
the synthesis of poly(2-thienyl)pyridine; their strategy was
efficient for the synthesis of trisubstituted32 (2,3,5 and 2,4,6)
and tetrasubstituted (2,3,5,6 and 2,3,4,6) poly(2-thienyl)-
pyridines. However, the introduction of the fifth thienyl
substituent was more difficult because of the loss of reactivity
resulting from the steric hindrance generated by the presence of
two aromatic rings at positions 2 and 4 as the neighboring
substituents of the remaining 3-OTf (compound II) or ONf
(compound III). However, after efforts to improve the final
step of the reaction, the authors obtained penta(2-thienyl)-
pyridines (compound IV)33 in moderate yields (26−41%,
Scheme 1). Few other studies dealing with the synthesis of
Scheme 2. Preparation of Key Intermediates 3−5 Leading to
Successive Regiocontrolled C-Arylation of Tri-, Tetra-, and
a
Pentasubstituted Pyridines
a
Reagents and conditions: (a) I2, Na2CO3, H2O, rt; (b) MOMCl,
Scheme 1. Known Examples for Pentasubstitution of
Pyridine
iPr2NH, CH2Cl2, rt; (c) (i) NBS, iPr2NH, CH2Cl2, rt; (ii) MOMCl, rt;
(d) iPrMgCl 2 M, −78 °C, THF, MeOH; (e) Pd(PPh3)4, 4-
MeOPhB(OH)2, Na2CO3, toluene/EtOH/H2O, 90 °C; (f) PhB-
(OH)2, Pd(PPh3)4, Na2CO3, toluene/EtOH/H2O, 90 °C.
scale with 68% yield.36,37 To ensure high chemoselectivity,
bromination was performed using NBS in the presence of
diisopropylamine. The di- and trihalogenated hydroxypyridine
intermediates were first O-protected as MOM ethers before
performing the Pd-catalyzed cross-coupling reactions. O-MOM
intermediates 3 and 4 were obtained in nearly quantitative
yields. Moreover, trihalogenated pyridine 4 was also efficiently
used as a substrate in halogen/metal-exchange reactions and
underwent clean magnesiation at −78 °C in THF in the
presence of iPrMgCl.38 The organomagnesium intermediate
was trapped with methanol to afford 2-chloro-4-bromo-
OMOM-pyridine 5 in 79% yield. All three halogenated O-
MOM pyridines, 3−5, were then submitted to the first C-
arylation reaction occurring at position 6 (compound 6, R1
Ar1), position 4 (compound 7, R2Ar2), or to two sequential
C-arylation reactions at positions 6 and 4 (compound 8, R1
Ar1, R2Ar2). All of these Suzuki−Miyaura reactions afford the
expected aryl derivatives in good yields (up to 90%, see the
Supporting Information for details). 3-OMOM pyridine
intermediates 6, 7, and 8 further provided compounds 22
and 34, 23 and 35, and 24 and 36, respectively, as detailed in
Scheme 3.
Notably, the OH group in hydroxypyridine 2 plays a double
role: (i) as an ortho-para-directing group, it favors further
halogenations in positions 6 and/or 4 of the pyridine nucleus
and (ii) it could be easily transformed into OTf or ONf33 and
thus could be employed for further C-arylation reactions.
Finally, resulting aryl pyridines 6−8 seemed to be promising
candidates for building highly polyarylated pyridines (Scheme
3). However, their application, particularly in the synthesis of
pentaarylpyridine, is limited by some drawbacks. Reissig and
co-workers already emphasized the rather disappointing
reactivity of the highly hindered 3-OTf and 3-ONf derivatives
of 2,4,5,6-tetra(2-thienyl)pyridine, as shown in Scheme 1, and
differently tetra- or pentasubstituted pyridines have been
reported using specific cycloaddition reactions (e.g., involving
the dimerization of neutral 2-azadienes (compound V)34 or the
subsequent Pd-catalyzed cyclization of allenyl imines)35. Some
limitations of diversity of aryl substituents resulted from either
the specific reaction mechanism34 (Scheme 1) or the
unavailability of the amino allenes.35
In this article, we report the synthesis of tri-, tetra-, and
pentasubstituted arylpyridines using complementary methods
by combining regioselective halogenations, protection/activa-
tion of phenol groups, and cross-coupling reactions.
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a
Scheme 3. Detailed Strategy Leading to Diversely Polyarylated Pyridines
a
Reagents and conditions: (a) Amberlyst, CH2Cl2/MeOH, rt; (b) Tf2O, Et3N, CH2Cl2, rt; (c) 4-MePhB(OH)2, 5% Pd(PPh3)4, K3PO4, 1,4-dioxane,
110 °C; (d) BnOH, 2.5% Pd(OAc)2, 5% Xantphos, Cs2CO3, 1,4-dioxane, 110 °C; (e) HCl 4 N/1,4-dioxane, CH2Cl2, 40 °C; (f) NBS, DMF, 40 °C;
(g) 3,4-(MeO)2PhB(OH)2, 5% Pd(PPh3)4, Na2CO3, toluene/EtOH/H2O, 110 °C; (h) 4-CNPhB(OH)2, 5% Pd(PPh3)4, K3PO4, 1,4-dioxane, 110
°C.
the yield of 2,3,4,5,6-penta(2-thienyl)pyridine (26−41%) could
not be optimized. Moreover, they recovered approximately 35%
of 2,4,5,6-tetra(2-thienyl)pyridine owing to the reductive
elimination of 3-OTf or 3-ONf groups at position 3 of pyridine
(Scheme 1).
A poor regioselectivity was also observed for 2-Cl-3-OTf
intermediate 9, as its C-arylation using of p-tolylboronic acid
resulted in a complex mixture of 2-p-tolyl and 2,3-di-p-tolyl
pyridine (Scheme 3).
From these results, it became clear that the last C-arylation
step to be performed on a highly hindered tetraarylpyridine
should be carried out at the least bulky position (i.e., position
2) close to the pyridine nitrogen. An OBn group is the most
suitable protecting group for 2-OH because (i) its ortho/para-
directing effect would allow bromination at position 5
(pyridines 25−27) and (ii) it could be deprotected and the
resulting 2-OH group can be transformed to the 2-OTf group
for further reaction (pyridines 19−21 and 31−33). Different
reaction conditions were explored for the preparation of the
OBn-MOM ethers 10−12. As previously reported,39 in the
presence of Pd(OAc)2 and BINAP, the reaction proceeded very
sluggishly (10% yield). When BINAP was replaced by Josiphos,
MOM ether 12 was obtained in nearly quantitative yield on a
small scale; however, the yields varied on larger scales. Finally,
the use of Xantphos afforded the expected 2-OBn-3-OMOM
derivatives 10−12 in 71−88% yields after purification. Starting
from compound 11 (R1 = H, R2 = Ph), corresponding OTf 14
was recovered after the chemoselective deprotection of the O-
MOM protecting group using Amberlyst (15 Wet) followed by
the treatment with triflic anhydride. Surprisingly, pyridine-OTf
14 reacted smoothly with p-tolylboronic acid (17, Ar3 = p-
MePh, 94%) in spite of the expected neighboring effects of
both the phenyl group at position 3 and the OBn group at
position 2. The resulting product, 3,4-diaryl-2-OBn-pyridine 17,
was then deprotected and transformed to 2-OTf intermediate
20, which then afforded corresponding 2,3,4-triaryl pyridine 23
after an additional Suzuki−Miyaura reaction using p-cyanophe-
nylboronic acid. One of the key steps leading to pentaarylpyr-
idines involves the additional functionalization at position 5 of
2-benzyloxypyridines 16−18. The bromination of 17 was
carried out using NBS in DMF to afford 5-bromoderivative 26
in 62% yield, which was reacted with 3,4-dimethoxy-phenyl-
boronic acid to afford triaryl-2-OBn-pyridine 29 in good yield.
After the deprotection of 29 and O-triflation of the
corresponding 2-hydroxypyridine intermediate, the last sequen-
tial Suzuki−Miyaura reaction afforded 2,3,4,5 tetraarylpyridine
35 in 96% yield (15% yield over 11 steps, Scheme 3).
To validate our general strategy and to establish the high
versatility of 2-benzyloxypyridine key intermediates 16−18 in
particular, novel differently substituted pentaarylpyridine 36
(Ar1 ≠ Ar2 ≠ Ar3 ≠ Ar4 ≠ Ar5) was prepared starting from 18.
The bromination of 18 followed by the C-arylation at position
5 (Ar4 = 3,4-(MeO)2Ph) afforded corresponding 3,4,5,6-
tetraaryl-2-OBn-pyridine 30 in 80% yield. The debenzylation
of 30 followed by O-triflation (72% for the two steps) afforded
final OTf key intermediate 33 that reacted nearly quantitatively
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with p-cyanophenylboronic acid to afford pentaarylpyridine 36
(13% yield over 13 steps).
The crystal structure of the first described differently
substituted pentaarylpyridine 36 has been determined (Figure
1). The five phenyl ring bonded to the pyridine core are not
and 6 positions of the pyridine ring, respectively. In addition,
the bonds joining the aryl substituents to the pyridine ring are
believed to be essentially σ bonds (1.488−1.497 Å).
The photophysical properties of the unsymmetrically
substituted pyridine derivatives in various solvents are listed
in Table 1. The pyridine derivatives show intense and broad
absorption spectra with a maximum centered around 300 nm
(Table 1).
The influence of the substituent attached to the pyridine
moiety on the absorption properties appeared limited, as only
slight bathochromic shifts were observed when the number of
aromatic rings increased around the central pyridine ring.
Unlike the absorption spectra, the emission spectra were
found to be quite sensitive to the substitution pattern. Indeed,
when the central pyridine moiety is substituted by three
aromatic rings, an additional substitution at position 6 with p-
methoxyphenyl shifted the emission maximum to the red and
increased the quantum yield, as shown by the comparison of
compounds 22 and 23. In contrast, these parameters were less
affected when a phenyl ring was inserted at position 4, as can be
seen from the comparison of compound 24 with compound 22.
Although large Stokes shifts of about 95 000 cm−1 were
observed for all three compounds (22, 23, and 24), their
maximum emission wavelengths showed only a limited
Figure 1. ORTEP drawing of 36 with 50% probability displacement
ellipsoids.
coplanar with the latter, with dihedral angles of 46.3, 58.8, 68.7,
61.8, and 44.9° between the phenyl ring planes in the 2, 3, 4, 5,
a
Table 1. Fluorescence Properties of Compounds 22−24 and 34−36
a
Errors on the ε and Φ values are estimated at 10%. n.d, not determined because 34 is very slightly soluble in EtOH.
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dependence on the solvent. Ab initio calculations on compound
24 taken as an example (Figure 2) showed that the electronic
value of 27 D was calculated for the excited-state dipole
moment of compound 36 in chloroform. This large value, as
compared to the 6.6 D value of the S0 dipole moment, readily
explains the strong solvatochromism observed for compound
36. This similar strong solvatochromism is typical for
compounds exhibiting ICT between their donor−acceptor
substituents.40−46 Moreover, as for compound 24, the
substantial change in the geometry of the S1 state as compared
to the S0 state, with a notable decrease from 36 to 6° in the
angle between the benzonitrile and pyridine rings as well as a
decrease from 63 to 50° in the angle between the 3,4-
(MeO)2Ph and pyridine rings, well explains the large Stokes
shift observed with compound 36 in apolar solvents.
CONCLUSIONS
■
The stepwise synthesis of differently tetrasubstituted (2,3,4,5,
2,3,5,6, and 2,3,4,6) pyridines described in this article consists
of a highly efficient strategy based on the regio and
chemoselective control of the reactivity of differently
substituted functional groups (halides and OTf) on the
pyridine nucleus. This allows progressive C-arylation of the
different combinations of positions on pyridine when
prototypical Pd-catalyzed Suzuki−Miyaura cross-coupling
reactions are used. All of the different intermediates were
prepared in good yields. The selection of position 2 of pyridine
as the last step of substitution in highly substituted pyridines
proved to be highly efficient because the 2-OBn pyridine
intermediates still allowed sufficient reactivity for additional
bromination at position 5 and could finally afford a reactive 2-
OTf species for the last substitution reaction. The method was
applied successfully to the first synthesis of a prototypical
pentaarylpyridine bearing five different substituents (Ar1 ≠ Ar2
≠ Ar3 ≠ Ar4 ≠ Ar5). The high versatility of the strategy
presented here opens a large avenue to novel applications of
this efficient method for building, in a combinatorial manner,
pyridines bearing up to five different substituents if we consider
the possible use of alkenyl or alkyl boronic acids or the
introduction of various substituted alkynes using Sonogashira
reaction and other types of C−C substitution reactions using
Pd or Cu catalysts. This method offers an enlarged chemical
diversity around the pyridine nucleus and may lead to novel
pyridine compounds with new chemical or pharmacological
properties. In particular, the photophysical properties of the
novel compounds were investigated. Compounds 34, 35, and
36 may be of special interest owing to their very large Stokes
shifts (up to 12 000 cm−1), fluorescence quantum yields (up to
47%), and strong solvatochromic properties. Therefore, these
compounds are promising building blocks for the development
of environment-sensitive probes.
Figure 2. Frontier molecular orbitals involved in the electronic
transitions of compounds 24 (A) and 36 (B).
distribution in the highest occupied molecular orbital
(HOMO) is mainly located on the p-methoxyphenyl
substituent at position 6. In contrast, this electronic distribution
is shifted toward the benzonitrile substituent at position 2 in
the lowest unoccupied molecular orbital (LUMO), indicating
an internal charge transfer (ICT) between the ground and
excited states. Accordingly, the charge density on the p-
methoxyphenyl group increases from 0.08 to 0.31 and that of
the benzonitrile substituent decreases from 0.04 to −0.29 in the
S0 → S1 transition. Furthermore, TDDFT/6-31g calculations
indicated substantial structural changes in the geometry of the
S1 state as compared to the S0 one; the most remarkable
changes being the decrease from 39 to 23° of the angle between
the benzonitrile substituent and the pyridine ring on one hand
and the decrease from 15 to 8° for the angle between the p-
methoxyphenyl and pyridine rings, on the other hand. These
structural changes between the S0 and S1 states are in line with
a conformational relaxation in the excited state that may well
explain the large Stokes shift observed for compound 24.
Moreover, the calculated magnitude of the dipole moment in
chloroform was found to increase from 6.5 D in the ground-
state S0 to 16 D in the excited-state S1. This limited increase in
the dipole moment that accompanies the ICT in the S0 → S1
transition is consistent with the limited solvatochromism
observed with this compound.
Importantly, a dramatic increase in the quantum yield as well
as a strong solvatochromism was observed for compounds 34,
35, and 36, where position 5 of the pyridine ring was
substituted with the electron-donor 3,4-(MeO)2Ph substituent.
For compound 36, the electronic distribution in HOMO
(Figure 2B) is mainly located on the 3,4-(MeO)2Ph
substituent. Oppositely, in LUMO, this electron distribution
is located on the electron-acceptor benzonitrile group at
position 2 of the pyridine ring. This indicates that the S0 → S1
transition is accompanied by an ICT between the two
substituents, which resulted in a strong increase (from 0.06
to 0.51) of the charge density on the 3,4-(MeO)2Ph substituent
together with a strong decrease (0.027 to −0.38) of the charge
density on the benzonitrile group. In line with these larger
changes in charge densities as compared to compound 24, a
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under a
nitrogen or argon atmosphere in flame-dried glassware as indicated.
Chemicals and solvents were used without further purification.
Analytical TLC was performed using silica gel plates, and plates
were visualized by exposure to ultraviolet light. Compounds were
purified using flash chromatography on silica gel (particle size 0.040−
0.063 mm). Yields refer to isolated compounds, estimated to be >97%
pure as determined by H NMR or HPLC. H and 13C NMR spectra
were recorded at 300 or 400 MHz and 100 MHz, respectively. All
chemical shift values, δ, and coupling constants, J, are quoted in ppm
and Hz, respectively, with the following abbreviations used for
multiplicity: s, singlet; d, doublet; t, triplet; m, multiplet; and br, broad.
RP-HPLC-MS was performed using a C18 column (30 mm ×1 mm;
1
1
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1.9 μm) using the following parameters: (1) solvent system: A
(CH3CN) and B (0.05% TFA in H2O); (2) linear gradient: t = 0 min,
98% B; t = 5 min, 5% B; t = 6 min, 5% B; t = 7 min, 98% B; t = 9 min,
98% B; (3) flow rate: 0.3 mL/min; (4) column temperature: 50 °C;
(5) ratio of products: determined by integration of spectra recorded at
210 or 254 nm; (6) ionization mode: MM-ES + APCI. High-
resolution spectra (HRMS) were recorded on a QTOF mass analyzer
with electrospray ionization (ESI). HPLC were performed using the
following parameters: flow rate: 0.5 mL/min; column temperature: 30
°C; solvent system: A (MeOH) and B (0.05% TFA in H2O);
conditions: t = 0−1 min, 50−60% of B; t = 1−10 min, 60 to 100% of
B; and t = 10−15 min, 100% of B. Infrared analyses were performed by
FT-IR, and wavenumbers wereare expressed in cm−1. Absorbance
spectra were recorded with a UV−vis spectrophotometer equipped
with a thermostatted multicell holder maintained at 20.0 °C.
Fluorescence spectra were measured with a spectrofluorimeter
equipped with a thermostatted cell compartment at 20.0 °C. Spectra
were corrected for the emission of the solvent, the lamp fluctuations,
and the wavelength dependence of the optics and detectors in the
emission pathway. All solvents (cyclohexane, chloroform, ethyl acetate,
ethanol, and dimethyl sulfoxide) were of spectroscopic grade.
Fluorescence intensities were recorded in dilute solutions (ca. 1
μM), and quantum yields were calculated using quinine sulfate in 0.05
M H2SO4 as a reference (0.53 0.0247) with an excitation wavelength
of 316 nm. The refractive indices of the organic solvents for the
compounds (1.424 for cyclohexane, 1.444 for chloroform, 1.370 for
ethyl acetate, 1.359 for ethanol, and 1.476 for dimethyl sulfoxide) and
the aqueous solvent for the standard (1.333) were taken into account
for quantum yield calculations.48
Computational Method. Ab initio calculations were performed as
described in Kenfack et al.49 The equilibrium structure of compound
36 at ground-state S0 was determined using the density functional
theory (DFT) in conjunction with the 6-31g basis set for all atoms,
starting from the X-ray crystallographic structure of compound 36
(Figure 1). For the ground-state structure of compound 24, we used
the same protocol except that we replaced the 3,4-(MeO)2Ph
substituent by a hydrogen atom in the crystallographic structure of
compound 36. The most stable conformations of the first excited state
for both compounds were also calculated using the time-dependent
density functional theory (TDDFT) with the same basis set. The
global hybrid functional PBE0 was adopted in all of our calculations.
General Procedures for Pd(0)-Catalyzed Suzuki Reaction.
Method A. General Suzuki−Miyaura procedure associate with the
use of Na2CO3 (preparation of compounds 6, 7, 8, and 37). A
microwave vial (oven-dried and under nitrogen) containing a Teflon
stirrer bar was charged with the corresponding halogeno-pyridine
derivatives (1 equiv, 1 mmol, compounds 3, 4, 5, and 37),
corresponding boronic acid (0.9 equiv, 0.9 mmol), and Na2CO3 (2
equiv, 2 mmol) followed by the addition of a mixture of toluene/
EtOH/H2O 6:1:1 (10 mL). The vessel was evacuated and backfilled
with nitrogen (this process was repeated a total of three times), and
Pd(PPh3)4 (0.05 equiv, 0.05 mmol) was introduced. The reaction
mixture was then capped properly and placed in a preheated oil bath at
90 °C until complete conversion of the starting material was detected.
The reaction mixture was monitored by HPLC analysis and was
usually complete within 2 h. The reaction mixture was then
concentrated under vacuum, and the crude product was purified by
chromatography on silica gel using EtOAc/heptane 1:9 to afford
expected products 6, 37, 7, and 8.
oil bath at 110 °C until complete conversion of the starting material
was detected. The reaction mixture was monitored by HPLC analysis
and was usually complete within 2 h. The reaction mixture was
concentrated under vacuum, and the crude product was purified by
chromatography on silica gel using EtOAc/heptane 1:9 to give
expected products 17, 18, 22, 23, 24, 34, 35, and 36.
Method C. General Suzuki−Miyaura procedure associate with
the use of 3,4-dimethoxyphenylboronic acid (preparation of
compounds 28, 29, and 30). A microwave vial (oven-dried and
under nitrogen) containing a Teflon stirrer bar was charged with the
corresponding 5-bromopyridine derivatives (1 equiv, 1 mmol,
compounds 25, 26, and 27), 3,4-dimethoxyphenylboronic acid (2
equiv, 2 mmol), and Na2CO3 (3 equiv, 3 mmol) followed by the
addition of a mixture of toluene/EtOH/H2O 6:1:1 (10 mL). The
mixture vessel was evacuated and backfilled with nitrogen (this process
was repeated a total of three times), and Pd(PPh3)4 (0.05 equiv, 0.05
mmol) was introduced. The reaction mixture was then capped
properly and placed in a preheated oil bath at 110 °C until complete
conversion of the starting material was detected. The reaction mixture
was monitored by HPLC analysis and was usually complete within 2 h.
The reaction mixture was concentrated under vacuum, and the crude
product was purified by chromatography on silica gel using EtOAc/
heptane 1:9 to give expected products 28, 29, and 30.
General Procedure for the Buchwald−Hartwig Reaction:
Preparation of 2-OBn Pyridines (Preparation of Compounds
10, 11, and 12). Method D. General procedure for the Buchwald−
Hartwig reaction using Xantphos. A microwave vial (oven-dried and
under nitrogen) containing a Teflon stirrer bar was charged with the
corresponding 2-Cl-Pyridine derivatives (1 equiv, 1 mmol, compounds
6, 7, and 8), benzyl alcohol (3 equiv, 3 mmol), and Cs2CO3 (4 equiv, 4
mmol) followed by the addition of anhydrous toluene (2.5 mL). The
mixture vessel was evacuated and backfilled with nitrogen (this process
was repeated a total of three times), and then Pd(OAc)2 (0.025 equiv,
0.025 mmol) and Xantphos (0.05 equiv, 0.05 mmol) were added. The
reaction mixture was then capped properly and placed in a preheated
oil bath at 110 °C until complete conversion of the starting material
was detected. The reaction mixture was monitored by HPLC analysis
and was usually complete within 2 h. The reaction mixture was
concentrated, and the crude product was purified by chromatography
on silica gel using EtOAc/heptane 1/9 to give expected products 10,
11, and 12.
Method E. General procedure for the Buchwald−Hartwig
reaction using Josiphos. A microwave vial (oven-dried and under
nitrogen) containing a Teflon stirrer bar was charged with the
corresponding 2-Cl-Pyridine derivatives (1 equiv, 1 mmol, compound
8), benzyl alcohol (1.5 equiv, 1.5 mmol), and Cs2CO3 (2 equiv, 2
mmol) followed by the addition of anhydrous toluene (6.7 mL). The
mixture vessel was evacuated and backfilled with nitrogen (this process
was repeated a total of three times), and then Pd(OAc)2 (0.05 equiv,
0.05 mmol) and Josiphos (0.1 equiv, 0.1 mmol) were added. The
reaction mixture was then capped properly and placed in a preheated
oil bath at 110 °C until complete conversion of the starting material
was detected. The reaction mixture was monitored by HPLC analysis
and was usually complete within 2 h. The reaction mixture was
concentrated, and the crude product was purified by chromatography
on silica gel using EtOAc/heptane 1/9 to give expected product 12.
General Procedure for Removal of the MOM Ether Group
and Preparation of Pyridin-3-yl Trifluoromethanesulfonate
Derivatives (Preparation of Compounds 9, 13, 14, and 15).
Method F. Step1: Removal of the MOM Ether Group. A round-
bottomed flask containing a stirrer bar was charged with MOM-
protected pyridine derivatives (1 equiv, 1 mmol, compounds, 8, 10, 11,
and 12), CH2Cl2/MeOH 1:9 (50 mL), and Amberlyst (15 mmol/g, 10
equiv, 10 mmol). The flask was cupped with a rubber septum and
placed under a nitrogen atmosphere. The resulting mixture was stirred
vigorously at rt until complete conversion of the starting material was
detected. The reaction mixture was monitored by HPLC analysis and
was usually complete within 2 h. After filtration through a pad of
Celite, the solvent was evaporated in vacuo to afford the
corresponding 3-hydroxypyridine as a yellow oil, which was
Method B. General Suzuki−Miyaura procedure associate with
the use of OTf-pyridine derivatives (preparation of compounds 16,
17, 18, 22, 23, 24, 34, 35, and 36). A microwave vial (oven-dried and
under nitrogen) containing a Teflon stirrer bar was charged with the
corresponding OTf-pyridine derivatives (1 equiv, 1 mmol, compounds
13, 14, 15, 19, 20, 21, 31, 32, and 33), corresponding boronic acid
(1.5 equiv, 1.5 mmol), and K3PO4 (3 equiv, 3 mmol) followed by the
addition of anhydrous 1,4-dioxane (10 mL). The vessel was evacuated
and backfilled with nitrogen (this process was repeated a total of three
times), and Pd(PPh3)4 (0.05 equiv, 0.05 mmol) was introduced. The
reaction mixture was then capped properly and placed in a preheated
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immediately used without further purification for the preparation of
the pyridine-3yl trifluoromethanesulfonate.
was purified by chromatography on silica gel using EtOAc/heptane 1:9
to afford 3 (3.33 g, 11.1 mmol, 95%) as a white solid. H NMR (400
MHz, CDCl3) δ 7.57 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H),
5.26 (s, 2H), 3.51 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.6,
140.7, 133.8, 125.0, 103.2, 94.8, 56.3. IR: 2959, 2831, 1549, 1426,
1069, 963. mp 35−37 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C7H7ClINO2, 299.9283; found, 299.9288.
1
Step2: Preparation of Pyridine-3-yl Trifluoromethanesulfonate.
The crude 3-hydroxypyridine derivative was dissolved in anhydrous
CH2Cl2 (5 mL) and cooled to 0 °C via an ice bath. Et3N (1.5 equiv,
1.5 mmol) was added followed by triflic anhydride (1.2 equiv, 1.2
mmol). The ice bath was removed after 5 min, and the solution was
stirred at rt for an additional 2 h. The solvent was concentrated, and
the crude product was purified by chromatography on silica gel using
EtOAc/heptane 1/9 to give expected products 9, 13, 14, and 15.
General Procedure for Removal of Bn Ether Group and
Preparation of Pyridine-2-yl Trifluoromethanesulfonate De-
rivatives (Preparation of Compounds 19, 20, 21, 31, 32, and
33). Method G. Step 1: Removal of the Bn Ether Group. A round-
bottomed flask containing a stirrer bar was charged with 2-O-Benzyl
protected pyridine derivatives (1 equiv, 1 mmol, compounds 16, 17,
18, 28, 29, and 30) in a mixture of anhydrous CH2Cl2 (6.7 mL) and
HCl 4 N/dioxane (10 equiv, 10 mmol). The reaction mixture was
stirred at 40 °C until complete conversion of the starting material was
detected. The reaction mixture was monitored by HPLC analysis and
was usually complete within 2 h. After evaporation of the volatiles, the
residue was diluted with EtOAc and successively washed with brine
and water. The organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The resulting residue was immediately used
without further purification for the preparation of the pyridine-2yl
trifluoromethanesulfonate.
Step 2: Preparation of Pyridine-2-yl Trifluoromethanesulfonate.
To a solution of the crude 2-hydroxypyridine derivative in anhydrous
CH2Cl2 (6.7 mL) was added pyridine (3 equiv, 3 mmol) followed by
triflic anhydride (1.2 equiv, 1.2 mmol). The solution was stirred at rt
for 2 h. The solvent was concentrated, and the crude product was
purified by chromatography on silica gel using EtOAc/heptane 1:9 to
give expected products 19, 20, 21, 31, 32, and 33.
Representative Preparation of 2-OBn-5-bromo-pyridine
Derivatives (Preparation of Compounds 25, 26, and 27).
Method H. To a solution of the corresponding 2-OBn pyridine
derivatives (1 equiv, 1 mmol, compounds 16, 17, and 18) in
anhydrous DMF (10 mL) was added NBS (1 equiv, 1 mmol). The
reaction mixture was stirred at 40 °C until complete conversion of the
starting material was detected. The reaction mixture was monitored by
HPLC analysis and was usually complete within 1−3 h. The solvent
was concentrated, and the crude product was purified by
chromatography on silica gel using EtOAc/heptane 1:9 to give
expected products 25, 26, and 27.
2-Chloro-6-iodopyridin-3-ol 2. 2-Chloro-3-pyridinol 1 (10 g,
77.2 mmol) and Na2CO3 (18 g, 169.8 mmol) were solubilized in H2O
(200 mL), and I2 (19.6 g, 77.2 mmol) was then added. The solution
was stirred at rt for 2 h. The pH of the solution was lowered with HCl
2 N until pH 6 was reached. The resulting precipitate was filtered,
washed with cool water, and dried. The solid was then dissolved in a
minimum of EtOAc (15 mL) and dropped into heptane (70 mL),
where it precipitated. The precipitate was filtered, the filtrate was
concentrated, and this precipitation process was repeated twice. All
recovered solids were mixed together. 2-Chloro-6-iopyridin-3-ol 8
(13.5 g, 52.7 mmol, 68%) was obtained as a white solid. 1H NMR (400
MHz, DMSO-d6) δ 11.03 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.09 (d, J
= 8.3 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 150.2, 137.6, 134.5,
126.5, 100.7. IR: 2961, 2824, 2746, 2662, 2697, 1552, 1452, 1392,
1286, 1222, 1085, 615. mp 141−143 °C.
2-Chloro-6-iodo-3-(methoxymethoxy)pyridine 3. A round-
bottomed flask (oven-dried and under Argon) containing a stirrer bar
was charged with 2-chloro-6-iopyridin-3-ol 2 (3.0 g, 11.7 mmol),
iPr2NH (2.67 mL, 18.8 mmol), and anhydrous CH2Cl2 (75 mL).
Chloro(methoxy)methane (1.41 g, 17.6 mmol) was then added, and
the resulting reaction mixture was stirred at rt until complete
conversion of the starting material was detected. The reaction mixture
was monitored by HPLC analysis and was complete within 2 h. After
evaporation of the volatiles, the residue was diluted with EtOAc and
successively washed with brine and water. The organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The crude product
4-Bromo-2-chloro-6-iodo-3-(methoxymethoxy)pyridine 4. A
round-bottomed flask (oven-dried and under Argon) containing a
stirrer bar was charged with 2-chloro-6-iodopyridin-3-ol 2 (5.0 g, 19.6
mmol), anhydrous CH2Cl2 (120 mL), iPr2NH (4.43 mL, 31.3 mmol),
and NBS (3.5 g, 19.6 mmol). The resulting reaction mixture was
stirred at rt until complete conversion of the starting material was
detected. The reaction mixture was monitored by HPLC analysis and
was complete within 2 h. Chloro(methoxy)methane (2.36 g, 29.36
mmol) was then added, and the solution was stirred for an additional 1
h. After evaporation of the volatiles, the residue was diluted with
EtOAc and successively washed with brine and water. The organic
layer was dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by chromatography on silica gel using
EtOAc/heptane 1:9 to afford 4 (6.80 g, 18.0 mmol, 92%) as a light
yellow solid. Chemical purity (90%), 10% of the corresponding 4, 6-
dibromo-2-chloro-3-(methoxymethoxy)pyridine, was detected by LC−
MS. The product was used for the next steps without further
purification. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 5.21 (s, 2H),
3.69 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 148.4, 145.6, 137.8,
129.8, 107.2, 99.8, 58.6. IR: 3090, 2958, 2830, 1513, 1418, 1380, 1311,
1204, 1159, 1065, 1099, 908, 652. mp 91−93 °C. HRMS (ESI-TOF)
m/z [M + H]+-MOM calcd for C5H2BrClINO, 333.8126; found,
333.8127.
4-Bromo-2-chloro-3-(methoxymethoxy)pyridine 5. A round-
bottomed flask (oven-dried and under Argon) containing a stir bar was
charged with 4-bromo-2-chloro-6-iodo-3-(methoxymethoxy)pyridine
4 (2.5 g, 6.6 mmol) and anhydrous THF (12 mL). The resulting
mixture was cooled at −78 °C, and a solution of iPrMgCl 2 M in THF
(3.14 mL, 6.28 mmol) was added dropwise. After 45 min at −78 °C,
MeOH (1.14 mL, 28.1 mmol) was added followed by NH4Cl (4 mL).
The reaction mixture was extracted with EtOAc, and the organic layer
was dried over Na2SO4 and concentrated under vacuum. The crude
product was purified by chromatography on silica gel using EtOAc/
heptane 5:95 to afford 5 (1.24 g, 4.93 mmol, 79%) as a white solid. 1H
NMR (400 MHz, CDCl3) δ 7.99 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 5.0
Hz, 1H), 5.24 (s, 2H), 3.72 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
147.7, 146.3, 144.3, 128.5, 127.5, 99.4, 58.2. IR: 2930, 1540, 1368,
1160, 1068, 922. mp 76−78 °C. HRMS (ESI-TOF) m/z [M + H]+-
MOM calcd for C5H3BrClNO, 207.9159; found, 207.9160.
2-Chloro-3-(methoxymethoxy)-6-(4-methoxyphenyl)-
pyridine 6. Following general method A and starting from 3 (2.29 g,
7.63 mmol) and 4-methoxyphenylboronic acid (1.06 g, 6.96 mmol), 6
1
was obtained as a light yellow solid (1.71 g, 6.11 mmol, 88%). H
NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.0 Hz, 2H), 7.58−7.49 (m,
2H), 6.97 (d, J = 9.0 Hz, 2H), 5.29 (s, 2H), 3.86 (s, 3H), 3.55 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 160.3, 150.5, 147.7, 141.0, 130.3,
127.8, 124.6, 118.8, 114.1, 95.3, 56.5, 55.3. IR: 2958, 2935, 2901, 2843,
1607, 1514, 1438, 1252, 1144, 1067, 819. mp 91−93 °C. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C14H14ClNO3, 280.0735; found,
280.0741.
2-Chloro-3-(methoxymethoxy)-4-phenylpyridine 7. Follow-
ing general method A and starting from 5 (1.38 g, 4.39 mmol) and
phenylboronic acid (509 mg, 4.17 mmol), 7 was obtained as a white
solid (959 mg, 3.84 mmol, 92%). 1H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 5.0 Hz, 1H), 7.50−7.46 (m, 2H), 7.42−7.32 (m, 3H), 7.16 (d, J
= 5.0 Hz, 1H), 4.75 (s, 2H), 3.05 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 147.0, 146.5, 145.4, 144.5, 135.6, 129.0, 128.8, 128.6, 124.5,
99.2, 57.5. IR: 2958, 2829, 1579, 1370, 1158, 1061, 927. mp 66−68
°C. HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H12ClNO2,
250.0629; found, 250.0636.
2-Chloro-3-(methoxymethoxy)-6-(4-methoxyphenyl)-4-phe-
nylpyridine 8. Following general method A and starting from 37
(464 mg, 1.30 mmol) and phenylboronic acid (144 mg, 1.18 mmol), 8
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was obtained as a white solid (414 mg, 1.17 mmol, 99%).1H NMR
(400 MHz, CDCl3) δ 7.95 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 6.5 Hz,
2H), 7.58 (s, 1H), 7.54−7.41 (m, 3H), 6.98 (d, J = 9.0 Hz, 2H), 4.85
(s, 2H), 3.87 (s, 3H), 3.14 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
160.6, 152.7, 145.9, 145.8, 145.1, 136.1, 130.1, 129.1, 128.7, 128.6,
128.2, 120.3, 114.1, 99.3, 57.5, 55.4. IR: 2950, 2910, 2826, 1606, 1592,
1416, 1247, 1148, 1030, 935. mp 114−116 °C. HRMS (ESI-TOF) m/
z [M + H]+ calcd for C20H18ClNO3, 356.1048; found, 356.1047.
2-Chloro-6-(4-methoxyphenyl)-4-phenylpyridin-3-yl Tri-
fluoromethanesulfonate 9. Following general method F and
starting from 8 (500 mg, 1.40 mmol), 9 was obtained as a white
solid (598 mg, 1.35 mmol, 96%). 1H NMR (400 MHz, CDCl3) δ 8.00
(d, J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.53 (s, 5H), 7.01 (d, J = 8.8 Hz,
2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.5, 156.2,
146.5, 145.0, 138.3, 133.8, 129.9, 129.0, 128.9, 128.8, 128.7, 120.6,
118.0 (q, J = 317 Hz), 114.4, 55.4. IR: 2923, 2853, 1590, 1516, 1426,
1412, 1209, 1177, 1133, 874. mp 143−145 °C. HRMS (ESI-TOF) m/
z [M + H]+ calcd for C19H13ClF3NO4S, 444.0279; found, 444.0289.
2-(Benzyloxy)-3-(methoxymethoxy)-6-(4-methoxyphenyl)-
pyridine 10. Following general method D and starting from 6 (672
mg, 2.40 mmol) and benzyl alcohol (747 μL, 7.21 mmol), 10 was
2-(Benzyloxy)-4-phenylpyridin-3-yl Trifluoromethanesulfo-
nate 14. Following general method F and starting from 11 (400
mg, 1.12 mmol), 14 was obtained as a colorless oil (296 mg, 0.723
mmol, 65%). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 5.3 Hz, 1H),
7.58−7.52 (m, 2H), 7.49 (s, 5H), 7.44−7.38 (m, 2H), 7.38−7.33 (m,
1H), 7.00 (d, J = 5.3 Hz, 1H), 5.55 (s, 2H). 13C NMR (101 MHz,
CDCl3) δ 156.4, 145.5, 144.7, 136.0, 133.5, 131.2, 129.5, 128.9, 128.8,
128.4, 128.2, 128.1, 119.0, 118.0 (q, J = 318 Hz), 69.0. IR: 3033, 2927,
1611, 1424, 1208, 1137. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C19H14F3NO4S, 410.0668; found, 410.0682.
2-(Benzyloxy)-6-(4-methoxyphenyl)-4-phenylpyridin-3-yl
Trifluoromethanesulfonate 15. Following general method F and
starting from 12 (880 mg, 2.06 mmol), 15 was obtained as a white
solid (859 mg, 1.66 mmol, 81%). 1H NMR (400 MHz, CDCl3) δ 7.93
(d, J = 9.0 Hz, 2H), 7.51 (d, J = 7.3 Hz, 2H), 7.48−7.38 (m, 5H),
7.38−7.31 (m, 2H), 7.31−7.22 (m, 2H), 6.95 (d, J = 9.0 Hz, 2H), 5.58
(s, 2H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.9, 155.5,
153.2, 145.2, 136.4, 134.1, 130.2, 129.6, 129.4, 128.9, 128.7, 128.4,
128.3, 128.2, 128.0, 118.1 (q, J = 323 Hz), 114.4, 114.1, 68.8, 55.4. IR:
3033, 2936, 2838, 1608, 1549, 1420, 1352, 1204, 1176, 1137. mp 129−
130 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H20F3NO5S,
516.1087; found, 516.1092.
1
obtained as a white solid (595 mg, 1.70 mmol, 71%). H NMR (400
2-(Benzyloxy)-6-(4-methoxyphenyl)-3-(p-tolyl)pyridine 16.
Following general method B and starting from 13 (523 mg, 1.19
mmol) and 4-methylphenylboronic acid (243 mg, 1.78 mmol), 16 was
MHz, CDCl3) δ 7.90 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 6.8 Hz, 2H),
7.41 (d, J = 8.0 Hz, 1H), 7.40−7.35 (m, 2H), 7.33−7.28 (m, 1H), 7.22
(d, J = 8.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 5.62 (s, 2H), 5.25 (s,
2H), 3.87 (s, 3H), 3.53 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
159.8, 153.8, 147.1, 139.9, 137.9, 131.6, 128.4, 128.0, 127.7, 127.5,
124.7, 114.0, 112.4, 95.6, 67.5, 56.3, 55.3. IR: 2953, 2834, 1609, 1455,
1244, 1155, 981. mp 79−81 °C. HRMS (ESI-TOF) m/z [M + H]+
calcd for C21H21NO4, 352.1543; found, 352.1552.
2-(Benzyloxy)-3-(methoxymethoxy)-4-phenylpyridine 11.
Following general method D and starting from 7 (182 mg, 0.729
mmol) and benzyl alcohol (226 μL, 2.19 mmol), 11 was obtained as a
white solid (206 mg, 0.641 mmol, 88%). 1H NMR (400 MHz, CDCl3)
δ 7.97 (d, J = 5.3 Hz, 1H), 7.61−7.57 (m, 2H), 7.52−7.48 (m, 2H),
7.47−7.42 (m, 2H), 7.42−7.36 (m, 3H), 7.36−7.30 (m, 1H), 6.93 (d, J
= 5.3 Hz, 1H), 5.49 (s, 2H), 4.94 (s, 2H), 2.95 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 157.5, 143.8, 141.0, 137.6, 137.2, 136.3, 129.3, 128.4,
128.2, 128.1, 127.9, 127.8, 118.7, 98.1, 68.0, 56.9. IR: 3061, 3031,
2953, 1594, 1422, 1355, 953. mp 80−82 °C. HRMS (ESI-TOF) m/z
[M + H]+ calcd for C20H19NO3, 322.1438; found, 322.1445.
1
obtained as a white solid (399 mg, 1.05 mmol, 88%). H NMR (300
MHz, CDCl3) δ 8.03 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H),
7.57 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 6.9 Hz, 2H), 7.41−7.30 (m, 4H),
7.30−7.21 (m, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.62 (s, 2H), 3.89 (s,
3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.3, 159.5,
152.8, 139.2, 138.2, 137.0, 133.8, 131.6, 129.0, 128.9, 128.3, 127.9,
127.5, 127.3, 122.1, 114.0, 112.6, 67.3, 55.3, 21.2. IR: 3029, 2922,
1608, 1585, 1450, 1246, 811. mp 117−119 °C. HRMS (ESI-TOF) m/
z [M + H]+ calcd for C26H23NO2, 382.1801; found, 382.1812.
2-(Benzyloxy)-4-phenyl-3-(p-tolyl)pyridine 17. Following gen-
eral method B and starting from 14 (326 mg, 0.796 mmol) and 4-
methylphenylboronic acid (162 mg, 1.19 mmol), 17 was obtained as a
white solid (263 mg, 0.748 mmol, 94%). 1H NMR (400 MHz, CDCl3)
δ 8.20 (d, J = 5.3 Hz, 1H), 7.39−7.31 (m, 4H), 7.30−7.25 (m, 1H),
7.25−7.21 (m, 3H), 7.15−7.13 (m, 2H), 7.10−7.03 (m, 4H), 7.01 (d, J
= 5.3 Hz, 1H), 5.49 (s, 2H), 2.34 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 161.2, 150.8, 145.1, 139.4, 138.0, 136.4, 132.0, 131.0, 129.4,
128.4, 128.2, 128.0, 127.3, 127.2, 127.1, 123.2, 119.0, 67.5, 21.3. IR:
3029, 2922, 1584, 1548, 1409, 1352, 1320, 1001. mp 116−118 °C.
HRMS (ESI-TOF) m/z [M + H]+ calcd for C25H21NO, 352.1696;
found, 352.1709.
2-(Benzyloxy)-6-(4-methoxyphenyl)-4-phenyl-3-(p-tolyl)-
pyridine 18. Following general method B and starting from 15 (90
mg, 0.148 mmol) and 4-methylphenylboronic acid (30 mg, 0.223
mmol), 18 was obtained as a white solid (62 mg, 0.134 mmol, 90%).
1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 2H), 7.42−7.36
(m, 2H), 7.35 (s, 1H), 7.32 −7.28 (m, 2H), 7.25−7.18 (m, 4H), 7.15−
7.12 (m, 2H), 7.05 (d, J = 7.9 Hz, 2H), 7.03−6.99 (m, J = 7.9 Hz, 2H),
6.97 (d, J = 8.8 Hz, 2H), 5.56 (s, 2H), 3.85 (s, 3H), 2.28 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 160.5, 160.4, 152.5, 151.5, 140.0, 138.4,
136.2, 132.1, 131.7, 131.1, 129.4, 128.4, 128.2, 128.0, 128.0, 127.3,
127.2, 120.9, 114.4, 114.0, 67.4, 55.4, 21.3. IR: 3030, 2929, 2835, 1607,
1588, 1513, 1343, 1250, 1173, 1137. mp 112−114 °C. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C32H27NO2, 458.2114; found,
458.2100.
2-(Benzyloxy)-3-(methoxymethoxy)-6-(4-methoxyphenyl)-
4-phenylpyridine 12. Following general method D and starting
from 8 (1.03 g, 2.89 mmol) and benzyl alcohol (450 μL, 3.34 mmol),
12 and 41 were obtained: 12 was obtained as a colorless oil (1894 mg,
2.09 mmol, 72%) and 41 was obtained as a white solid (229 mg, 0.714
mmol, 25%). Following general method E and starting from 8 (300
mg, 0.84 mmol) and benzyl alcohol (131 μL, 1.26 mmol), 12 was
1
obtained as a colorless oil (299 mg, 0.70 mmol, 83%). H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H),
7.54 (d, J = 7.3 Hz, 2H), 7.49−7.43 (m, 2H), 7.41−7.37 (m, 3H),
7.35−7.33 (m, 2H), 6.98 (d, J = 8.8 Hz, 2H), 5.61 (s, 2H), 4.95 (s,
2H), 3.87 (s, 3H), 2.97 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
160.1, 156.5, 148.7, 144.4, 137.6, 136.8, 136.0, 131.5, 129.3, 128.4,
128.2, 128.1, 128.0, 127.8, 127.7, 114.2, 114.0, 98.2, 67.8, 56.9, 55.3.
IR: 3032, 2955, 2835, 1608, 1450, 1351, 1249, 1157, 952. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C27H25NO4, 428.1856; found,
428.1861.
2-(Benzyloxy)-6-(4-methoxyphenyl)pyridin-3-yl Trifluoro-
methanesulfonate 13. Following general method F and starting
from 10 (579 mg, 1.65 mmol), 13 was obtained as a white solid (535
mg, 1.22 mmol, 74%). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.0
Hz, 2H), 7.56 (d, J = 8.3 Hz, 1H), 7.54−7.51 (m, 2H), 7.43−7.38 (m,
2H), 7.36−7.33 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.00(d, J = 9.0 Hz,
2H), 5.61 (s, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
161.0, 154.6, 154.1, 136.4, 132.2, 131.5, 130.1, 128.4, 128.3, 128.0,
127.9, 114.2, 112.4, 118.7 (q, J = 316 Hz), 68.4, 55.4. IR: 2960, 1608,
1599, 1455, 1423, 1362, 1246, 870. mp 50−52 °C. HRMS (ESI-TOF)
m/z [M + H]+ calcd for C20H16F3NO5S, 440.0774; found, 440.0782.
6-(4-Methoxyphenyl)-3-(p-tolyl)pyridin-2-yl Trifluorometha-
nesulfonate 19. Following general method G and starting from 16
(270 mg, 0.708 mmol), 19 was obtained as a white solid (236 mg,
0.557 mmol, 79%). 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 9.0 Hz,
2H), 7.89 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 8.1
Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 3.89 (s,
3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 154.8,
152.7, 141.9, 138.7, 130.8, 129.5, 129.2, 128.8, 128.3, 125.7, 119.2,
118.6 (q, J = 312 Hz), 114.4, 55.4, 21.3. IR: 2928, 1603, 1460, 1419,
915
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1213, 1133, 905, 833, 815. mp 84−86 °C. HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C20H16F3NO4S, 424.0825; found, 424.0835.
143−145 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C26H22BrNO2, 460.0907; found, 460.0902.
4-Phenyl-3-(p-tolyl)pyridin-2-yl Trifluoromethanesulfonate
20. Following general method G and starting from 17 (164 mg,
0.467 mmol), 20 was obtained as a white solid (169 mg, 0.430 mmol,
2-(Benzyloxy)-5-bromo-4-phenyl-3-(p-tolyl)pyridine 26. Fol-
lowing general method H and starting from 17 (263 mg, 0.748 mmol),
1
26 was obtained as a white solid (200 mg, 0.465 mmol, 62%). H
1
92%). H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 5.3 Hz, 1H), 7.43
NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.33−7.30 (m, 4H), 7.29−
7.26 (m, 1H), 7.26−7.20 (m, 3H), 7.05−7.01 (m, 2H), 6.99−6.91 (m,
4H), 5.43 (s, 2H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
160.3, 151.0, 146.8, 138.0, 137.5, 136.6, 131.6, 130.4, 129.6, 128.2,
128.2, 127.7, 127.5, 127.4, 127.2, 126.0, 114.3, 67.7, 21.2. IR: 3029,
2923, 1562, 1405, 1306, 1243, 1034. mp 107−109 °C. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C25H20BrNO, 430.0801; found,
430.0810.
2-(Benzyloxy)-5-bromo-6-(4-methoxyphenyl)-4-phenyl-3-
(p-tolyl)pyridine 27. Following general method H and starting from
18 (293 mg, 0.64 mmol), 27 was obtained as a white solid (327 mg,
0.61 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.8 Hz,
2H), 7.28−7.22 (m, 4H), 7.22−7.11 (m, 5H), 6.99 (m, 2H), 6.91 (d, J
= 8.8 Hz, 2H), 6.89−6.87 (m, 3H), 5.36 (s, 2H), 3.80 (s, 3H), 2.18 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 159.8, 159.1, 153.7, 152.9, 139.4,
137.9, 136.4, 133.0, 131.8, 131.2, 130.5, 129.7, 128.2, 128.2, 127.6,
127.4, 127.3, 127.0, 124.2, 113.1, 112.8, 67.6, 55.3, 21.2. IR: 2929,
1608, 1513, 1412, 1341, 1249, 1031. mp 61−63 °C. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C32H26BrNO2, 536.1219; found,
536.1207.
(d, J = 5.0 Hz, 1H), 7.30−7.21 (m, 3H), 7.15−7.07 (m, 4H), 7.04−
6.97 (m, 2H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.4,
154.0, 146.4, 138.1, 137.4, 130.3, 129.2, 129.0, 128.9, 128.3, 128.3,
127.6, 125.5, 118.3 (q, J = 321 Hz), 21.3. IR: 2926, 1596, 1419, 1207,
910. mp 110−112 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C19H14F3NO3S, 394.0719; found, 394.0728.
6-(4-Methoxyphenyl)-4-phenyl-3-(p-tolyl)pyridin-2-yl Tri-
fluoromethanesulfonate 21. Following general method G and
starting from 18 (150 mg, 0.329 mmol), 21 was obtained as a white
1
solid (124 mg, 0.248 mmol, 76%). H NMR (400 MHz, CDCl3) δ
8.05 (d, J = 9.0 Hz, 2H), 7.78 (s, 1H), 7.31−7.25 (m, 3H), 7.18 − 7.15
(m, 2H), 7.13−7.07 (m, 2H), 7.05−7.00 (m, 4H), 3.89 (s, 3H), 2.34
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.3, 154.5, 154.5, 154.0,
138.1, 137.9, 130.4, 129.3, 129.2, 129.1, 128.9, 128.3, 128.3, 128.2,
124.6, 120.6, 118.5 (q, J = 323 Hz), 114.3, 55.4, 21.3. IR: 2925, 1599,
1418, 1218, 1176. mp 134−136 °C. HRMS (ESI-TOF) m/z [M + H]+
calcd for C26H20F3NO4S, 500.1138; found, 500.1146.
4-(6-(4-Methoxyphenyl)-3-(p-tolyl)pyridin-2-yl)benzonitrile
22. Following general method B and starting from 19 (80 mg, 0.189
mmol) and 4-cyanophenylboronic acid (42 mg, 0.283 mmol), 22 was
2-(Benzyloxy)-5-(3,4-dimethoxyphenyl)-6-(4-methoxyphen-
yl)-3-(p-tolyl)pyridine 28. Following general method C and starting
from 25 (222 mg, 0.482 mmol) and 3,4-dimethoxyphenylboronic acid
(175 mg, 0.964 mmol), 28 was obtained as a light yellow solid (214
1
obtained as a white solid (59 mg, 0.157 mmol, 83%). H NMR (400
MHz, CDCl3) δ 8.09 (d, J = 9.0 Hz, 2H), 7.80−7.74 (m, 2H), 7.63−
7.54 (m, 4H), 7.13 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.03
(d, J = 9.0 Hz, 2H), 3.89 (s, 3H), 2.38 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 160.7, 155.5, 154.1, 145.2, 139.5, 137.4, 136.1, 134.0, 131.5,
131.2, 130.8, 129.3, 129.3, 128.1, 119.0, 118.6, 114.1, 111.2, 55.3, 21.1.
IR: 2923, 2836, 2226, 1607, 1581, 1448, 1249, 815. mp 173−174 °C.
HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H20N2O, 377.1648;
found, 377.1657.
4-(4-Phenyl-3-(p-tolyl)pyridin-2-yl)benzonitrile 23. Following
general method B and starting from 20 (156 mg, 0.397 mmol) and 4-
cyanophenylboronic acid (87 mg, 0.595 mmol), 23 was obtained as a
white solid (95 mg, 0.275 mmol, 70%). 1H NMR (400 MHz, CDCl3)
δ 8.72 (d, J = 5.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.41−7.35 (m,
3H), 7.26−7.19 (m, 3H), 7.12−7.04 (m, 2H), 6.92−6.86 (d, J = 8.0
Hz, 2H), 6.76−6.67 (d, J = 8.0 Hz, 2H), 2.26 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 156.4, 150.3, 148.3, 145.5, 138.9, 137.0, 134.8, 133.7,
131.4, 131.0, 130.6, 129.2, 128.8, 128.0, 127.6, 124.6, 118.9, 111.0,
21.2. IR: 3052, 2922, 2226, 1607, 1576, 1391. mp 131−133 °C. HRMS
(ESI-TOF) m/z [M + H]+ calcd for C25H18N2, 347.1543; found,
347.1551.
1
mg, 0.413 mmol, 86%). H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H),
7.61 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 7.0 Hz 2H), 7.42−7.36 (m, 4H),
7.33−7.28 (m, 1H), 7.26 (d, J = 7.0 Hz, 2H), 6.86−6.83 (m, 2H), 6.81
(d, J = 8.8 Hz, 2H), 6.68 (s, 1H), 5.60 (s, 2H), 3.91 (s, 3H), 3.82 (s,
3H), 3.67 (s, 3H), 2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
159.3, 158.4, 151.6, 148.6, 148.0, 141.5, 138.2, 137.3, 133.5, 132.9,
132.4, 131.2, 129.1, 129.0, 128.9, 128.3, 127.6, 127.4, 122.3, 121.7,
113.3, 113.2, 111.2, 67.5, 55.9, 55.7, 55.2, 21.2. IR: 2999, 2930, 2835,
1607, 1513, 1429, 1246. mp 65−68 °C. HRMS (ESI-TOF) m/z [M +
H]+ calcd for C34H31NO4, 518.2326; found, 518.2316.
2-(Benzyloxy)-5-(3,4-dimethoxyphenyl)-4-phenyl-3-(p-
tolyl)pyridine 29. Following general method C and starting from 26
(149 mg, 0.346 mmol) and 3,4-dimethoxyphenylboronic acid (126
mg, 0.693 mmol), 29 was obtained as a light yellow solid (149 mg,
1
0.306 mmol, 88%). H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H),
7.38−7.30 (m, 4H), 7.29−7.25 (m, 1H), 7.06−6.97 (m, 7H), 6.86−
6.81 (m, 2H), 6.79−6.76 (m, 2H), 6.35−6.31 (m, 1H), 5.51 (s, 2H),
3.85 (s, 3H), 3.47 (s, 3H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 160.3, 149.6, 148.0, 147.7, 145.7, 138.0, 137.9, 136.1, 132.2, 131.0,
130.8, 130.7, 130.6, 128.2, 128.2, 127.5, 127.2, 127.1, 126.6, 123.8,
121.8, 113.7, 110.7, 67.4, 55.7, 55.5, 21.2. IR: 2930, 1604, 1517, 1453,
1250, 1237, 1027. mp 58−60 °C. HRMS (ESI-TOF) m/z [M + H]+
calcd for C33H29NO3, 488.2220; found, 488.2235.
4-(6-(4-Methoxyphenyl)-4-phenyl-3-(p-tolyl)pyridin-2-yl)-
benzonitrile 24. Following general method B and starting from 21
(110 mg, 0.220 mmol) and 4-cyanophenylboronic acid (49 mg, 0.33
mmol), 24 was obtained as a white solid (77 mg, 0.170 mmol, 77%).
1H NMR (300 MHz, CDCl3) δ 8.13−8.06 (d, J = 8.9 Hz, 2H), 7.74 (s,
1H), 7.51−7.45 (m, 4H), 7.26−7.20 (m, 3H), 7.16−7.08 (m, 2H),
7.05−6.97 (d, J = 8.9 Hz, 2H), 6.92−6.84 (d, J = 8.1 Hz, 2H), 6.78−
6.71 (d, J = 8.1 Hz, 2H), 3.87 (s, 3H), 2.27 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 160.7, 155.7, 155.4, 150.9, 146.0, 139.5, 136.7, 134.0,
132.4, 131.3, 131.3, 131.1, 130.8, 129.2, 128.7, 128.2, 128.0, 127.4,
120.3, 119.0, 114.1, 110.8, 55.4, 21.1. IR: 2925, 2226, 1607, 1582,
1513, 1251. mp 170−172 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd
for C32H24N2O, 453.1961; found, 453.1962.
2-(Benzyloxy)-5-bromo-6-(4-methoxyphenyl)-3-(p-tolyl)-
pyridine 25. Following general method H and starting from 16 (300
mg, 0.708 mmol), 25 was obtained as a white solid (282 mg, 0.613
mmol, 87%). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.78 (d, J =
8.8 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.40−
7.33 (m, 2H), 7.32−7.29 (m, 1H), 7.29−7.25 (m, 2H), 7.00 (d, J = 8.8
Hz, 2H), 5.50 (s, 2H), 3.90 (s, 3H), 2.42 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 159.9, 158.3, 152.2, 143.3, 137.8, 137.6, 132.1, 131.6,
131.0, 129.0, 129.0, 128.3, 127.6, 127.5, 124.3, 113.2, 110.2, 67.8, 55.3,
21.2. IR: 3031, 2929, 2835, 1608, 1510, 1428, 1248, 1030, 820. mp
2-(Benzyloxy)-5-(3,4-dimethoxyphenyl)-6-(4-methoxyphen-
yl)-4-phenyl-3-(p-tolyl)pyridine 30. Following general method C
and starting from 27 (300 mg, 0.56 mmol) and 3,4-dimethoxyphe-
nylboronic acid (204 mg, 1.12 mmol), 30 was obtained as a white solid
1
(265 mg, 0.446 mmol, 80%). H NMR (400 MHz, CDCl3) δ 7.40−
7.36 (m, 2H), 7.35−7.23 (m, 5H), 7.03−6.94 (m, 7H), 6.82−6.72 (m,
4H), 6.53 (d, J = 8.3 Hz, 1H), 6.39 (dd, J = 2.0, 8.3 Hz, 1H), 6.31 (d, J
= 2.0 Hz, 1H), 5.56 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.44 (s, 3H),
2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.2, 158.8, 152.7,
151.8, 148.0, 147.2, 138.6, 138.5, 135.9, 133.4, 132.6, 131.3, 131.2,
130.8, 130.4, 128.1, 128.1, 127.4, 127.1, 127.1, 126.1, 124.3, 122.2,
115.4, 115.4, 112.9, 110.3, 67.2, 55.6, 55.6, 55.2, 21.2. IR: 2928, 2835,
1607, 1514, 1416, 1345, 1242, 1237. mp 75−77 °C. HRMS (ESI-
TOF) m/z [M + H]+ calcd for C40H35NO4, 594.2639; found,
594.2650.
5-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-3-(p-tolyl)-
pyridin-2-yl Trifluoromethanesulfonate 31. Following general
method G and starting from 28 (199 mg, 0.38 mmol), 31 was
916
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obtained as a white solid (205 mg, 0.366 mmol, 95%). 1H NMR (400
MHz, CDCl3) δ 7.86 (s, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.43−7.36 (d, J
= 8.9 Hz, 2H), 7.35−7.29 (d, J = 8.3 Hz, 2H), 6.90−6.85 (m, 2H),
6.80 (d, J = 8.9 Hz, 2H), 6.70 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.68
(s, 3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.0, 153.6,
151.1, 148.9, 148.9, 143.8, 138.9, 136.0, 131.4, 131.0, 130.5, 130.1,
129.6, 128.9, 126.1, 121.7, 118.6 (q, J = 293 Hz), 113.5, 112.8, 111.4,
55.9, 55.8, 55.3, 21.3. IR: 2935, 2838, 1607, 1513, 1420, 1251, 1220.
mp 153−155 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C28H24F3NO6S, 560.1349; found, 560.1362.
154.1, 150.6, 148.1, 147.5, 145.7, 138.1, 136.4, 134.6, 134.1, 133.8,
133.6, 133.2, 131.3, 131.3, 131.0, 130.8, 130.6, 128.4, 126.3, 123.9,
119.0, 116.3, 115.0, 113.1, 110.7, 110.4, 55.6, 55.6, 55.2, 21.1. IR: 2927,
2226, 1607, 1513, 1246. mp 240−242 °C. HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C40H32N2O3, 589.2486; found, 589.2495.
4-Bromo-2-chloro-3-(methoxymethoxy)-6-(4-methoxy-
phenyl)pyridine 37. Following general method A and starting from
4 (1.0 g, 2.64 mmol) and 4-methoxyphenylboronic acid (366 mg, 2.41
mmol), 37 was obtained as a white solid (763 mg, 2.13 mmol, 88%).
1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.0 Hz, 2H), 7.80 (s, 1H),
6.98 (d, J = 9.0 Hz, 2H), 5.24 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 161.0, 153.2, 145.7, 145.7, 129.3, 128.8,
128.3, 123.3, 114.3, 99.7, 58.5, 55.4. IR: 3012, 2971, 2936, 2832, 1604,
1506, 1232, 1155, 1061, 1021, 921. mp 93−95 °C. HRMS (ESI-TOF)
m/z [M + H]+ calcd for C14H13BrClNO3, 357.9840; found, 357.9847.
2-Chloro-3-(methoxymethoxy)-4,6-bis(4-methoxyphenyl)-
pyridine 38. Following general method A and starting from 4 (1.0 g,
2.64 mmol) and 4-methoxyphenylboronic acid (366 mg, 2.41 mmol),
38 was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3 δ 7.94
(d, J = 8.8 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.55 (s, 1H), 7.01 (d, J =
8.8 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 4.85 (s, 2H), 3.88 (s, 3H), 3.86
(s, 3H), 3.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.6, 160.0,
152.6, 145.8, 145.3, 144.9, 130.3, 130.2, 128.2, 128.1, 120.1, 114.1,
114.0, 99.1, 57.7, 55.3, 55.3. IR: 2929, 2836, 1607, 1507, 1434, 1242,
1174, 1157, 928. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C21H20ClNO4, 386.1153; found, 386.1162.
5-(3,4-Dimethoxyphenyl)-4-phenyl-3-(p-tolyl)pyridin-2-yl
Trifluoromethanesulfonate 32. Following general method G and
starting from 29 (122 mg, 0.25 mmol), 32 was obtained as a white
1
solid (121 mg, 0.229 mmol, 92%). H NMR (400 MHz, CDCl3) δ
8.42 (s, 1H), 7.13−7.01 (m, 5H), 6.98−6.91 (m, 2H), 6.85−6.78 (m,
4H), 6.37 (s, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 2.29 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 153.2, 152.2, 148.6, 148.4, 147.2, 137.8, 137.6,
136.3, 130.2, 130.2, 129.2, 129.0, 128.7, 128.4, 127.9, 127.4, 122.1,
118.4 (q, J = 316 Hz), 113.3, 110.9, 55.8, 55.6, 21.2. IR: 2933, 1587,
1512, 1417, 1212, 1136, 922. mp 62−64 °C. HRMS (ESI-TOF) m/z
[M + H]+ calcd for C27H22F3NO5S, 530.1243; found, 530.1241.
5-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-4-phenyl-3-
(p-tolyl)pyridin-2-yl Trifluoromethanesulfonate 33. Following
general method G and starting from 30 (265 mg, 0.45 mmol), 33 was
obtained as a white solid (203 mg, 0.319 mmol, 72%). 1H NMR (400
MHz, CDCl3) δ 7.31 (d, J = 9.0 Hz, 2H), 7.07−6.92 (m, 7H), 6.82−
6.69 (m, 4H), 6.58 (d, J = 8.3 Hz, 1H), 6.43 (dd, J = 2.0, 8.0 Hz, 1H),
6.32 (d, J = 2.0 Hz, 1H), 3.79 (s, 6H), 3.46 (s, 3H), 2.29 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 159.6, 154.9, 154.6, 152.4, 148.4, 147.9,
137.5, 137.0, 135.0, 131.5, 131.0, 130.3, 130.0, 129.6, 129.5, 128.6,
127.4, 126.9, 126.2, 123.8, 118.4 (q, J = 318 Hz), 114.7, 113.2, 110.6,
55.7, 55.6, 55.2, 21.2. IR: 2932, 1607, 1517, 1416, 1252, 1226, 1209,
735. mp 83−85 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C34H28F3NO6S, 636.1662; found, 636.1664.
5-(Methoxymethoxy)-2-(4-methoxyphenyl)-4-phenylpyri-
dine 41. Following general method D and starting from 8 (1.03 g,
2.89 mmol) and benzyl alcohol (450 μL, 3.34 mmol), 41 was obtained
1
as a white solid (229 mg, 0.714 mmol, 25%). H NMR (400 MHz,
CDCl3) δ 8.75 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.67−
7.60 (m, 2H), 7.56−7.43 (m, 3H), 7.04 (d, J = 8.8 Hz, 1H), 5.22 (s,
2H), 3.87 (s, 3H), 3.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
160.9, 150.3, 149.8, 135.6, 135.2, 129.1, 129.0, 128.5, 128.4, 122.5,
114.5, 95.9, 77.3, 76.7, 56.5, 55.4. IR: 2937, 2837, 1607, 1477, 1243,
1150, 976. mp 79−81 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C20H19NO3, 322.1438; found, 322.1440.
4-(5-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-3-(p-
tolyl)pyridin-2-yl)benzonitrile 34. Following general method B
and starting from 31 (190 mg, 0.30 mmol) and 4-cyanophenylboronic
acid (866 mg, 0.45 mmol), 34 was obtained as a white solid (175 mg,
1
0.297 mmol, 99%). H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H),
ASSOCIATED CONTENT
■
7.65−7.59 (d, J = 8.5 Hz, 2H), 7.58−7.52 (d, J = 8.5 Hz, 2H), 7.44 (d,
J = 8.8 Hz, 2H), 7.18−7.09 (m, 4H), 6.93−6.84 (m, 2H), 6.82 (d, J =
8.8 Hz, 2H), 6.72 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.66 (s, 3H),
2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.6, 155.2, 152.7,
148.7, 148.6, 144.8, 141.0, 137.6, 136.0, 134.7, 134.3, 132.3, 132.0,
131.6, 131.3, 130.8, 129.4, 129.3, 121.7, 119.0, 113.5, 113.0, 111.3,
111.2, 55.9, 55.8, 55.3, 21.2. IR: 2933, 2836, 2226, 1607, 1514, 1429,
1248. mp 275−277 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C34H28N2O3, 513.2173; found, 513.2176.
4-(5-(3,4-Dimethoxyphenyl)-4-phenyl-3-(p-tolyl)pyridin-2-
yl)benzonitrile 35. Following general method B and starting from 32
(109 mg, 0.206 mmol) and 4-cyanophenylboronic acid (45 mg, 0.309
mmol), 35 was obtained as a white solid (95 mg, 0.197 mmol, 96%).
1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H),
S
* Supporting Information
Optimization data, NMR spectra, fluorescent spectra, atom
coordinates, absolute energies, and X-ray crystallographic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mschmitt@unistra.fr.
Author Contributions
∥These authors contributed equally to this work.
Notes
7.42 (d, J = 8.3 Hz, 2H), 7.09−7.02 (m, 3H), 6.89−6.79 (m, 6H), 6.71
(d, J = 8.0 Hz, 2H), 6.40 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.48 (s,
3H), 2.22 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.8, 149.3,
148.4, 148.4, 148.2, 145.5, 137.3, 136.6, 135.9, 135.4, 134.1, 131.4,
131.0, 130.5, 130.4, 130.1, 128.6, 127.7, 126.8, 122.1, 118.9, 113.5,
110.9, 110.8, 55.8, 55.5, 21.1. IR: 2933, 2835, 2226, 1605, 1510, 1250.
mp 217−219 °C. HRMS (ESI-TOF) m/z [M + H]+ calcd for
C33H26N2O2, 483.2067; found, 483.2075.
4-(5-(3,4-Dimethoxyphenyl)-6-(4-methoxyphenyl)-4-phe-
nyl-3-(p-tolyl)pyridin-2-yl)benzonitrile 36. Following general
method B and starting from 33 (80 mg, 0.189 mmol) and 4-
cyanophenylboronic acid (42 mg, 0.283 mmol), 36 was obtained as a
white solid (59 mg, 0.157 mmol, 83%). 1H NMR (400 MHz, CDCl3)
δ 7.49 (dd, J = 8.5 Hz, 4H), 7.35 (d, J = 8.8 Hz, 2H), 7.03−6.95 (m,
3H), 6.87−6.70 (m, 8H), 6.55 (d, J = 8.5 Hz, 1H), 6.45 (dd, J = 2.0,
8.3 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 3.84−3.74 (m, 6H), 3.46 (s,
3H), 2.21 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.1, 156.4,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to MESR for a doctoral fellowship, Dr. Lydia
Karmazin-Brelot for the X-ray crystallographic determination,
Pascale Buisine and Patrick Wehrung for HRMS results, and
Dr. Gilbert Schlewer for helpful discussions.
REFERENCES
■
(1) Fu, P.; Wang, S.; Hong, K.; Li, X.; Liu, P.; Wang, Y.; Zhu, W. J.
Nat. Prod. 2011, 1751−1756.
(2) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627−646.
(3) Plunkett, A. O. Nat. Prod. Rep. 1994, 11, 581−590.
(4) Pinder, A. R. Nat. Prod. Rep. 1992, 4, 491−504.
917
dx.doi.org/10.1021/jo402200q | J. Org. Chem. 2014, 79, 908−918

The Journal of Organic Chemistry
Article
(5) Daly, J. W.; Martin Garraffo, H.; Spande, T. F.; Decker, M. W.;
Sullivan, J. P.; Williams, M. Nat. Prod. Rep. 2000, 17, 131−135.
(6) Coppola, G. M.; Schuster, H. F. The Chemistry of Heterocyclic
Compounds; Wiley-VCH: New York, 1981.
(7) Spande, H. F. The Alkaloids; Academic Press: New York, 1987;
Vol. 31.
(35) He, Z.; Dobrovolsky, D.; Trinchera, P.; Yudin, A. K. Org. Lett.
2013, 15, 334−337.
(36) Wishka, D. G.; Graber, D. R.; Seest, E. P.; Dolak, L. a.; Han, F.;
Watt, W.; Morris, J. J. Org. Chem. 1998, 63, 7851−7859.
(37) Lin, W.; Chen, L.; Knochel, P. Tetrahedron 2007, 63, 2787−
2797.
(38) Song, J. J.; Yee, N. K.; Tan, Z.; Xu, J.; Kapadia, S. R.;
Senanayake, C. H. Org. Lett. 2004, 6, 4905−4907.
(39) Maligres, P. E.; Li, J.; Krska, S. W.; Schreier, J. D.; Raheem, I. T.
Angew. Chem., Int. Ed. 2012, 51, 9071−9074.
(8) Chen, Y. L.; Braselton, J.; Forman, J.; Gallaschun, R. J.;
Mansbach, R.; Schmidt, A. W.; Seeger, T. F.; Sprouse, J. S.; Tingley, F.
D.; Winston, E.; Schulz, D. W. J. Med. Chem. 2008, 51, 1377−1384.
(9) Basnet, A.; Thapa, P.; Karki, R.; Na, Y.; Jahng, Y.; Jeong, B.-S.;
Jeong, T. C.; Lee, C.-S.; Lee, E.-S. Bioorg. Med. Chem. 2007, 4351−
4359.
(40) Katan, C.; Terenziani, F.; Mongin, O.; Werts, M. H. V.; Porres,
L.; Pons, T.; Mertz, J.; Tretiak, S.; Blanchard-Desce, M. J. Phys. Chem.
A. 2005, 109, 3024−3037.
(10) Langtry, H. D.; Markham, A. Drugs 1999, 58, 725−742.
(41) Diwu, Z.; Zhang, C.; Klaubert, R. P.; Haughland, J. J. Photochem.
Photobiol. 2000, 131, 95−100.
(42) Detert, H.; Schmidt, V. J. Phys. Org. Chem. 2004, 17, 1051−
1056.
(11) Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, S.; Dube,
́
D.; Ethier, D.; Falgueyret, J. P.; Friesen, R. W.; Gordon, R.; Greig, G.;
Guay, J.; Mancini, J.; Ouellet, M.; Wong, E.; Xu, L.; Boyce, S.; Visco,
D.; Girard, Y.; Prasit, P.; Zamboni, R.; Rodger, I. W.; Gresser, M.;
Ford-Hutchinson, A. W.; Young, R. N.; Chan, C. C. J. Pharmacol. Exp.
Ther. 2001, 296, 558−566.
(43) Lartia, R.; Allain, C.; Bordeau, G.; Schmidt, F.; Fiorini-
Debuisscert, C.; Charra, F.; Teulade-Fichou, M.-P. J. Org. Chem. 2008,
73, 1732−1744.
(12) Kletas, D.; Li, W.; Han, Z.; Papadoulos, V. Biochem. Pharmacol.
2004, 67, 1927−1932.
(13) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Willey-
Blackwell: Chichester, UK, 2010.
(44) Panthi, K.; Adhikari, R. M.; Kinstle, T. H. J. Phys. Chem. A 2010,
114, 4542−4549.
́
(45) Cornec, A. S.; Baudequin, C.; Fiol-Petit, C.; Ple, N.; Dupas, G.;
Ramondenc, Y. Eur. J. Org. Chem. 2013, 10, 1908−1915.
(46) Achelle, S.; Robin-le Guen, F. Tetrahedron Lett. 2013, 54, 4491−
4496.
(14) Durola, F.; Sauvage, J.-P.; Wenger, O. S. Chem. Commun. 2006,
2, 171−173.
(15) Kozhevnikov, V. N.; Kozhevnikov, D. N.; Nikitina, T. V;
(47) Brouwer, A. M. Pure Appl. Chem. 2011, 83, 2213−2228.
(48) Handbook of Chemistry and Physics, 56th ed.; Weast, R. C., Ed.;
CRC Press: Cleveland, OH, 1975.
(49) Kenfack, C. A.; Klymchenko, A. S.; Duportail, G.; Burger, A.;
́
Mely, Y. Phys. Chem. Chem. Phys. 2012, 14, 8910−8918.
Rusinov, V. L.; Chupakhin, O. N.; Zabel, M.; Konig, B. J. Org. Chem.
̈
2003, 68, 2882−2888.
(16) Sweetman, B. A.; Muller-Bunz, H.; Guiry, P. J. Tetrahedron Lett.
̈
2005, 46, 4643−4646.
(17) Tang, B.; Yu, F.; Li, P.; Tong, L.; Duan, X.; Xie, T.; Wang, X. J.
Am. Chem. Soc. 2009, 131, 3016−3023.
(18) Havas, C. F.; Leygue, N.; Danel, M.; Mestre, B.; Galaup, C.;
Picard, C. Tetrahedron 2009, 7673−7686.
(19) Yan, B.-P.; Cheung, C. C. C.; Kui, S. C. F.; Xiang, H.-F.; Roy, V.
a. L.; Xu, S.-J.; Che, C.-M. Adv. Mater. 2007, 19, 3599−3603.
(20) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100,
3553−3590.
(21) Linder, I.; Gerhard, M.; Schefzig, L.; Andra, M.; Bentz, C.;
̈
Reissig, H.-U.; Zimmer, R. Eur. J. Org. Chem. 2011, 30, 6070−6077.
(22) (a) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem.
2012, 77, 2501−2507. (b) Takahashi, T.; Tsai, F. Y.; li, Y.; Wang, H.;
Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc.
2002, 124, 5059−5067. (c) Takahashi, T.; Tsai, F. Y.; Kotora, M. J.
Am. Chem. Soc. 2000, 122, 4994−4995.
(23) Diring, S.; Retailleau, P.; Ziessel, R. Synlett 2007, 19, 3027−
3031.
(24) Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O.
Tetrahedron 2004, 60, 8633−8644.
(25) Spinella, S. M.; Guan, Z.-H.; Chen, J.; Zhang, X. Synthesis 2009,
18, 3094−3098.
(26) Mello, J. V; Finney, N. S. Org. Lett. 2001, 3, 4263−4265.
(27) Doebelin, C.; Wagner, P.; Bertin, I.; Simonin, F.; Schmitt, M.;
Bihel, F.; Bourguignon, J.-J. RSC Adv. 2013, 3, 10296−10300.
(28) Usuki, T.; Yamada, H.; Hayashi, T.; Yanuma, H.; Koseki, Y.;
Suzuki, N.; Masuyama, Y.; Lin, Y. Y. Chem. Commun. 2012, 48, 3233−
32355.
(29) Bracher, F.; Daab, J. Eur. J. Org. Chem. 2002, 14, 2288−2291.
(30) Daykin, L. M.; Siddle, J. S.; Ankers, A. L.; Batsanov, A. S.; Bryce,
M. R. Tetrahedron 2010, 66, 668−675.
(31) Ehlers, P.; Neubauer, A.; Lochbrunner, S.; Villinger, A.; Langer,
P. Org. Lett. 2011, 13, 1618−1621.
(32) Bera, M. K.; Hommes, P.; Reissig, H.-U. Chem.Eur. J. 2011,
17, 11838−11843.
(33) Gholap, S. L.; Hommes, P.; Neuthe, K.; Reissig, H.-U. Org. Lett.
2013, 15, 318−321.
(34) Palacios, F.; Alonso, C.; Rubiales, G.; Ezpeleta, J. M. Eur. J. Org.
Chem. 2001, 11, 2115−2122.
918
dx.doi.org/10.1021/jo402200q | J. Org. Chem. 2014, 79, 908−918