Application of 1,4-Oxazinone Precursors to the Construction of Pyridine Derivatives by Tandem Intermolecular Cycloaddition/Cycloreversion

Article abstract of DOI:10.1021/acs.joc.1c00288

This study reveals a new method for the preparation of 1,4-oxazinone derivatives by Staudinger reductive cyclization of functionalized vinyl azide precursors. The resulting oxazinone derivatives prepared in this manner were intercepted with terminal alkyne substrates through an intermolecular cycloaddition/cycloreversion sequence to afford polysubstituted pyridine products. Alkyne substrates bearing propargyl oxygen substitution showed good regioselectivity in the cycloaddition operation selectively affording 2,4,6-substituted pyridines. Application of this chemistry to the synthesis of an ErbB4 receptor inhibitor is also described.

Full text of DOI:10.1021/acs.joc.1c00288

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Article
Application of 1,4-Oxazinone Precursors to the Construction of
Pyridine Derivatives by Tandem Intermolecular Cycloaddition/
Cycloreversion
Nicole A. Carrillo Vallejo and Jonathan R. Scheerer*
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ABSTRACT: This study reveals a new method for the preparation of 1,4-oxazinone derivatives by Staudinger reductive cyclization
of functionalized vinyl azide precursors. The resulting oxazinone derivatives prepared in this manner were intercepted with terminal
alkyne substrates through an intermolecular cycloaddition/cycloreversion sequence to afford polysubstituted pyridine products.
Alkyne substrates bearing propargyl oxygen substitution showed good regioselectivity in the cycloaddition operation selectively
affording 2,4,6-substituted pyridines. Application of this chemistry to the synthesis of an ErbB4 receptor inhibitor is also described.
cycloreversion sequence) and proceed readily with either
electron-rich or electron-deficient substrates to yield pyridine
products after loss of carbon dioxide.7 Because of the increased
reactivity, 1,4-oxazinones are attractive substrates that can
enable the use of less reactive 2π cycloaddition reaction
components and/or permit use of milder reaction conditions.8
In this way, ubiquitous alkyne precursors may be used
routinely and at reaction temperatures that are operationally
convenient for the practicing chemist. Pyridine synthesis using
oxazinone precursors was established from the foundational
work of Hoornaert9 and co-workers but remains obscure in
comparison to use of triazines.
INTRODUCTION
■
The synthesis of polysubstituted pyridine structures through
cycloaddition and cycloreversion strategies is a topic of historic
importance1 as well as the focus of current research.2 Through
these efforts, a variety of reactive aromatic heterocycles have
emerged as valid cycloaddition/cycloreversion precursors
capable of constructing diverse pyridine derivatives.3 The
isomeric 1,2,4- and 1,2,3-triazines 2 and 3 remain the most
commonly explored substrates for cycloaddition/cyclorever-
sion sequences directed toward pyridine products (Figure
1).4,5 Cycloaddition with triazine substrates proceeds favorably
We hypothesized that the underutilized nature of oxazinones
related to 1 was attributable not to reactivity but to the limited
methods available to prepare them. Excluding two examples,10
1,4-oxazinones have been prepared from cyanohydrin deriva-
tives in the presence of excess oxalyl chloride at elevated
temperatures (>90 °C).9,11 This method, though direct, suffers
from use of toxic cyanohydrin starting materials, harsh reaction
conditions, and modest yields for some derivatives (in
particular 4a) and necessarily produces the 3,5-dichloro
substitution (eq 1, Figure 2). Although further derivation of
3,5-dichlorooxazinones is possible at the more reactive 3-
Figure 1. Diels−Alder/retro Diels−Alder sequence with 1,4-
oxazinone and triazines.
within the inverse electron demand paradigm, most often with
enamine precursors. Alkyne 2π components have been shown
to be competent in the intermolecular cycloaddition with
triazines in only a handful of specialized cases.4a,6
1,4-Oxazinones (represented by general structure 1) are
complementary substrates in [4 + 2]/retro[4 + 2] tandem
sequences leading to pyridines. Recent computational efforts
suggest that oxazinones are the most reactive precursors for the
[4 + 2] reaction component (of the tandem cycloaddition/
Received: February 4, 2021
Published: April 2, 2021
https://doi.org/10.1021/acs.joc.1c00288
© 2021 American Chemical Society
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isomerization, cycloaddition (with the alkyne), and cyclo-
reversion (extrusion of CO2) would be executed in a single
reaction vessel. In order to facilitate a more rapid isomerization
of the exocyclic-alkene in 9 to the Diels−Alder-reactive
endocyclic oxazinone 10, catalytic NEt3 was added in
conjunction with the alkyne. These reaction conditions proved
effective in constructing the isomeric 2,3- and/or 2,4-pyridine
derivatives 11a and 11b and formed the basis of our initial
investigations into this tandem reaction sequence.
Using the reaction conditions highlighted above, we began
exploring the reaction scope of the key intermediate oxazinone
10 in order to demonstrate both cycloaddition reactivity with
several alkyne components and to establish meaningful
regioselectivity trends with these substrates. Table 1 describes
our preliminary results evaluating a series of terminal alkyne
reaction components 12a−f. Notably, aryl substitution on the
alkyne (phenylacetylene 12a, entry 1) showed favorable 9:1
selectivity for predominantly the 2,3-regioisomer 13a. A
Figure 2. Method for preparation of substituted oxazinone
derivatives.
position12 through palladium or SNAr chemistries, room for
improvement and additional methods for the construction of
1,4-oxazinones is evident.
We sought to explore an alternative route that utilized α-
amino acid derivatives as starting materials for the construction
of 3,5-carbon-substituted oxazinone substrates. Because
precedent for cycloaddition of such carbon-substituted
oxazinones is limited, we hoped a new synthesis of these
derivatives would enable exploration of the reactivity and
selectivity in the tandem cycloaddition/cycloreversion se-
quence.11 To this end, the goals of pyridine synthesis were
to confirm the reactivity of substituted oxazinones with
terminal alkyne precursors and discern baseline regioselectivity
trends.
Table 1. Evaluation of Scope of the Reaction
a b c d
, , ,
Sequence
Because oxazinones bearing 6-H substitution (e.g., 4a) are
some of the most challenging to construct using existing
methods, we elected to first direct our attention to the
construction of these substrates: 1,4-oxazinones with C3, C5,
and H6 substitution.
RESULTS AND DISCUSSION
■
We initiated the synthesis with aldol condensation between
anisaldehyde and azidoacetate 5 to give the azidoacrylate 6
(Scheme 1).13 Hydrolysis of 6 followed by direct alkylation of
Scheme 1. Synthesis of 1,4-Oxazinone and Tandem [4 + 2]/
Retro[4 + 2] Reaction to Give Substituted Pyridines
the derived carboxylate with bromoacetophenone cleanly
delivered product 8. Staudinger reduction with PPh3 was
performed at reflux in toluene (for 12 or more hours) in order
to affect the subsequent intramolecular cyclization of the
derived aza-Wittig intermediate on the pendant ketone. The
concentration of the reaction mixture revealed both oxazinone
isomers 9 and 10. The observed mixture of isomers 9 and 10
(∼1:1) appears to be the thermodynamic equilibrium ratio;
efforts to perturb this ratio with additional time, heat, or
additives (e.g., catalytic NEt3) did not alter the isomeric ratio.
Given this observation, we elected to explore ‘one-pot’ reaction
conditions whereby Staudinger reductive cyclization, alkene
a
b
Key: Isolated yield of the major isomer. An additional 22% yield
containing mixed 14a,b and an unreacted oxazinone precursor (21%
yield) was obtained. Isomers inseparable by chromatography. Yield
refers to the combined yield of both isomers. Reaction conditions: a
mixture of 8 (1 equiv) and PPh3 (1 equiv) were heated to reflux in
toluene. Following completion of the cyclization, the alkyne and
catalytic NEt3 were subsequently added and the reaction returned to
reflux.
c
d
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reversal in regioselectivity was observed when the reaction
sequence was executed with trimethylsilylacetylene (12b, entry
2). Accordingly, 2,4-substituted pyridine 14b was isolated as
the major product (regioselection 1:7). Pyridine yield in this
case is diminished, an observation we attribute to the high
volatility of alkyne 12b (bp 53 °C), which both lowered the
internal reaction reflux temperature and led to some
evaporation of the precursor during the course of reaction.
Consistent with this hypothesis, a small amount of unreacted
oxazinone mix 9 and 10 (21% yield, ca. 1:1 isomeric mixture)
was also observed in this case using the standard reaction
conditions. Separation of the isomeric mixture 14a and 14b
was challenging, and a mixed fraction (ca. 1:1 isomeric
mixture, 22% yield) was also obtained. When the sequence was
performed with propargyl alcohol (12c, entry 3), the major
product was again the 2,4-regioisomer and a 1:5 ratio of
pyridines 15a and 15b was obtained in 69% combined yield.
Success of this reaction demonstrates that the overall reaction
sequence leading to pyridine products is tolerant of primary
alcohol functional groups, a welcome feature given the
proclivity of lactone functionalities to undergo ring opening
and polymerization.
Because useful cycloaddition regioselectivity was achieved
with propargyl alcohol, we selected modified precursors
bearing propargyl heteroatom substitution in order to evaluate
subtle electronic and steric components. Propargyl ether 12d
(entry 4) performed similarly to the aforementioned propargyl
alcohol, producing a 1:4 ratio of the 2,3- and 2,4-regioisomeric
pyridines 16a and 16b was obtained in 70% combined yield.
We anticipated that propargyl acetal 12e would offer enhanced
regioselection. To this end, acetal 12e (entry 5) was employed
and analysis of the resulting unpurified reaction mixture
revealed a 1:14 ratio mixture of the pyridine products. The
major 2,4-pyridine 17b was isolated in 78% yield.
More electron-deficient substrates, such as methyl propiolate
12f, were poor substrates for the tandem reaction sequence.
When propiolate 12f was employed (entry 6), the reaction was
poorly regioselective (2:1) and led to low yields of desired
pyridine products, which could not be effectively separated, as
well as other undesired unidentified products. We do not have
an explanation for the low regioselectivity in this case;
however, the low yield is likely attributed to other reaction
pathways accessible to electron-deficient alkynes, such as a
Michael reaction and other conjugate addition processes.
Given the favorable regioselection for the formation of 1,3-
pyridine isomers with alkynes bearing propargylic oxygen
functionalization, we sought to apply this method to the
construction of target molecule 22, a selective ErbB4 inhibitor
that was discovered as part of a library synthesis.14 Although
the related membrane receptor kinases ErbB1 and ErbB2
receptors are well-characterized targets for cancer therapeutics,
much less is understood about ErbB4 and its effects on disease.
Gene expression and genetic analysis suggest that the receptor
is involved in the progression of breast cancer and other
disorders, and the ErbB4 gene is overexpressed or mutated in
several solid tumors.15 Screening efforts identified pyridine 22
as a potent inhibitor of the ErbB4 receptor, with an EC50 of
0.30 μM.14 Development of a versatile synthetic sequence for
the preparation of inhibitor 22 (and related structures) would
potentially facilitate exploration on the role of the ErbB4
receptor and the development of novel treatments.
oxazinone 20 for the cycloaddition/cycloreversion operation
that would provide access to pyridine 22. To this end, the
route was initiated with aldol condensation with trimethox-
ybenzaldehyde (Scheme 2) and further elaboration to the
Scheme 2. Synthesis of the ErbB4 Inhibitor from the 1,4-
Oxazinone Intermediate
azido cinnamate precursor 19 was accomplished in 50% yield
over the three steps. Adhering to the ‘one pot’ conditions
previously described, PPh3 was added, which led to Staudinger
reductive cyclization. The derived isomerized oxazinone
intermediate 20 (not isolated) was engaged in productive
cycloaddition/cycloreversion with the propargylic pentynol
21a. In this way, pyridine 22 was afforded as the major isomer
(regioselection 1:8 as judged by 1H NMR) and was isolated in
78% yield following careful chromatographic separation on
silica gel. We hypothesized that a more electron-withdrawing
propargyl ester would potentially enhance the observed ratio of
the 2,4-isomer relative to the isomeric 2,3-isomer. Accordingly,
the analogous sequence was performed with propargylic
benzoate 21b. A similar efficiency (79% yield) was observed
in the reaction sequence; however, our hypothesis regarding
regioselection was not realized and a slightly lower 1:6 ratio
was observed also favoring the 2,4 isomer.
In conclusion, we have devised a new method for the
synthesis of Diels−Alder/retro-Diels−Alder reactive 1,4-
oxazinone structures and have exploited this intermediate in
the construction of substituted pyridine derivatives. The key
reaction was executed in a single reaction vessel, whereby a
Staudinger reductive cyclization precedes an alkene isomer-
ization to the reactive oxazinone, and is intercepted by
intermolecular [4 + 2] cycloaddition and tandem cyclo-
reversion (−CO2). Several terminal alkyne reaction partners
were evaluated in the reaction sequence to afford trisubstituted
pyridine derivatives. We determined that phenylacetylene
favored the 2,3-isomer and derivatives with polar heteroatom
functionalization at the propargylic site show good regiose-
lection for the pyridine bearing the alternate 2,4-substitution
pattern. Application of this chemistry to the synthesis of a
known ErbB4 inhibitor was realized. Further efforts to advance
this methodology in the selective preparation of other complex
pyridine derivatives, including tetra- and penta-substituted
variants, are ongoing.
EXPERIMENTAL SECTION
■
General Experimental Considerations. All reactions were
carried out under an atmosphere of nitrogen in flame-dried or
oven-dried glassware with magnetic stirring unless otherwise
indicated. Acetonitrile, THF, toluene, and Et2O were degassed with
With minor changes to the sequence previously described
(in Scheme 1), we devised a modified route intercepting
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argon and purified by passage through a column of molecular sieves
and a bed of activated alumina. Dichloromethane was distilled from
CaH2 prior to use. All reagents were used as received unless otherwise
noted. Flash column chromatography was performed using SiliCycle
siliaflash P60 silica gel (230−400 mesh). Analytical thin layer
chromatography was performed on SiliCycle 60 Å glass plates.
Visualization was accomplished with UV light, anisaldehyde, ceric
ammonium molybdate, potassium permanganate, or ninhydrin
followed by heating. Film infrared spectra were recorded using a
Digilab FTS 7000 FTIR spectrophotometer. Optical rotations were
determined using a Perkin-Elmer 341 polarimeter at 25 °C. 1H NMR
spectra were recorded on a Varian Mercury 400 (400 MHz)
spectrometer and are reported in ppm using solvent as an internal
standard (CDCl3 at 7.26 ppm) or tetramethylsilane (0.00 ppm).
Proton-decoupled 13C-NMR spectra were recorded on a 100 MHz
spectrometer and are reported in ppm using solvent as an internal
standard (CDCl3 at 77.00 ppm). All compounds were judged to be
homogeneous (>95% purity) by 1H and 13C NMR spectroscopy.
Mass spectral data analysis was performed through positive electro-
spray ionization (w/NaCl) using a Bruker 12 Tesla APEX−Qe
FTICR-MS with an Apollo II ion source.
Methyl (Z)-2-azido-3-(4-methoxyphenyl)acrylate (6). A dry
flask was charged with sodium metal (1.00 g, 43.5 mmol) and allowed
to dissolve in MeOH (22 mL). After 1 h at room temperature, the
NaOMe solution was cooled to −10 °C. 4-Methoxybenzaldehyde and
azidomethyl acetate were inserted into an addition funnel with MeOH
(22 mL), and the reagents were added dropwise to the cold NaOMe
solution in MeOH over 15 min. The reaction was let to stir at −10 °C
for 5.5 h and then warmed to 5 °C over 1 h. The reaction was
quenched with 1 M HCl and partitioned between a 1:1 mixture of
Et2O/H2O (150 mL each). The organic layer was removed, and the
aqueous layer was extracted with Et2O (3 × 30 mL). The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated. The resulting residue was purified by flash column
chromatography on silica gel (gradient elution: 0% EtOAc to 20%
EtOAc in hexanes) to afford acrylate 6 (3.82 g, 16.4 mmol, 66% yield)
as bright yellow crystals: TLC (20% EtOAc in hexane), Rf: 0.70
(CAM). Spectral data for the azido acrylate 6 are in agreement with
published data.16
2-(4-Methoxybenzyl)-3,6-diphenylpyridine (13a) and 2-(4-
Methoxybenzyl)-4,6-diphenylpyridine (13b). A dry flask was
charged with acrylate 8 (58.2 mg, 0.17 mmol) and dissolved in PhMe
(2 mL). The flask was fitted with a water condenser, and PPh3 (45.2
mg, 0.17 mmol) was added in one portion at room temperature. After
gas evolution steadied, the reaction mixture was heated to reflux for
20 h using an aluminum heating block. The reaction was allowed to
cool to 90 °C before adding phenylacetylene (35.7 mg, 0.35 mmol)
and one drop (10 μL) of triethylamine. The reaction temperature was
heated to reflux again and allowed to stir for 5 h. The reaction mixture
was cooled to room temperature and concentrated in vacuo. 1H NMR
analysis of the unpurified mixture revealed a 9:1 mixture of
regioisomeric pyridine products 13a and 13b. This mixture was
purified by flash column chromatography on silica gel (gradient
elution: 5% EtOAc to 40% EtOAc in hexanes) to afford pyridine 13a
(41.8 mg, 0.12 mmol, 70% yield) and pyridine 13b (5 mg, 0.01 mmol,
8% yield), both as yellow oils.
Data for compound 13a: TLC (20% EtOAc in hexane), Rf: 0.65
(CAM); IR (film) 3057, 3030, 2951, 2833, 1608, 1508, 1244, 759,
731, cm−1; 1H NMR (400 MHz, CDCl3) 8.09−8.07 (m, 2H), 7.64 (d,
J = 7.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.50−7.46 (m, 2H), 7.43−
7.39 (m, 4H), 7.26−7.24 (m, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.74 (d, J
= 8.6 Hz, 2H), 4.14 (s, 2H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 157.8, 157.7, 155.6, 139.8, 139.3, 138.5, 135.6, 132.3, 129.8,
129.3, 128.8, 128.7, 128.6, 128.3, 127.4, 126.9, 117.7, 113.5, 55.2,
40.9. Exact mass calcd for C25H21NONa + 374.1516, found 374.1516.
Data for compound 13b: TLC (20% EtOAc in hexane), Rf: 0.60
(CAM); IR (film) 3057, 3030, 2951, 2833, 1608, 1508, 1244, 759,
731, cm−1; 1H NMR (400 MHz, CDCl3) 8.08−8.06 (m, 2H), 7.74 (d,
J = 1.6 Hz, 1H), 7.62−7.60 (m, 2H), 7.51−7.41 (m, 6H), 7.30 (d, J =
8.6, 2H), 7.22 (d, J = 1.2 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.24 (s,
2H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 158.2,
157.5, 149.8, 139.8, 138.9, 131.8, 130.2, 129.0, 128.84, 128.82, 128.7,
127.14, 127.11, 119.5, 116.4, 114.0, 55.2, 44.1. Exact mass calcd for
C25H21NONa + 374.1516, found 374.1516.
2-(4-Methoxybenzyl)-6-phenyl-4-(trimethylsilyl)pyridine
(14b). A dry flask was charged with acrylate 8 (100 mg, 0.3 mmol)
and dissolved in PhMe (1 mL). The reaction flask was fitted with a
water condenser, and PPh3 (78 mg, 0.3 mmol) was added in one
portion at room temperature. After gas evolution steadied, the
reaction mixture was heated to reflux for 2 h using an aluminum
heating block. The reaction was allowed to cool to 60 °C before
adding TMS acetylene (206 mg, 2.1 mmol) and one drop (10 μL) of
triethylamine. The reaction temperature was heated to reflux and
allowed to stir for an additional 16 h. The reaction mixture was cooled
to room temperature and concentrated in vacuo. 1H NMR analysis of
the unpurified mixture revealed a 1:6 mixture of regioisomeric
pyridine products. This mixture was purified by flash column
chromatography on silica gel (gradient elution: 0% EtOAc to 30%
EtOAc in hexanes), and the major isomeric pyridine 14b (42 mg, 0.12
mmol, 40% yield) was obtained as a yellow oil. An additional amount
(22 mg, 22% yield) of mixed fractions containing both 14a and 14b
was also obtained (1:1 ratio). A small amount of unreacted oxazinone
precursors 9 and 10 (26 mg, 21% yield, ca. 1:1 ratio) was also
isolated. Data for compound 14b: TLC (20% EtOAc in hexane), Rf:
0.80 (CAM); IR (film) 2974, 2929, 2895, 2883, 1607, 1510, 1246,
2-Oxo-2-phenylethyl (Z)-2-azido-3-(4-methoxyphenyl)-
acrylate (8). A dry flask was charged with acrylate 6 (1.00 g, 4.3
mmol) and dissolved in warm MeOH (25 mL). In a 25 mL
Erlenmeyer flask, LiOH (360 mg, 8.5 mmol) was dissolved in water
(17 mL). The aqueous solution was added to the reaction flask, and
the vessel was fitted with a Vigreux condenser and heated on an
aluminum heating block to 40 °C. After stirring for 15 h, the reaction
was cooled to room temperature, acidified with 1 M HCl, and
extracted with EtOAc (50 mL × 4). The combined organic layers
were washed with brine, dried over Na2SO4, and filtered.
Concentration in vacuo yielded the intermediate acrylic acid, which
was dissolved in butanone (14 mL). The flask was fitted with a
Vigreux condenser, and bromoacetophenone (824 mg, 4.1 mmol) and
K2CO3 (571 mg, 4.1 mmol) were added in one portion at room
temperature. The reaction was stirred for 3 h at 40 °C and then
cooled slightly prior to dilution of the mixture with 1:1 Et2O/hexanes
(20 mL) and filtration through Celite. The filtrate was concentrated in
vacuo, and the resulting solid was washed with cold 1:3 Et2O/hexanes
(10 mL × 3) using a Buchner filter to remove the small amount of
excess bromoacetophenone. After drying the solid under vacuum, the
resulting product 8 (1.09 g, 3.2 mmol, 78% yield) was obtained as a
light yellow solid that was used without further purification: mp:
113.4−115.8 °C; TLC (20% EtOAc in hexane) Rf: 0.50 (CAM); IR
1
1053, 1033, 692 cm−1; H NMR (400 MHz, CDCl3) 8.00−7.98 (m,
2H), 7.62 (s, 1H), 7.48−7.45 (m, 2H), 7.41−7.39 (m, 1H), 7.29−
7.25 (m, 2H), 7.15 (s, 1H), 6.85 (d, J = 8.0 Hz, 2H), 4.16 (s, 2H),
3.79 (s, 3H), 0.28−0.26 (m, 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 159.8, 158.0, 155.8, 151.3, 10.1, 132.1, 130.0, 128.6, 128.5, 127.1,
125.7, 122.4, 113.8, 55.2, 43.9. -1.6; exact mass calcd for
C22H25NOSiNa+ 370.1598, found 370.1598.
1
(film) 2114, 1693, 1595, 1259, 1176, 1026, 835, 732, 646, cm−1; H
(2-(4-Methoxybenzyl)-6-phenylpyridin-3-yl)methanol (15a)
and (2-(4-Methoxybenzyl)-6-phenylpyridin-4-yl)methanol
(15b). A dry flask was charged with acrylate 8 (50 mg, 0.15 mmol)
and dissolved in PhMe (1.0 mL). The flask was fitted with a water
condenser, and PPh3 (39.3 mg, 0.15 mmol) was added in one portion
at room temperature. After gas evolution steadied, the reaction
mixture was heated to reflux for 8 h using an aluminum heating block.
NMR (400 MHz, CDCl3) 7.95 (dd, J1 = 7.0 Hz, J2 = 1.6 Hz, 2H),
7.84 (d, J = 8.6 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (ap. T, J = 7.63
Hz, 2H), 7.09 (s, 1H), 6.92 (d, J = 9.0, 2H), 5.55 (s, 2H), 3.86 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.4, 163.2, 160.6, 134.1,
134.0, 132.6, 128.9, 127.8, 126.8, 125.9, 122.4, 113.9, 66.9, 55.3; exact
mass calcd for C18H15N3O4Na+ 360.0954, found 360.0945.
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The reaction was cooled to 90 °C before addition of propargyl alcohol
(16.8 mg, 0.3 mmol) and one drop (10 μL) of triethylamine. The
reaction temperature was heated to reflux and stirred for 6 h. After
cooling to room temperature, the reaction mixture was concentrated
17a and 17b was also obtained (7 mg, 4% yield). Data for compound
17b: TLC (20% EtOAc in hexane), Rf: 0.50 (CAM); IR (film) 2974,
2929, 2895, 2883, 1607, 1510, 1246, 1053, 1033, 692 cm−1; 1H NMR
(400 MHz, CDCl3) 8.05−8.02 (m, 2H), 7.65 (d, J = 0.8 Hz, 1H),
7.48−7.44 (m, 2H), 7.41−7.39 (m, 1H), 7.26 (d, J = 8.6 Hz, 2H),
7.11 (s, 1H), 6.85 (d, J = 8.6 Hz, 2H), 5.46 (s, 1H), 4.18 (s, 2H), 3.79
(s, 3H), 3.62−3.51 (m, 4H), 1.23 (t, J = 7.0 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.5, 158.1, 157.1, 148.8, 139.6, 131.8, 130.1,
128.8, 128.6, 119.3, 115.9, 113.9, 100.2, 61.3, 55.3, 44.0; exact mass
calcd for C24H27NO3H+ 378.2064, found 378.2063.
Methyl (Z)-2-azido-3-(3,4,5-trimethoxyphenyl)acrylate. A
dry flask was charged with sodium metal (0.5 g, 21.8 mmol) and
dissolved in MeOH (10 mL) with stirring at room temperature for 1 h
and cooled to −10 °C. 2,3,4-Trimethoxybenzaldehyde and
azidomethyl acetate were inserted into an addition funnel and diluted
with MeOH (10 mL), and the reagents were added dropwise to the
NaOMe/MeOH mixture over 20 min. The reaction was stirred at
−10 °C for 6 h and warmed to 5 °C over the course of 1 h. The
reaction was quenched with 1 M HCl and partitioned between a 1:1
mixture of Et2O/H2O (150 mL). The aqueous portion was removed
and extracted with additional Et2O (20 mL × 3). The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated. The resulting residue was purified by flash column
chromatography on silica gel (gradient elution: 2% EtOAc to 35%
EtOAc) to afford the acrylate product (1.28 g, 4.37 mmol, 43% yield)
as a light yellow crystal: TLC (20% EtOAc in hexane), Rf: 0.45
(CAM). Spectral data for the azido acrylate product are in agreement
with published data.17
2-Oxo-2-phenylethyl (Z)-2-azido-3-(3,4,5-trimethoxy-
phenyl)acrylate (19). A dry flask was charged with methyl (Z)-2-
azido-3-(3,4,5-trimethoxyphenyl)acrylate, the azidoacrylate (767 mg,
2.62 mmol), and dissolved in warm MeOH (5 mL) and THF (10
mL). In a 25 mL Erlenmeyer flask, LiOH (274 mg, 6.5 mmol) was
dissolved in water (13 mL). The aqueous solution was added to the
flask, and the reaction vessel was fitted with a Vigreux condenser and
stirred at 55 °C for 1.5 h using an aluminum heating block. After
cooling to room temperature, the reaction mixture was acidified with
1 M HCl and extracted with EtOAc (30 mL × 4). The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentration in vacuo. The resulting acrylic acid (700 mg, 2.5
mmol) was dissolved in butanone (11 mL), and the reaction flask was
fitted with a Vigreux condenser. To this reaction flask, bromoaceto-
phenone (636 mg, 3.2 mmol) and K2CO3 (450 mg, 3.3 mmol) were
added, and the reaction was warmed to 40 °C using an aluminum
heating block. After stirring for 7 h, the reaction was cooled slightly
and diluted with 1:1 Et2O/hexanes (20 mL) and filtered using a glass
frit and Celite. The filtrate was concentrated in vacuo, and the
resulting solid was washed with cold 1:3 Et2O/hexanes (3 × 10 mL)
using a Buchner filter to remove a small amount of excess
bromoacetophenone. The resulting acrylate 19 (801 mg g, 2.0
mmol, 50% yield) was obtained as a light yellow solid and used
without further purification: mp: 117.1−119.2 °C; TLC (20% EtOAc
in hexane) Rf: 0.25 (CAM); IR (film) 2938, 2122, 1712, 1695, 1417,
1242, 1221, 1124, 748, 688, 669 cm−1; 1H NMR (400 MHz, CDCl3)
7.97−7.94 (m, 2H), 7.67−7.63 (m, 1H), 7.55−7.51 (m, 2H), 7.14 (s,
2H), 7.05 (s, 1H), 5.57 (s, 2H), 3.91 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 191.2, 163.0, 152.8, 139.5, 134.1, 133.9, 128.9, 128.4,
127.7, 126.7, 123.8, 108.2, 67.0, 60.9, 56.1; exact mass calcd for
C20H19N3O6Na+ 420.1166, found 420.1165.
1
in vacuo. H NMR analysis of the unpurified mixture revealed a 1:5
mixture of regioisomeric pyridine products 15a and 15b. This mixture
was purified by flash column chromatography on silica gel (gradient
elution: 5% EtOAc to 45% EtOAc in hexanes). The resulting
pyridines 15a and 15b (31.6 mg, 0.10 mmol, 69% yield) proved
inseparable and were obtained as a yellow oil: TLC (20% EtOAc in
hexane), Rf: 0.10 (CAM); IR (film) 3289, 3059, 2908, 2833, 1608,
1560, 1508, 1417, 1244, 1176, 1029, 771 cm−1; 1H NMR (400 MHz,
CDCl3, data for 15a) 8.01−7.99 (m, 2H), 7.51 (s, 1H), 7.48−7.37
(m, 3H), 7.27−7.24 (m, 2H), 6.96 (s, 1H), 6.84 (d, J = 8.6 Hz, 2H),
4.66 (s, 2H), 4.16 (s, 2H) 3.78 (s, 3H); (1H NMR data for 15b)
8.05−8.03 (m, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.8 Hz,
1H), 7.48−7.37 (m, 3H), 7.19 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6
Hz, 2H), 4.66 (s, 2H), 4.23 (s, 2H), 3.75 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3, data for mixture of 15a and 15b) δ 161.5, 158.1,
157.1150.9, 139.5, 136.7, 131.7, 131.3, 130.2, 129.6, 128.81, 128.77,
128.7, 128.6, 127.0, 126.9, 118.6, 118.4, 115.5, 113.92, 113.91, 63.8,
61.9, 55.22, 55.21, 43.9, 41.0; exact mass calcd for C20H19NO2Na+
328.1308, found 328.1307.
3-((Benzyloxy)methyl)-2-(4-methoxybenzyl)-6-phenylpyri-
dine (16a) and 4-((Benzyloxy)methyl)-2-(4-methoxybenzyl)-6-
phenylpyridine (16b). A dry flask was charged with acrylate 8 (85
mg, 0.25 mmol) and dissolved in PhMe (1.5 mL). The flask was fitted
with a water condenser, and PPh3 (66 mg, 0.25 mmol) was added in
one portion at room temperature. After gas evolution steadied, the
reaction mixture was heated to reflux for 16 h using an aluminum
heating block. The reaction was allowed to cool to 90 °C before
addition of benzyl propargyl ether (74 mg, 0.5 mmol) and one drop
(10 μL) of triethylamine. The reaction temperature was returned to
reflux and stirred for 5 h. The reaction mixture was cooled to room
temperature and concentrated in vacuo. 1H NMR analysis of the
unpurified mixture revealed a 1:4 mixture of regioisomeric pyridine
products 16a and 16b. This mixture was purified by flash column
chromatography on silica gel (gradient elution: 5% EtOAc to 20%
EtOAc in hexanes). The resulting pyridines 16a and 16b (83 mg, 0.21
mmol, 70% yield) proved inseparable and were obtained as a yellow
oil: TLC (20% EtOAc in hexane), Rf: 0.50 (CAM); IR (film) 3057,
3032, 2833, 1603, 1558, 1510, 1244, 1178, 819, 777, 731, 694 cm−1;
1H NMR (400 MHz, CDCl3, data for 16a) 8.03−8.01 (m, 2H), 7.54
(s, 1H), 7.48−7.30 (m, 8H), 7.27−7.25 (m, 2H), 6.98 (s, 1H), 6.86
(d, J = 8.6 Hz, 2H), 4.56 (s, 2H), 4.53 (s, 2H), 4.17 (s, 2H) 3.79 (s,
3H); (1H NMR data for 16b) 8.06−8.05 (m, 2H), 7.74 (d, J = 7.8 Hz,
2H), 7.59 (d, J = 7.8 Hz, 2H), 7.48−7.30 (m, 8H), 7.13 (d, J = 8.6
Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.53 (d, J = 6.7 Hz, 2H), 4.21 (s,
2H), 3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3, data for the
mixture of 16a and 16b) δ 161.5, 158.2, 157.1, 148.6, 139.6, 137.7,
137.5, 131.8, 131.4, 130.2, 130.0, 129.8, 128.8, 128.76, 128.7, 128.5,
128.48, 127.9, 127.88, 127.84, 128.82, 127.1, 126.9, 119.5, 118.1,
116.3, 113.9, 113.7, 72.7, 72.65, 70.7, 68.9, 55.3, 55.2, 44.0, 40.8; exact
mass calcd for C27H25NO2Na+ 418.1778, found 418.1778.
4-(Diethoxymethyl)-2-(4-methoxybenzyl)-6-phenylpyridine
(17b). A dry flask was charged with acrylate 8 (150 mg, 0.44 mmol)
and dissolved in PhMe (3 mL). The flask was fitted with a water
condenser, and PPh3 (116.5 mg, 0.44 mmol) was added in one
portion at room temperature. After gas evolution steadied, the
reaction mixture was heated to reflux for 6 h using an aluminum
heating block. The reaction was cooled to 90 °C before addition of
propargylaldehyde diethyl acetal (85.5 mg, 0.67 mmol) and one drop
(10 μL) of triethylamine. The reaction temperature was returned to
reflux and stirred for 16 h, cooled to room temperature, and
1-(2-Phenyl-6-(3,4,5-trimethoxybenzyl)pyridin-4-yl)propan-
1-ol (22). A dry flask was charged with acrylate 19 (100 mg, 0.25
mmol) and dissolved in PhMe (1.75 mL). The flask was fitted with a
water condenser, and PPh3 (66 mg, 0.25 mmol) was added in one
portion at room temperature. After gas evolution steadied, the
reaction mixture was heated to reflux for 16 h using an aluminum
heating block. The reaction was cooled to 90 °C before adding 1-
pentyn-3-ol (42 mg, 0.5 mmol) and one drop (10 μL) of
triethylamine. The reaction temperature was returned to reflux and
stirred for 6 h. The reaction mixture was cooled to room temperature
and concentrated in vacuo. 1H NMR analysis of the unpurified
1
concentrated in vacuo. H NMR analysis of the unpurified mixture
revealed a 1:14 mixture of regioisomeric pyridine products. This
mixture was purified by flash column chromatography on silica gel
(gradient elution: 2% EtOAc to 20% EtOAc in hexanes) to afford
pyridine 17b (129.5 mg, 0.34 mmol, 78% yield) as a yellow oil.
Additionally, a small amount of the mixed product containing both
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J. Org. Chem. 2021, 86, 5863−5869

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pubs.acs.org/joc
Article
mixture revealed a 1:8 mixture of regioisomeric pyridine products.
This mixture was purified by flash column chromatography on silica
gel (gradient elution: 5% EtOAc to 40% EtOAc in hexanes) to afford
pyridine 22 (76.7 mg, 0.20 mmol, 78% yield) as a yellow oil: TLC
(40% EtOAc in hexane), Rf: 0.30 (CAM); IR (film) 3403, 2933, 1589,
Author
Nicole A. Carrillo Vallejo − Department of Chemistry, The
College of William & Mary, Williamsburg, Virginia 23187,
United States
1
1504, 1417, 1236, 1122, 972, 777.3, 723.3, 694.4 cm−1; H NMR
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00288
(400 MHz, CDCl3) 8.02 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 7.49−7.40
(m, 3H), 7.02 (s, 1H), 6.59 (s, 2H), 4.62 (t, J = 6.5 Hz, 1H), 4.15 (s,
2H), 3.83 (s, 9H), 2.02 (bs, 1H) 1.78−1.73 (m, 2H), 0.94 (t, J = 7.4
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.8, 157.1, 154.6,
153.1, 139.5, 136.4, 135.3, 128.8, 128.7, 127.0, 118.6, 115.4, 106.2,
74.6, 60.8, 56.1, 45.1, 31.7, 9.8; exact mass calcd for C24H27NO4Na+
416.1832, found 416.1830.
Pent-1-yn-3-yl benzoate (21b). A dry flask was charged with 1-
pentyn-3-ol (890 mg, 10.6 mmol) and dissolved in CH2Cl2 (45 mL).
Triethylamine and DMAP were added, and the reaction was allowed
to stir for 5 min. The reaction temperature was cooled to 0 °C, and
benzoyl chloride was added dropwise. The mixture stirred for 30 min,
warmed to room temperature, and stirred for 1 h. The reaction
mixture was acidified with 1 M HCl (11 mL) and water (15 mL) and
extracted with CH2Cl2 (30 mL × 4). The combined organic layers
were washed with sat. aqueous NaHCO3 (10 mL × 2), brine, dried
over Na2SO4, and filtered and concentrated. The resulting residue was
purified by flash column chromatography on silica gel (gradient
elution: 0% EtOAc to 20% EtOAc). The resulting alkyne product 21b
(1.61 g, 8.55 mmol, 81% yield) was obtained as a colorless oil: TLC
(10% EtOAc in hexanes), Rf: 0.60 (CAM). Spectral data for the
alkyne 21b are in agreement with published data.18
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge support from the National Institutes
of Health (R15GM107702 to J.R.S.). N.A.C.V. acknowledges
the Arnold and Mabel Beckman Foundation for research
support.
REFERENCES
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(CAM); IR (film) 2966, 2936, 1716, 1589, 1450, 1419, 1269, 1240,
1122, 1107, 1070, 711, 694 cm−1; 1H NMR (400 MHz, CDCl3) 8.05
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00288.
■
sı
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for all new compounds (PDF)
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Chemistry of 1,2,4-Triazines. In Advances in Heterocyclic Chemistry;
Katrizky, A. R., Ed. Elsevier Academic Press, 2010; 100, 75−100.
AUTHOR INFORMATION
Corresponding Author
■
Jonathan R. Scheerer − Department of Chemistry, The
College of William & Mary, Williamsburg, Virginia 23187,
United States; orcid.org/0000-0003-3283-0220;
Email: jrscheerer@wm.edu
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