Route to Highly Substituted Pyridines

Article abstract of DOI:10.1021/acs.joc.6b01370

Pyridine rings are common structural motifs found in a number of biologically active compounds, including some top-selling pharmaceuticals. We have developed a new approach to access substituted pyridines. The method aims to provide a reliable synthesis of a diverse range of substituted pyridines through a three-step procedure. Readily available enones are first converted into 1,5-dicarbonyls through a two-step Hosomi-Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method.

Full text of DOI:10.1021/acs.joc.6b01370

Article
pubs.acs.org/joc
Route to Highly Substituted Pyridines
Justin A. Hilf, Michael S. Holzwarth, and Scott D. Rychnovsky*,†
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences II, Irvine, California 92697, United States
S
* Supporting Information
ABSTRACT: Pyridine rings are common structural motifs
found in a number of biologically active compounds, including
some top-selling pharmaceuticals. We have developed a new
approach to access substituted pyridines. The method aims to
provide a reliable synthesis of a diverse range of substituted
pyridines through a three-step procedure. Readily available
enones are first converted into 1,5-dicarbonyls through a two-
step Hosomi−Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding
pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method.
cyclized to pyridines with substitution at both the 2- and 6-
positions.9 Accessing pyridines without 6-substitution can be
difficult using these methods. More recently, routes based on
modern transition-metal catalysis have gained popularity,
utilizing a variety of transition metals including Ti,10 Mn,11
Ni,12 Cu,13 Zr,14 Ru,15 Rh,16 and Pd.17 Although many of the
recently published methods for synthesizing pyridines are high
yielding, most require the use of expensive reagents and
catalysts. In addition, the synthesis of starting materials required
for some of these transformations are often lower yielding than
the methods themselves. With many options to choose from,
the availability and cost of starting materials and reagents
needed for a method are often taken into consideration. When
faced with an apparent simple problem in pyridine ring
construction from readily available starting materials, we were
dismayed to find that neither the classic condensation
routes,8a,b a more modern hetero Diels−Alder approach,18
nor the recent organometallic methods were effective or
applicable.10−17 We developed an alternative route from several
stalwart reactions that allowed us to construct the requisite
pyridine target and report a brief exploration of the scope of the
method herein.
INTRODUCTION
■
Pyridines and pyridine rings fused to other heterocycles are
very commonly found in pharmaceutical lead compounds and
are well represented in clinically approved pharmaceuticals.1
These compounds have drawn inspiration from naturally
occurring pyridine-containing molecules, including vitamins
B3 and B6, as well as NADP and nicotine.2 Pyridine rings are
also excellent ligands for first-row transition metals,3 forming
reactive complexes capable of unique transformations.4 For
many applications in this area, multiple pyridine rings are
preferred because they act as polydentate ligands.5 The
synthesis of substituted pyridines is usually approached in
one of two ways: (1) site-specific functionalization of an
existing pyridine6 or (2) construction of the pyridine ring from
functionalized precursors. The latter strategy has been an area
of study for over a century,7 exemplified by a few classic named
reactions.8 Several examples are illustrated in Figure 1. In an
approach related to Krohnke’s method, researchers have
utilized a Michael addition of a ketone equivalent to an
enone to generate 1,5-diketones, which are subsequently
̈
The method utilizes robust chemistry to provide a simple, yet
reliable way of accessing substituted pyridines from starting
materials that are easily synthesized or are commercially
available. The general approach is outlined in Figure 2.
Condensation of a functionalized 1,5-dicarbonyl would provide
pyridines using well-established cyclization chemistry.19 The
dicarbonyl intermediate could be accessed from enones, an
easily accessible motif commonly synthesized in high yield
through a variety of methods including aldol condensations and
HWE olefinations.20 In order to introduce the two-carbon unit
needed, we envisioned a two-step procedure, by first
Special Issue: Heterocycles
Received: June 7, 2016
Figure 1. Common approaches to pyridine ring construction.
© XXXX American Chemical Society
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Table 1. Scope of 2,4- and 2,3,4-Substituted Pyridines
Figure 2. Retrosynthesis approach to pyridines with enone and allyl
nucleophile components.
introducing an allylic nucleophile to the Michael acceptor,
followed by oxidative cleavage of the resulting olefin.
RESULTS AND DISCUSSION
■
Initial studies focused on a general procedure for converting
enones (chalcone derivatives) to the desired pyridines, Scheme
1. Optimization of the sequence was accomplished using
Scheme 1. Optimized Synthetic Route to a Pyridine Ring
Using Chalcone and Allyltrimethylsilane
synthesized using the same three-step procedure, albeit in
slightly diminished yields.
Substitution at the 3-position of the pyridine can be
introduced with the use of α-substituted enones. This
modification allows for the synthesis of polycyclic pyridines,
as demonstrated by 7l−n, as well as 2,3,4-trisubstituted
pyridines 7o. The method can be used with a variety of simple
substituents to produce disubstituted and trisubstituted
pyridine rings.
Using the method to introduce a fluorine atom on the
pyridine ring25 led to an unexpected result, Scheme 2.
Fluoroenone 6p reacted with allylsilane as expected to give
the alkene. Ozonolysis produced the aldehyde in good yield,
but treatment with hydroxylamine hydrochloride went astray.
The expected 3-fluoropyridine 7p was produced, but as the
minor component of the product mixture. The major product
chalcone (1) as the enone precursor. The conjugate addition
was achieved by reacting enone 1 with commercially available
allyltrimethylsilane (2) under Hosomi−Sakurai reaction
conditions.21 A variety of Lewis acids and additives can be
used to effect this transformation,22 but TiCl4 was found to
work best for most of the substrates tested in the course of our
investigation. Oxidation of olefin 3 was carried out using
ozonolysis.23 Other oxidations were also competent in this
sequence, including Johnson−Lemieux conditions,24 but the
ozonolysis procedure provided the desired crude aldehyde 4
with good purity and minimal side products. Finally, the
cyclization of aldehyde 4 was carried out using hydroxylamine
hydrochloride at elevated temperatures to provide pyridine 5 in
modest to high yields. Several solvents were investigated for the
cyclization, and acetonitrile was found to be superior to alcohol
solvents with respect to scope and yield. The synthesis uses two
purifications by column chromatography, one after oxidation of
the olefin and another following the cyclization. In many cases,
the first purification can be omitted.
Scheme 2. Competitive Elimination for Fluorine in the
Aromatization Step
With an optimized procedure in hand, the substrate scope
was explored. Sakurai reactions using allyltrimethylsilane (2)
were the primary focus, yielding pyridines without substitution
at the 5 and 6 positions (Table 1). Reactions using aryl−aryl-
disubstituted enones provided 2,4-substituted pyridines (7a−g)
in 60−80% yield. The three-step sequence was tolerant of a
variety of substitution patterns and substituents, including
electron-donating and -withdrawing groups. More notably,
halogenated aromatic systems could be used (7c,g) without
concern of loss of the halogen, since no oxidative addition steps
with transition metals are used in the sequence. These
substrates also provide a handle for further functionalization
using traditional cross-coupling reactions. The 2,2′-bipyridines
(7h), as well as alkyl-substituted pyridines (7i−k), can also be
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was identified as the pyridine N-oxide 7q, which was isolated in
52% yield. One can envision intermediates that would either
eliminate water to give 7p, the normal course of the reaction, or
eliminate HF to give the N-oxide 7q. Both pathways are
competitive with fluorine; presumably, better leaving groups
would lead entirely to the N-oxide structure.
squaring the yield of the single ring formation of 7a. Using bis-
enone 12 with an existing pyridine ring, a tris-pyridine ligand
13 was assembled in 21% yield using this method. This
approach may provide a useful entry into new polydentate
pyridine ligands.28
A simple method for constructing highly substituted pyridine
rings was developed. It begins with an enone structure, itself
available with many substitution patterns. Hosomi−Sakurai
addition with allylsilanes provided a robust method to add the
remaining carbon atoms for the ring. Oxidation and cyclization
with hydroxylamine completes the synthesis. The method has a
reasonable scope, uses simple and reliable steps, and should be
useful for the preparation of new bioactive materials or metal
ligands.
Further investigation of the scope of the method is presented
in Table 2. The allylsilane component can carry additional
Table 2. Scope of 6-Substituted Pyridines
EXPERIMENTAL SECTION
■
General Information. 1H NMR and 13C NMR spectra were
recorded at ambient temperature. The data are reported as follows:
chemical shift in ppm on a δ scale and referenced to internal
tetramethylsilane or residual solvent (1H NMR = TMS: δ 0.00 or
CHCl3: δ 7.26; 13C NMR = CHCl3: δ 77.16), multiplicity (appar =
apparent, br = broad, s = singlet, d = doublet, t = triplet, q = quartet,
quint = quintet, sext = sextet, m = multiplet), coupling constants (Hz),
and integration. Infrared (IR) spectra were obtained. Accurate mass
spectra were acquired on a quadrupole time-of-flight spectrometer and
were obtained by peak matching. Analytical thin layer chromatography
was performed on glass-backed silica gel 60 Å F254 plates and visualized
by UV light, p-anisaldehyde, potassium permanganate, or vanillin.
Liquid chromatography was performed using forced flow (flash
chromatography) with an automated purification system on prepacked
silica gel (SiO2) columns. CH2Cl2 was dried by filtration through
alumina according to the method of Grubbs.29 All reactions using
CH2Cl2 as solvents were run under an atmosphere of argon in
glassware that was flame- or oven-dried, unless otherwise stated. All
commercially available reagents were used as received unless stated
otherwise. Enone starting materials were either commercially available
or were synthesized using aldol condensation conditions. Spectral data
of all synthesized enones matched previously reported literature data.
General Procedure Using Allyltrimethylsilane (2). Hosomi−
Sakurai Addition. To a stirred solution of enone (1.0 mmol) in
CH2Cl2 (1.5 mL) was added titanium tetrachloride (1.2 mmol) as a
single portion, and the solution turned dark red. A separate solution of
allyltrimethylsilane (2) (1.3 mmol) in CH2Cl2 (1.5 mL) was prepared
and then added as a single portion to the stirring enone solution. The
reaction mixture was allowed to stir at room temperature for 2 h. Once
the reaction was complete, the reagents were quenched with the slow
addition of H2O (3 mL), resulting in a cloudy biphasic solution. The
phases were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 2 mL). The combined organic layers were dried over
Na2SO4, run through a plug of silica gel, and concentrated in vacuo.
The resulting crude oil was taken on to the next step without further
purification.
substituents. Commercially available methallyltrimethylsilane
(8) was evaluated in order to introduce a methyl group at the
6-position of the constructed pyridine ring. The Hosomi−
Sakurai reactions using methallyltrimethylsilane were not as
widely effective as those using allyltrimethylsilane.26 At this
time, it is unclear why these reactions were difficult to carry out
on some substrates, while others worked without issue.27 In
cases where the Sakurai addition worked well, the oxidation and
cyclization reactions proceeded uneventfully to provide the
desired pyridines, Table 2. Pyridine 9c offers an example of a
tetrasubstituted pyridine prepared by this strategy.
The construction of bis- and tris-pyridines was also explored
using symmetric enones, Scheme 3. Bis-enone 10 underwent
Sakurai addition successfully. Oxidation gave the bis-aldehyde,
which was treated with hydroxylamine hydrochloride under
standard conditions to deliver bis-pyridine 11 in 41% yield. In
this case, the yield is slightly lower than one might predict from
Scheme 3. Synthesis of Bis-pyridines by Simultaneous
Construction of Pyridine Rings from Bis-enones
General Procedure. Ozonolysis. A stirred solution of olefin (1.0
mmol) in CH2Cl2 (7 mL) was cooled to −78 °C. Ozone was then
bubbled through the solution until a blue color persisted for 1 min.
Oxygen was then bubbled through the solution for 5 min to displace
any remaining ozone in solution. Triphenylphosphine (1.5 mmol) was
then added, and the mixture was capped and stirred overnight at room
temperature. Once the reaction was complete, the solvent was
evaporated and PPh3 and OPPh3 were removed using ISCO flash
chromatography on SiO2 (elution gradient of hexanes with EtOAc =
0−100%). All fractions not containing PPh3 and OPPh3 were
combined, concentrated, and carried on to the next step.
General Procedure. Cyclization of the Pyridine Ring. To a
scintillation vial containing a solution of aldehyde (1.0 mmol) in
acetonitrile (12 mL) was added hydroxylamine hydrochloride (3.0
mmol). (Larger scale reactions were run in a round-bottom flask
equipped with a stir bar and a reflux condenser.) After capping the vial,
C
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the mixture was heated to 80 °C, where it was left to stir overnight.
The next day, the reaction was cooled to room temperature, and the
MeCN was removed under reduced pressure. The dark-colored solid
was then dissolved in 10 mL of saturated aqueous K2CO3/H2O (1:1)
and was extracted with EtOAc (3 × 5 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The crude
residue was purified using ISCO flash chromatography on SiO2
(elution gradient of hexanes with EtOAc = 0−100%) to afford the
desired pyridine. All yields presented are over the three steps of the
procedure.
158.1, 150.1, 149.2, 140.1, 139.5, 130.2, 129.1, 128.8, 127.1, 120.4,
119.6, 118.9, 114.3, 113.0, 55.4; IR (thin film) 1593, 1543, 1210, 772,
691 cm−1; accurate mass (ES/MeOH) m/z calcd for C18H15NONa (M
+ Na)+ 284.1051, found 284.1049.
4-(2-Methoxyphenyl)-2-phenylpyridine (7f). Light pink oil (212
1
mg, 81%): H NMR (500 MHz, CDCl3) δ 8.72 (d, J = 5.1 Hz, 1H),
8.06−8.00 (m, 2H), 7.90 (s, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.45−7.38
(m, 4H), 7.09 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 3.86 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 157.5, 156.7, 149.5, 147.3,
139.9, 130.6, 130.3, 128.9, 128.8, 128.2, 127.2, 123.0, 121.6, 121.2,
1
2,4-Diphenylpyridine (7a). Colorless oil (171 mg, 74%): H NMR
(500 MHz, CDCl3) δ 8.72 (d, J = 5.0 Hz, 1H), 8.04 (d, J = 7.3 Hz,
2H), 7.91 (s, 1H), 7.67 (d, J = 6.8 Hz, 2H), 7.50−7.41 (m, 7H); 13C
NMR (125 MHz, CDCl3) δ 158.1, 150.1, 149.3, 139.5, 138.6, 129.16,
129.07, 128.8, 127.12, 127.07, 120.3, 118.8; 1H and 13C NMR spectral
data are in agreement with previously reported literature data.30
1
111.6, 55.8; H and 13C NMR spectral data are in agreement with
previously reported literature data.30
2-(4-Bromophenyl)-4-phenylpyridine (7g). White solid (248 mg,
1
80%): H NMR (500 MHz, CDCl3) δ 8.72 (d, J = 5.1 Hz, 1H), 7.93
(d, J = 8.7 Hz, 2H), 7.88 (s, 1H), 7.67 (dd, J = 7.2, 1.1 Hz, 2H), 7.61
(d, J = 8.7 Hz, 2H), 7.54−7.42 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 157.0, 150.3, 149.6, 138.5, 132.0, 129.3, 128.7, 127.2, 123.7,
4-(4-Nitrophenyl)-2-phenylpyridine (7b). White solid (221 mg,
80%): H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 4.5 Hz, 1H), 8.38
1
(d, J = 8.8 Hz, 2H), 8.06 (d, J = 7.1 Hz, 2H), 7.94 (s, 1H), 7.85 (d, J =
8.8 Hz, 2H), 7.52 (t, J = 7.1 Hz, 2H), 7.47 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 158.8, 150.7, 148.4, 147.1, 145.1, 139.1, 129.6, 129.1,
128.3, 127.2, 124.5, 120.4, 118.9; 1H and 13C NMR spectral data are in
agreement with previously reported literature data.31
1
120.7, 118.6; H and 13C NMR spectral data are in agreement with
previously reported literature data.30
1
4-Phenyl-2,2′-bipyridine (7h). Light yellow oil (93 mg, 40%): H
NMR (500 MHz, CDCl3) δ 8.75−8.64 (m, 3H), 8.45 (d, J = 8.0 Hz,
1H), 7.81 (td, J = 7.5, 1.8 Hz, 1H), 7.75 (m, 2H), 7.52 (dd, J = 5.1, 1.9
Hz, 1H), 7.50−7.45 (m, 2H), 7.45−7.39 (m, 1H), 7.30 (ddd, J = 7.5,
4.8, 1.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 156.7, 156.2, 149.7,
149.4, 149.3, 138.3, 137.0, 129.1, 129.1, 127.2, 123.9, 121.7, 121.3,
119.1; IR (thin film) 3055, 1582, 1456, 1389, 759, 694 cm−1; accurate
mass (ES/MeOH) m/z calcd for C16H12N2H (M + H)+ 233.1079,
found 233.1069.
4-(4-Chlorophenyl)-2-phenylpyridine (7c). Brown oil (160 mg,
60%): 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 5.2 Hz, 1H), 8.06−
7.97 (m, 2H), 7.83 (d, J = 0.8 Hz, 1H), 7.58−7.54 (m, 2H), 7.51−7.39
(m, 5H), 7.36−7.32 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 158.3,
150.3, 148.0, 139.3, 136.9, 135.3, 129.4, 129.2, 128.9, 128.4, 127.1,
1
120.0, 118.5; H and 13C NMR spectral data are in agreement with
previously reported literature data.32
1
4-Methyl-2-phenylpyridine (7i). Colorless oil (76 mg, 45%): H
NMR (500 MHz, CDCl3) δ 8.55 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 8.2
Hz, 2H), 7.55 (s, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.45−7.37 (m, 1H),
7.06 (d, J = 4.4 Hz, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
4-(4-Methoxyphenyl)-2-phenylpyridine (7d). White solid (178 mg,
68%): 1H NMR (500 MHz, CDCl3) δ 8.70 (d, J = 5.1 Hz, 1H), 8.04−
8.03 (m, 2H), 7.89 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.51−7.41 (m,
4H), 7.03 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 160.7, 158.2, 150.2, 148.9, 139.8, 130.9, 129.1, 128.9, 128.4,
127.2, 119.9, 118.4, 114.7, 55.6; 1H and 13C NMR spectral data are in
agreement with previously reported literature data.30
1
157.5, 149.6, 147.9, 139.7, 129.0, 128.8, 127.1, 123.3, 121.7, 21.4; H
and 13C NMR spectral data are in agreement with previously reported
literature data.32
2-Methyl-4-phenylpyridine (7j). Orange oil (81 mg, 48%): 1H
NMR (500 MHz, CDCl3) δ 8.53 (d, J = 5.3 Hz, 1H), 7.61 (d, J = 8.5
Hz, 2H), 7.50−7.44 (m, 2H), 7.41 (m, 1H), 7.36 (s, 1H), 7.30 (d, J =
5.3 Hz, 1H), 2.62 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.9,
4-(3-Methoxyphenyl)-2-phenylpyridine (7e). Brown oil (133 mg,
51%): H NMR (500 MHz, CDCl3) δ 8.74 (d, J = 5.1 Hz, 1H), 8.07
(d, J = 7.1 Hz, 2H), 7.93 (s, 1H), 7.51 (t, J = 7.1 Hz, 2H), 7.47−7.39
(m, 3H), 7.28 (d, J = 8.3 Hz, 1H), 7.23−7.21 (m, 1H), 7.00 (dd, J =
8.3, 2.5 Hz, 1H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.2,
1
149.7, 148.8, 138.5, 129.1, 129.0, 127.1, 121.3, 119.0, 24.7; 1H and 13
C
NMR spectral data are in agreement with previously reported
literature data.30
D
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4-Hexyl-2-methylpyridine (7k). Brown oil (78 mg, 44%): 1H NMR
(500 MHz, CDCl3) δ 8.36 (d, J = 5.1 Hz, 1H), 6.97 (s, 1H), 6.91 (d, J
= 5.1 Hz, 1H), 2.57−2.53 (t, J = 7.5 Hz, 2H), 2.52 (s, 3H), 1.60 (dt, J
= 15.2, 7.5 Hz, 2H), 1.37−1.21 (m, 6H), 0.88 (t, J = 6.6 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 158.2, 152.3, 149.0, 123.6, 121.2, 35.4,
31.8, 30.5, 29.0, 24.4, 22.7, 14.2; IR (thin film) 2926, 2856, 1604, 1456
cm−1; accurate mass (ES/MeOH) m/z calcd for C12H19NH (M + H)+
178.1596, found 178.1604.
3-Fluoro-2-phenyl-4-(p-tolyl)pyridine (7p). Tan solid (42 mg,
16%): mp 76−77 °C; 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 4.8
Hz, 1H), 7.98 (d, J = 7.3 Hz, 2H), 7.55 (dd, J = 7.9, 1.2 Hz, 2H), 7.51
(t, J = 7.3 Hz, 2H), 7.48−7.43 (m, 1H), 7.37−7.28 (m, 3H), 2.44 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 154.7 (d, J = 260.8 Hz), 147.2
(d, J = 13.0 Hz), 145.4 (d, J = 6.7 Hz), 139.4, 137.4 (d, J = 13.0 Hz),
135.8 (d, J = 4.9 Hz), 130.6, 130.0, 129.6, 129.2, 129.15 (d, J = 5.5
Hz), 129.0 (d, J = 3.2 Hz), 128.9, 128.5, 127.1 (d, J = 18.4 Hz), 123.7,
21.4; 19F NMR (376 MHz, CDCl3) δ − 130.65; IR (thin film) 2915,
1597, 1396, 1204, 815, 750, 695, 497 cm−1; accurate mass (ES/
MeOH) m/z calcd for C18H14FNNa (M + Na)+ 286.1008, found
286.1019.
1-Methyl-5,6,7,8-tetrahydroisoquinoline (7l). Light orange oil (66
1
mg, 45%): H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 5.1 Hz, 1H),
6.83 (d, J = 5.1 Hz, 1H), 2.72 (t, J = 6.3 Hz, 2H), 2.62 (t, J = 6.4 Hz,
2H), 2.43 (s, 3H), 1.89−1.82 (m, 2H), 1.81−1.72 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 157.1, 146.0, 145.3, 131.0, 122.2, 29.5, 26.1,
23.1, 22.3, 22.2; IR (thin film) 2928, 1587, 1428, 1411, 834, 807 cm−1;
accurate mass (ES/MeOH) m/z calcd for C10H13NH (M + H)+
148.1126, found 148.1123.
2-Phenyl-4-(p-tolyl)pyridine N-Oxide (7q). Yellow oil (136 mg,
52%): H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 7.0 Hz, 1H), 7.82
1
(d, J = 7.0 Hz, 2H), 7.58 (dd, J = 2.5 Hz, 1H), 7.47−7.37 (m, 6H),
7.23 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
149.1, 140.4, 139.3, 138.8, 133.4, 132.8, 130.1, 129.7, 129.4, 128.4,
126.3, 124.7, 122.0, 21.3; IR (thin film) 3395, 2919, 1468, 1420, 1249,
812 cm−1; accurate mass (ES/MeOH) m/z calcd for C18H15ONNa (M
+ Na)+ 284.1051, found 284.1041.
General Procedure Using Methallyltrimethylsilane (8).
Hosomi−Sakurai Addition. To a cooled (−78 °C) solution of
enone (1.0 mmol) in CH2Cl2 (4 mL) was added titanium tetrachloride
(1.2 mmol) dropwise, and the solution turned red. A separate solution
of methallyltrimethylsilane (8) (1.4 mmol) in CH2Cl2 (1.5 mL) was
prepared and then added dropwise to the stirring enone solution after
it had stirred for 10 min. The reaction mixture was allowed to stir at
−78 °C for 2 h. Once the reaction was complete, the reagents were
quenched by the slow addition of H2O (3 mL), and the mixture was
warmed to room temperature, resulting in a cloudy biphasic solution.
The phases were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 2 mL). The combined organic layers were dried over
Na2SO4, run through a plug of silica gel, and concentrated in vacuo.
The resulting crude oil was taken on to the next step without further
purification.
4-Phenyl-5,6-dihydrobenzo[h]quinoline (7m). Tan solid (176 mg,
66%): H NMR (500 MHz, CDCl3) δ 8.55 (d, J = 4.9 Hz, 1H), 8.36
1
(dd, J = 7.7, 1.0 Hz, 1H), 7.46−7.28 (m, 7H), 7.19 (d, J = 7.4 Hz, 1H),
7.09 (d, J = 4.9 Hz, 1H), 2.90−2.87 (m, 2H), 2.80−2.78 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 153.1, 148.7, 147.3, 139.0, 138.2, 135.0,
129.6, 129.2, 128.9, 128.6, 128.2, 127.6, 127.3, 125.6, 123.4, 28.2, 25.6;
1H and 13C NMR spectral data are in agreement with previously
reported literature data.30
10-Phenylacenaphtho[1,2-b]pyridine (7n). Orange oil (143 mg,
1
51%): H NMR (500 MHz, CDCl3) δ 8.61 (d, J = 5.1 Hz, 1H), 8.35
(d, J = 6.9 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H),
7.76 (t, J = 7.5 Hz, 1H), 7.67 (dd, J = 8.0, 1.7 Hz, 2H), 7.61−7.53 (m,
3H), 7.52−7.42 (m, 2H), 7.18 (d, J = 5.1 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 159.7, 147.8, 145.7, 138.7, 135.3, 133.5, 132.3, 131.0,
129.8, 129.0, 128.9, 128.6, 128.4, 128.0, 127.8, 123.9, 123.0, 121.9; IR
(thin film) 3053, 1428, 825, 776, 763, 701 cm−1; accurate mass (ES/
MeOH) m/z calcd for C21H13NH (M + H)+ 280.1126, found
280.1123.
1
2-Methyl-4,6-diphenylpyridine (9a). Brown oil (91 mg, 37%): H
NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.1 Hz, 2H), 7.73 (s, 1H),
7.69 (d, J = 7.1 Hz, 2H), 7.52−7.41 (m, 6H), 7.34 (s, 1H), 2.71 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 158.8, 157.6, 150.0, 138.8,
1
129.1, 129.01, 128.96, 128.8, 127.3, 127.2, 120.0, 116.4, 24.8; H and
13C NMR spectral data are in agreement with previously reported
literature data.33
3-Methyl-2,4-diphenylpyridine (7o). Brown oil (155 mg, 63%): 1H
NMR (500 MHz, CDCl3) δ 8.57 (d, J = 5.0 Hz, 1H), 7.57 (d, J = 8.2
Hz, 2H), 7.51−7.44 (m, 4H), 7.44−7.35 (m, 4H), 7.16 (d, J = 5.0 Hz,
1H), 2.23 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.8, 151.0,
146.5, 141.1, 139.9, 129.2, 128.8, 128.6, 128.5, 128.2, 128.0, 123.3,
18.1; 1H and 13C NMR spectral data are in agreement with previously
reported literature data.30
4-(2-Methoxyphenyl)-2-methyl-6-phenylpyridine (9b). Colorless
oil (215 mg, 78%): 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.2 Hz,
2H), 7.68 (s, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.42−7.34 (m, 3H), 7.26
(s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.84 (s,
E
DOI: 10.1021/acs.joc.6b01370
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Article
3H), 2.67 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 158.2, 157.0,
156.7, 147.4, 140.3, 130.6, 130.0, 128.8, 128.7, 128.5, 127.3, 122.4,
121.1, 118.9, 111.5, 55.7, 25.0; IR (thin film) 1604, 1399, 1246, 1024,
751, 693 cm−1; accurate mass (ES/MeOH) m/z calcd for
C19H17NONa (M + Na)+ 298.1208, found 298.1204.
613 cm−1; accurate mass (ES/MeOH) m/z calcd for C28H20N2H (M +
H)+ 385.1705, found 385.1694.
4,4″-Di-p-tolyl-2,2′:6′,2″-terpyridine (13). Tan solid (43 mg, 21%):
1
mp 210−211 °C (decomposition); H NMR (500 MHz, CDCl3) δ
8.86 (d, J = 1.1 Hz, 2H), 8.73 (d, J = 5.1 Hz, 2H), 8.49 (d, J = 7.8 Hz,
2H), 7.99 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 4H), 7.55 (dd, J =
5.1, 1.8 Hz, 2H), 7.33 (d, J = 8.0 Hz, 4H), 2.45 (s, J = 10.6 Hz, 6H);
13C NMR (125 MHz, CDCl3) δ 156.9, 155.6, 149.7, 149.2, 139.3,
138.1, 135.7, 130.0, 127.1, 121.6, 121.4, 119.1, 21.4; IR (thin film)
2920, 1572, 1383, 802, 453 cm−1; accurate mass (ES/MeOH) m/z
calcd for C29H23N3Na (M + Na)+ 436.1790, found 436.1782.
2-Methyl-4-phenyl-5,6-dihydrobenzo[h]quinoline (9c). Orange oil
(174 mg, 64%): H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 7.6 Hz,
1
1H), 7.46 (m, 2H), 7.43−7.38 (m, 1H), 7.35 (m, 3H), 7.30 (td, J =
7.4, 1.3 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.00 (s, 1H), 2.88−2.83 (m,
2H), 2.83−2.77 (m, 2H), 2.63 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 155.9, 152.4, 148.8, 139.4, 138.3, 135.3, 128.94, 128.90, 128.5, 128.0,
127.5, 127.2, 126.4, 125.5, 122.9, 28.4, 25.3, 24.6; IR (thin film) 2927,
1590, 1547, 1497, 750, 701 cm−1; accurate mass (ES/MeOH) m/z
calcd for C20H17NH (M + H)+ 272.1439, found 272.1426.
General Procedure Using Bis-enones. Hosomi−Sakurai
Addition. To a stirring solution of bis-enone (0.50 mmol) in
CH2Cl2 (1.5 mL) was added titanium tetrachloride (1.2 mmol) as a
single portion, and the solution turned dark red. A separate solution of
allyltrimethylsilane (2) (1.3 mmol) in CH2Cl2 (1.5 mL) was prepared
and then added as a single portion to the stirring enone solution. The
reaction mixture was allowed to stir at room temperature for 2 h. Once
the reaction was complete, the reagents were quenched with the slow
addition of H2O (3 mL), resulting in a cloudy biphasic solution. The
phases were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 2 mL). The combined organic layers were dried over
Na2SO4, run through a plug of silica gel, and concentrated in vacuo.
The resulting crude oil was taken on to the next step without further
purification.
General Procedure Using Bis-enones. Ozonolysis. A stirring
solution of bis-olefin (0.50 mmol) in CH2Cl2 (7 mL) was cooled to
−78 °C. Ozone was then bubbled through the solution until a blue
color persisted for 1 min. Oxygen was then bubbled through the
solution for 5 min to displace any remaining ozone in solution.
Triphenylphosphine (1.5 mmol) was then added, and the reaction was
capped and stirred overnight at room temperature. Once the reaction
was complete, the solvent was evaporated and PPh3 and OPPh3 were
removed using flash chromatography on SiO2 (hexanes/EtOAc =
75:25). All fractions not containing PPh3 and OPPh3 were combined,
concentrated, and carried on to the next step.
General Procedure Using Bis-enones. Cyclization of the
Pyridine Rings. To a scintillation vial containing a solution of bis-
aldehyde (0.50 mmol) in acetonitrile (12 mL) was added hydroxyl-
amine hydrochloride (3 mmol). After the vial was capped, the solution
was heated to 80 °C, where it was left to stir overnight. The next day,
the reaction mixture was cooled to room temperature, and the MeCN
was removed under reduced pressure. The dark-colored solid was then
dissolved in 10 mL of saturated aqueous K2CO3/H2O (1:1) and was
extracted with EtOAc (3 × 5 mL). The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The crude residue was
purified using flash chromatography on SiO2 (hexanes/EtOAc =
70:30) to afford the desired bis-pyridine. All yields presented are over
the three steps.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01370.
■
S
Spectroscopic characterization for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: srychnov@uci.edu.
■
Notes
The authors declare no competing financial interest.
†ISHC member.
ACKNOWLEDGMENTS
■
Support was provided by the University of California, Irvine
and the United Against Lung Cancer organization (200613).
This material is based upon work conducted while S.D.R. was
supported by and serving at the National Science Foundation.
M.S.H. thanks the German Academic Exchange Service
(DAAD) for a postdoctoral fellowship.
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