Organocatalytic aza-Michael Reaction to 3-Vinyl-1,2,4-triazines as a Valuable Bifunctional Platform

Article abstract of DOI:10.1021/acs.joc.9b00141

An unprecedented catalytic aza-Michael addition to substituted 3-vinyl-1,2,4-triazines, as original bifunctional platforms for the domino conjugate addition inverse-electron-demand hetero-Diels-Alder/retro-Diels-Alder (ihDA/rDA) reaction, was achieved using the highly acidic triflimide as an organocatalyst. Based on the use of alkoxyamine nucleophiles, this sequence not only highlights a rare example of the catalytic aza-Michael reaction to alkenylazaarenes but also proves to be useful for the elaboration of an array of biorelevant tetrahydro-[1,6]-naphthyridines.

Full text of DOI:10.1021/acs.joc.9b00141

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Note
Organocatalytic aza-Michael Reaction to 3-Vinyl-1,2,4-
Triazines as a Valuable Bifunctional Platform
Floris Buttard, Clément Berthonneau, Marie-Aude Hiebel, Jean-François Brière, and Franck Suzenet
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00141 • Publication Date (Web): 22 Feb 2019
Downloaded from http://pubs.acs.org on February 23, 2019
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Organocatalytic aza-Michael Reaction to 3-Vinyl-1,2,4-Triazines as a Valuable
Bifunctional Platform
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Floris Buttard,a Clément Berthonneau,b Marie-Aude Hiebel,a Jean-François Brière,b* and
Franck Suzeneta*
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a
Universitꢀ d’Orlꢀans, CNRS, ICOA, UMR 7311, 45067 Orlꢀans, France.
Phone: (+33)-2-3849-4580; E-mail: franck.suzenet@univ-orleans.fr
b
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France.
Phone: (+33)-2-3552-2464; e-mail: jean-francois.briere@insa-rouen.fr.
An unprecedented catalytic aza-Michael addition to substituted 3-vinyl-1,2,4-triazines, as
original bifunctional platforms for domino conjugate addition-ihDA/rDA reaction, was
achieved using the highly acidic triflimide as organocatalyst. Based on the use of
alkoxyamine nucleophiles, this sequence not only highlights a rare example of catalytic aza-
Michael reaction to alkenylazaarenes but proved to be useful for the elaboration of an array of
biorelevant tetrahydro-[1,6]-naphthyridines.
Medicinal chemistry and chemical biology are currently seeking original heterocyclic
scaffolds as biological tools. Accordingly, the development of new synthetic methodologies
aiming at exploring chemical space, while increasing molecular diversity and complexity, is a
current concern in organic synthesis.1 The construction of fused non-aromatic/heteroaromatic
bicycles has emerged as a promising strategy furnishing unprecedented potent bioactive
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molecules.2 The tuning of the selectivity and properties such as solubility was allowed by
changing aromatic polycyclic drug candidates into partially saturated ones.3 Additionally, by
escaping the flatland, the presence of sp3 hybridized carbons and chiral stereocenters within
bioactive compounds maximizes the on-target profile, which decreases the risk of toxicity
issues in the clinic setting.4 However, the introduction of substituents on the saturated moiety
of fused non-aromatic/heteroaromatic bicycles remains a challenging synthetic task.
We recently introduced 3-vinyl-1,2,4-triazines 1 behaving as (1) an original Michael acceptor
belonging to the alkenylazaarene series,5,6 and (2) an aza-diene during the subsequent
intramolecular domino inverse-electron-demand hetero-Diels–Alder/retro-Diels-Alder
(ihDA/rDA) reaction (Scheme 1a).7,8 This versatile platform 1 gave access to non-
aromatic/heteroaromatic bicycles8 displaying a privileged pyridine scaffold9,10,11 flanked by a
saturated carba8c and thia-ring.8a In a recent aza-Michael based extension (Nu = N), platform
1 furnished a novel entry to tetrahydro-[1,6]-naphthyridines (Scheme 1b).8b
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Scheme 1. Context of the investigation
While this preliminary investigation afforded various derivatives functionalized on the
pyridine ring, only a few substituents (i.e. methyl) were distributed on the saturated moiety.
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Indeed, the 1,4-conjugate addition to 1 proved to be more challenging when the vinyl moiety
is substituted. The reaction proceeded with high temperature or an excess of Lewis acid which
poses compatibility issues with the subsequent (ihDA/rDA) reaction.8b To overcome this
limited reactivity, an improved catalytic aza-Michael reaction was sought which would also
provide a new route to diversely substituted tetrahydro-[1,6]-naphthyridines. Importantly,
despite the importance of this non-aromatic/heteroaromatic bicycles in medicinal chemistry,
the reported syntheses addressed in some cases the substitution at C5 position (R5),12 but the
strategies allowing the introduction of R3-4 remains rather limited.13
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The conjugate addition reactions to alkenylazaarenes have elicited useful synthetic
applications in organic synthesis,5 but the catalytic versions appeared only recently. Apart
from metal-based catalysis,5a a few elegant organocatalytic approaches,14,15,16 emerged to
activate vinyl-derived pyridines (X = CH), diazole (X = N), -oxazole (X = O) and thiazole (X
= S) compounds toward 1,4-conjugate addition reaction (Scheme 1a). Meanwhile, the
catalytic aza-Michael reaction to alkenylazaarenes has remained elusive,5,17,18 until the recent
asymmetric catalytic 1,4-conjugated addition of pyrazole-heterocycle derivatives to
alkenylbenzimidazoles (X = N) described by the group of Terada.14c Recently, Watson and
colleagues reported an original catalytic and enantioselective aza-Michael-protonation
reaction of aniline-derivatives to α-substituted vinyl-pyridines and derivatives (R3 = Ar, R4 =
H, X = CH, S, O) in the presence of phosphoric acids.19
3-Vinyl-1,2,4-triazines 1 are novel platforms in this field of catalytic Michael reactions.20
Herein, we are pleased to disclose an original Brønsted acid catalyzed aza-Michael reaction of
alkoxyamine nucleophiles 2 to variously substituted 3-vinyl-1,2,4-triazines 1 (Scheme 1c).
This organocatalytic approach not only overrides the previous limitation regarding the access
of adducts 3 but also expands the scope for the subsequent construction of tetrahydro-[1,6]-
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naphthyridines 4 diversely substituted on the saturated ring thanks to a straightforward
ihDA/rDA sequence.
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We previously observed the conjugate addition reaction of N-methylbenzylamine 2a to
unsubstituted 3-vinyl-1,2,4-triazine in MeOH at 30 °C to give adduct 3a in quantitative yield
(Table 1, entry 1).8b
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TABLE 1. Proof of principlea
Entry 1 (R1)
Amine (R2) Solvent Cat. Product (%)b
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1a (H)
2a (Me)
MeOH
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
-
-
99% (3a)
Traces
0
0
0
1b (Me) 2a (Me)
1b (Me) 2a (Me)
1b (Me) 2b (H)
1b (Me) 2c (Ph)
1b (Me) 2d (OMe)
1b (Me) 2d (OMe)
1b (Me) 2e (Cbz)
1b (Me) 2f (NMe2)
CSA
CSA
CSA
CSA 72c (3b)
-
0
0
0
CSA
CSA
aReaction performed on 0.1 mmol of 3-vinyl-1,2,4-triazine 1a-b
(0.1 M in solvent), with amines 2 (1.5 equiv). b 1H NMR yield
with an internal standard. c 28% of starting material 1b remained.
CSA = (1S)-10-Camphorsulfonic acid.
However, this smooth reactivity was not adapted to more hindered 3-vinyl-1,2,4-triazines
such as 1b giving only traces of the corresponding adduct (entry 2). In line with the use of
phosphoric acid in this field,14b-d,19 we foresaw that a more effective organocatalytic activation
of the Michael acceptor 1b would take place with a sufficiently strong acid catalyst through
protonation of the triazine ring of 1b. However, a Brønsted acid organocatalyst in the
presence of a moderately basic triazine moiety may competitively lead to a non-productive
protonation of either the amine 2 or the aza-Michael adduct 3. First of all, we used camphor
sulfonic acid (CSA, 20 mol%) as catalyst in acetonitrile with benzylamines 2a-d bearing
different N-functional groups (entries 3-6). While no transformation was observed with
amines 2a-c (entries 3-5), which possess carbon-based substituents, the methoxyamine
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nucleophile 2d (entry 6) led to the desired aza-Michael adduct 3b in a promising 72% NMR
yield. The CSA catalyst appeared to be essential for this transformation (entry 7), as well as
the NHOMe motif since no aza-Michael reaction took place with NHCbz 2e or hydrazine 2f
nucleophiles (entries 8-9). Although the exact mechanism deserves further investigations, it
can be assumed that the moderate basicity of the methoxyamine 2d minimizes its competitive
(non-productive) protonation versus the protonative-activation of triazine 1b while keeping a
sufficiently nucleophilic character (in comparison to RNHCbz 2e for instance) to secure the
conjugate addition process.
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TABLE 2. Catalyst screeninga
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Entry Catalyst Time (h) Solvent
(mol%)
Product 3b (%)b
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A (20)
B (20)
C (20)
D (20)
E (20)
E (20)
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E (20)
E (20)
E (20)
E (10)
E (5)
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3
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3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
CHCl3
Et2O
toluene
toluene
toluene
0
0
72
45
90 (81)c
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99
89
28
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aReaction performed on 0.1 mmol of 3-vinyl-1,2,4-triazine
1b (0.1 M in solvent), with amine 2d (1.5 equiv). b 1H NMR
yield with an internal standard. cIsolated yield after silica
gel column chromatography.
With this preliminary result in hand, different kind of organocatalysts (20 mol%) were
subsequently evaluated with methoxybenzylamine nucleophile 2d (Table 2, see supporting
information for further details). It was demonstrated that neither Brønsted bases such as DBU
A (entry 1), nor Schreiner’s type catalyst B (entry 2), as a hydrogen bond donor species, were
capable to provide any Michael-adduct. Brønsted acid catalysts, as expected, allowed the
formation of adduct 3b (entries 3-5). Interestingly, the efficiency of the reaction was directly
correlated to the acidity of the catalyst. Lower activity was observed with phosphoric acid D
(45%, entry 6, pKa  3.8 in DMSO) with regard to CSA C (72%, entry 5, pKa  1.6 in
DMSO). Eventually, the highly acidic triflimide E proved to be the more potent
organocatalyst (entry 5),21,22 allowing the formation of product 3b with an excellent 90%
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NMR yield after 24 hours reaction (81% isolated yield). Solvent optimization (entries 6-11)
revealed that diethyl ether (entry 10), as a less polar solvent, gave the best conversions
together with toluene in 3 hours (entry 7), which secured an excellent 99% NMR yield after
24 hours (entry 11). In these conditions, the triflimide catalyst E loading was decreased to 10
mol% with a minor impact on efficiency (entry 12, 89% yield) whereas a limit was reached
with 5 mol% of E (entry 13, 28% yield after 24 hours).
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We subsequently evaluated the scope of the optimal conditions (20 mol% of HNTf2 E in
toluene for 24 hours) by focusing on vinyl-triazines 1 with various substituents on the vinyl
moiety (Figure 1). The precursors 1 were readily synthesized by means of a Liebeskind-Srogl-
type coupling reaction23 between alkenyl-boronic acid derivatives and 3-thiomethyl-
funtionalized triazines24 in line with our previous developments.8 The conjugated addition
reaction proceeded uneventfully with substrates possessing α- or β-substituted alkenes giving
rise to adducts 3b and 3c with methyl group in 97% and 77% isolated yields, respectively. For
comparison, we previously showed that the 2-propenyl platform 3c required a large excess of
BF3.OEt2 at refluxing THF to undergo the aza-Michael reaction.8b Interestingly, an alcohol
pendant was also tolerated with the catalytic conditions (3d, 85%). More hindered β-n-pentyl
3e (79%), -cyclopropyl 3f (46%) and -benzyl 3g (39%) were also good substrates even if they
required longer reaction times for completion (72-96 h). Due to instability issues on silica-gel
column chromatography, 3g was isolated in a moderate isolated 39% yield although 80% was
1
estimated by H NMR with an internal standard. Limitations were observed with more
hindered cyclohexyl (3h) or phenyl (3i) derivatives. It was also proven that the reaction
occurred efficiently with triazines flanked by various substituents such as 5-methyl (3j-73%),
5-CF3 (3k-79%) or 5,6-diMe (3l-87%). The more challenging 5,6-unsubstituted triazine 1m,
as a less stable platform, was also transformed into 3m with a promising 39% yield. The aza-
Michael reaction was also extrapolated either to propargylamine nucleophiles 2g-h and
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primary BnONH2 2i to furnish the corresponding adducts 3n-3p in very good yields (81-
91%), and up to 1.1 mmol scale for product 3n (88% isolated yield).
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a
Figure 1. Scope and limitations of the aza-Michael reaction. Reaction performed on 0.1 mmol of 3-vinyl-
1,2,4-triazines 1 (0.1 M), with amines 2 (1.5 equiv) in 24 hours. Isolated yield after silica gel column
chromatography. b 1H NMR yield determined by an internal standard into bracket. Carried out on 1.1 mmol
c
scale.
In order to address the synthesis of tetrahydro-[1,6]-naphthyridines such as 4a, we
investigated the ihDA/rDA sequence with the model substrate 3q (Figure 2). The hetero-
Diels-Alder reaction proceeded rapidly in 2 hours when 180 °C heating was carried out
conveniently upon microwave (MW) irradiation. These conditions furnished 4a in a complete
conversion and high 95% yield up to 1.7 mmol scale. Importantly, it was observed that the
pyridine product 4a, or an intermediate derived thereof, were unstable upon longer heating
time, as evidenced by a 79% yield obtained after 3 hours at 180 °C (Figure 2), showing the
importance of mastering this cycloaddition step.
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Figure 2. Optimization and prospective of the domino ihDA/rDA reaction. Conditions: starting material 3q
in CF3Ph (0.1 M) was heated under microwave irradiation (MW). a 1H NMR yield determined by an internal
standard. bIsolated yield on 1.7 mmol scale after column chromatography.
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Given this stability issue, a sequential aza-Michael reaction with a complete transformation
followed by a well-controlled ihDA/rDA sequence upon heating in 2 hours was conducted in
order to synthesize novel tetrahydro-[1,6]-naphthyridines 4 (Figure 3).8b
a
Figure 3. Scope and limitations of the domino sequential aza-Michael-ihDA/rDA reaction. Reaction
performed on 0.3 mmol of 3-vinyl-1,2,4-triazines 1 (0.1 M), with propargylamines 2g-h (1.5 equiv) in 24 hours.
b
Isolated yield after silica gel column chromatography (over two steps). 1H NMR yield determined by an
internal standard into bracket. cCarried out on 1 mmol scale for 90 hours.
This one-pot process was carried out in trifluorotoluene, as a microwave friendly solvent.
Early attempts demonstrated that the presence of triflimide E led to major decomposition
events during the cycloaddition process at high temperature. To prevent this acid promoted
degradation, K2CO3 (1 equivalent) was added before the cycloaddition step allowing an
efficient one-pot process (see experimental section) towards the formation of a series of novel
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tetrahydro-[1,6]-naphthyridines 4b-j flanked by various substituents as depicted in Figure 3,
with good to excellent overall yields (55-93%). Even the more challenging 5,6-unsubstituted
triazine starting material 1m gave the corresponding product 4k in 27% yield in two steps.
Interestingly, the N-OBn derived product 4l (via adduct 3n) was also accessible albeit in a
moderate 30% isolated yield, likely due to decomposition events.
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Finally, in order to further exploit the new and valuable pyridine derivatives 4 in medicinal
chemistry programs for example, we turned our attention to converting representative
methoxyamine derived products 4 into the secondary amines 5. A straightforward N-O bond
cleavage took place in the presence of SmI2, according to Brandi’s procedure,25 opening the
access to NH-tetrahydro-[1,6]-naphthyridines 5a-c with yields ranging from 70% to 84%
(Scheme 2).
Scheme 2. N-O bond cleavage by SmI2
In summary, the first catalytic aza-Michael reaction to substituted 3-vinyl-1,2,4-triazines 1
was achieved by means of the strong triflimide acid E as organocatalyst in the presence of
alkoxyamines 2. This approach shows a rare example of catalytic aza-Michael reaction to
alkenylazaarene derivatives, and markedly broadens the scope of triazine aza-Michael adducts
3 accessible from various substituents on the vinyl moiety. Thanks to the unique dual
reactivity of platform 1, the subsequent ihDA/rDA reaction took place in a convenient one-
pot fashion from the corresponding propargylamines 2 allowing the elaboration of various
biorelevant tetrahydro-[1,6]-naphthyridine derivatives 4. Investigations towards an
enantioselective version are currently in progress.
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Experimental Section
General Remarks
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Unless otherwise specified, all reagent-grade chemicals and solvents commercially available
were used without further purification. The reactions were monitored by thin-layer
chromatography (TLC) using aluminum sheets coated with silica gel 60 F254. Flash column
chromatography was carried out using silica gel 60 ꢁ (0.04−0.06 mm). Solvents mentioned as
dry were purified with a dry station GT S100 immediately prior to use. Microwave irradiation
experiments were performed on a Monowave 300 single-mode microwave reactor (Anton
Paar GmbH) using standard 10 or 30 mL Pyrex vessels (G10 or G30) equipped with Teflon-
coated magnetic stir bar and closed with snap cap and silicone septum. The microwave
apparatus has to be equipped with a safety pressure shutoff. Experiments carried out on 0.3
mmol scale of triazine in a 10 mL vial can generate 6–9 bars of pressure. NMR spectra were
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13
recorded with a 250 MHz (1H: 250 MHz and C: 63 MHz) or 400 MHz (1H: 400 MHz and
13C: 100.7 MHz) Bruker spectrometer. Unless noted the spectra were recorded at 25 °C.
Chemical shifts are given in parts per million (ppm) from tetramethylsilane (TMS), calibrated
to the residual solvent peak. Coupling constants “J” are expressed in hertz (multiplicity: s =
singlet, br s = broad singlet, d = doublet, dd = double doublet, dt = double triplet, t = triplet, q
= quartet, p = pentuplet, h = hexuplet, hept = heptuplet, m = multiplet …). The 13C NMR peak
assignments have been confirmed using Heteronuclear Multiple Bond Correlation (HMBC)
and Distortionless Enhancement by Polarization Transfer (DEPT-135) experiments. High-
resolution accurate mass measurements (HRAM) were performed on a Bruker maXis mass
spectrometer by the "Fédération de Recherche" ICOA/CBM (FR2708) platform using an
electrospray ionization source (ESI) in positive mode and a time-of-flight (TOF) analyzer.
Melting points were measured in open capillary tubes. The infrared spectra were recorded on
a FT-IR Thermo Scientific Nicolet iS10 and maximum absorption wavenumbers 휈max are
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given in cm-1.
5
6
3-(methylthio)-1,2,4-triazine,26
3-(methylthio)-5-(trifluoromethyl)-1,2,4-triazine,10e
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N-Benzyl-O-methylhydroxylamine 2d,27 benzyl N-benzylcarbamate 2e28 and 2-benzyl-1,1-
dimethylhydrazine 2f29 were synthetized according to literature procedures. 3-(methylthio)-5-
phenyl-1,2,4-triazine,6 5,6-dimethyl-3-(methylthio)-1,2,4-triazine,8b 3-vinyl-1,2,4-triazine 1a,6
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(E)-5-phenyl-3-(prop-1-en-1-yl)-1,2,4-triazine
1b,8b
5-phenyl-3-(prop-1-en-2-yl)-1,2,4-
triazine 1c8b and (E)-3-(5-phenyl-1,2,4-triazin-3-yl)prop-2-en-1-ol 1d8b were synthetized as
previously described.
5-methyl-3-(methylthio)-1,2,4-triazine
A solution of S-methylthiosemicarbazide iodohydrate (11.7 g, 50.2 mmol) in 50 mL of water
at 0 °C was added to a stirred solution of pyruvaldehyde (40% in water, 9.2 mL, 61 mmol, 1.2
equiv) and sodium carbonate (5.8 g, 55 mmol, 1.1 equiv) at 0 °C. The mixture was then
stirred at room temperature for 6 hours. The resulting aqueous media was extracted with
dichloromethane (3 × 100 mL) and the combined organic extracts were dried over magnesium
sulfate and concentrated on rotary evaporator. 3.86 g (55% yield) of the spectroscopically
pure triazine were obtained after recrystallization from a 9:1 isopropanol/heptane mixture as a
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brown solid. H NMR (250 MHz, chloroform-d): δH 8.81 (s, 1H), 2.67 (s, 3H), 2.49 (s, 3H).
13C{1H} NMR (63 MHz, chloroform-d): δC 173.5 (C), 159.0 (C), 146.0 (CH), 21.8 (CH3),
14.0 (CH3). ESI+-HRAM: m/z calculated for [C5H8N3S]+ ([M+H]+) 142.043345, found
142.043308. IR (neat): 휈max 3006, 2928, 1544, 1422, 1249. mp = 72-73 °C.
General procedure A for 3-vinyl-1,2,4-triazines (1) synthesis from boronic acid pinacol
esters
3-methylthio-1,2,4-triazine, copper(I) 3-methylsalicylate (2.2 equiv) and vinylboronic acid
pinacol ester (2.2 equiv) were dissolved in dry and degassed tetrahydrofuran (0.1 M of
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triazine) under argon atmosphere. The solution was degassed by argon bubbling for 15
minutes before tetrakis(triphenylphosphine)palladium (5 mol%) was added. The mixture was
subjected to argon bubbling for extra 15 minutes and subsequently heated up to reflux during
20 to 42 hours. Once cooled down to room temperature, the reaction mixture was filtered
through a pad of diatomaceous earth. A 0.3 M aqueous solution of sodium bicarbonate was
then added to the filtrate and the mixture was extracted with dichloromethane (three times).
The combined organic layers were dried over magnesium sulfate and concentrated on rotary
evaporator. The expected substituted 3-vinyl-1,2,4-triazine was finally isolated after silica gel
column chromatography.
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General procedure B for 3-vinyl-1,2,4-triazines (1) synthesis from boronic acids.
3-methylthio-5-phenyl-1,2,4-triazine, copper(I) 3-methylsalicylate (2.2 equiv) and
vinylboronic acid (2.2 equiv) were dissolved in a degassed 9:1 tetrahydrofuran/water mixture
(0.1 M of triazine) under argon atmosphere. The solution was degassed by argon bubbling for
15 minutes before tetrakis(triphenylphosphine)palladium (5 mol%) was added. The mixture
was subjected to argon bubbling for extra 15 minutes and subsequently heated up to reflux
during 20 to 48 hours. Once cooled down to room temperature, the reaction mixture was
filtered through a pad of diatomaceous earth. A 0.3 M aqueous solution of sodium bicarbonate
was then added to the filtrate and the mixture was extracted with dichloromethane (three
times). The combined organic layers were dried over magnesium sulfate and concentrated on
rotary evaporator. The attempted substituted 3-vinyl-1,2,4-triazine was finally isolated by
silica gel column chromatography.
(E)-3-(hept-1-en-1-yl)-5-phenyl-1,2,4-triazine (1e).
Following the general procedure A from 3-methylthio-5-phenyl-1,2,4-triazine (500 mg, 2.46
mmol) and hept-1-en-1-ylboronic acid pinacol ester (1.22 g, 5.41 mmol, 2.2 equiv)30 for 24
hours, the title compound (429 mg, 69% yield) was obtained as a yellow oil after purification
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by column chromatography (eluent = 9:1 petroleum ether/ethyl acetate, Rf = 0.2).
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1H NMR (400 MHz, chloroform-d): δH 9.46 (s, 1H), 8.23 – 8.16 (m, 2H), 7.63 – 7.53 (m, 3H),
7.46 (dt, J = 15.6, 7.0 Hz, 1H), 6.82 (dt, J = 15.7, 1.5 Hz, 1H), 2.39 (qd, J = 7.2, 1.6 Hz, 2H),
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1.65 – 1.53 (m, 2H), 1.43 – 1.34 (m, 4H), 0.98 – 0.85 (m, 3H). C{1H} NMR (101 MHz,
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chloroform-d): δC 163.7 (C), 155.0 (C), 144.9 (CH), 143.9 (CH), 134.0 (C), 132.4 (CH), 129.5
(2 CH), 127.7 (2 CH), 127.0 (CH), 33.1 (CH2), 31.6 (CH2), 28.4 (CH2), 22.7 (CH2), 14.2
(CH3). ESI+-HRAM: m/z calculated for [C16H20N3]+ ([M+H]+) 254.165174, found
254.165147. IR (neat): 휈max 2955, 2927, 2856, 1538, 1501, 1366, 765, 689.
(E)-3-(2-cyclopropylvinyl)-5-phenyl-1,2,4-triazine (1f).
Following the general procedure A from 3-methylthio-5-phenyl-1,2,4-triazine (456 mg, 2.25
mmol) and 2-cyclopropylvinylboronic acid pinacol ester (1.00 g, 4.95 mmol, 2.2 equiv) for 24
hours, the title compound (315 mg, 63% yield) was obtained as yellow solid after purification
by silica gel column chromatography (eluent = 8:2 petroleum ether/ethyl acetate, Rf = 0.4).
1H NMR (400 MHz, chloroform-d): δH 9.42 (s, 1H), 8.22 – 8.12 (m, 2H), 7.63 – 7.50 (m, 3H),
6.99 – 6.83 (m, 2H), 1.85 – 1.71 (m, 1H), 1.06 – 0.94 (m, 2H), 0.79 – 0.68 (m, 2H). 13C{1H}
NMR (101 MHz, chloroform-d): δC 163.6 (C), 154.9 (C), 149.1 (CH), 143.6 (C), 134.0 (C),
132.3 (CH), 129.4 (2 CH), 127.6 (2 CH), 124.2 (C), 15.4 (CH), 8.8 (2 CH2). ESI+-HRAM:
m/z calculated for [C14H14N3]+ ([M+H]+) 224.118224, found 224.117939. IR (neat): 휈max
3057, 3010, 2926, 1645, 1537, 1508, 1283, 944, 761, 687. mp = 65 °C.
(E)-5-phenyl-3-(3-phenylprop-1-en-1-yl)-1,2,4-triazine (1g)
Following the general procedure B from 3-methylthio-5-phenyl-1,2,4-triazine (553 mg, 2.72
mmol) and (3-phenylprop-1-en-1-yl)boronic acid (1.00 g, 5.99 mmol, 2.2 equiv) for 36 hours,
the title compound (119 mg, 16% yield) was obtained as a yellow solid after purification by
silica gel column chromatography (eluent = 9:1 pentane/ethyl acetate, Rf = 0.4).
1H NMR (400 MHz, chloroform-d): δH 9.48 (s, 1H), 8.23 – 8.08 (m, 2H), 7.68 – 7.44 (m, 4H),
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7.38 – 7.23 (m, 5H), 6.86 (dt, J = 15.5, 1.6 Hz, 1H), 3.73 (dd, J = 7.0, 1.6 Hz, 2H). C{1H}
NMR (101 MHz, chloroform-d): δC 163.6 (C), 155.0 (C), 144.0 (CH), 142.6 (CH), 138.7 (C),
133.9 (C), 132.5 (CH), 129.5 (2 CH), 129.1 (2 CH), 128.8 (2 CH), 128.1 (CH), 127.7 (2 CH),
126.7 (CH), 39.4 (CH2). ESI+-HRAM: m/z calculated for [C18H16N3]+ ([M+H]+) 274.133874,
found 274.133688. IR (neat): 휈max 3053, 2911, 1539, 1508, 1316, 974, 693. mp = 63–64 °C.
(E)-3-(2-cyclohexylvinyl)-5-phenyl-1,2,4-triazine (1h)
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Following the general procedure A from 3-methylthio-5-phenyl-1,2,4-triazine (781 mg, 3.84
mmol) and (2-cyclohexylvinyl)boronic acid pinacol ester (2.00 g, 8.45 mmol, 2.2 equiv)30 for
24 hours, the title compound (164 mg, 16% yield) was obtained as an orange oil after
purification by silica gel column chromatography (eluent = dichloromethane, Rf = 0.2).
1H NMR (400 MHz, chloroform-d): δH 9.46 (s, 1H), 8.26 – 8.04 (m, 2H), 7.61 – 7.52 (m, 3H),
7.41 (dd, J = 16.0, 6.9 Hz, 1H), 6.77 (dd, J = 16.0, 1.5 Hz, 1H), 2.39 – 2.26 (m, 1H), 1.95 –
1.86 (m, 2H), 1.86 – 1.77 (m, 2H), 1.76 – 1.68 (m, 1H), 1.40 – 1.20 (m, 5H). C{1H} NMR
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(101 MHz, chloroform-d): δC 164.0 (C), 155.1 (C), 149.8 (CH), 143.8 (CH), 134.0 (C), 132.4
(CH), 129.4 (2 CH), 127.7 (2 CH), 124.7 (CH), 41.3 (CH), 32.3 (2 CH2), 26.2 (CH2), 26.1 (2
CH2). ESI+-HRAM: m/z calculated for [C17H20N3]+ ([M+H]+) 266.165174, found 266.165352.
IR (neat): 휈max 2923, 2850, 1537, 1503, 1360, 1282, 977, 689.
(E)-5-phenyl-3-styryl-1,2,4-triazine (1i).
Following the general procedure B from 3-methylthio-5-phenyl-1,2,4-triazine (203 mg, 1.00
mmol) and styrylboronic acid (326 mg, 2.2 mmol, 2.2 equiv) for 48 hours, the title compound
(71 mg, 27% yield) was obtained as a yellow oil after purification by silica gel column
chromatography (eluent = 9:1 petroleum ether/ethyl acetate, Rf = 0.2).
1H NMR (250 MHz, chloroform-d): δH 9.50 (s, 1H), 8.29 – 8.19 (m, 3H), 7.73 – 7.67 (m, 2H),
7.65 – 7.56 (m, 3H), 7.49 (d, J = 16.1 Hz, 1H), 7.49 – 7.37 (m, 3H). 13C{1H} NMR (63 MHz,
chloroform-d): δC 164.1 (C), 155.1 (C), 143.9 (CH), 140.1 (CH), 135.8 (C), 134.0 (C), 132.5
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(CH), 129.8 (CH), 129.5 (2 CH), 129.1 (2 CH), 128.1 (2 CH), 127.8 (2 CH), 124.7 (CH).
ESI+-HRAM: m/z calculated for [C17H14N3]+ ([M+H]+) 260.118224, found 260.118214. IR
(neat): 휈max 3056, 1636, 1537, 1505, 1451, 973, 767, 681.
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(E)-5-methyl-3-(prop-1-en-1-yl)-1,2,4-triazine (1j)
Following the general procedure A from 5-methyl-3-methylthio-1,2,4-triazine (370 mg, 2.62
mmol) and trans-1-propenylboronic acid pinacol ester (1.00 g, 5.77 mmol, 2.2 equiv) for 24
hours, the title compound (57 mg, 16% yield) was obtained as a light-yellow solid after
purification by silica gel column chromatography (eluent = gradient from dichloromethane to
9:1 dichloromethane/ethyl acetate, Rf (9:1 CH2Cl2/EtOAc) = 0.4).
1H NMR (400 MHz, chloroform-d): δH 8.89 (s, 1H), 7.31 (dq, J = 15.6, 6.9 Hz, 1H), 6.72 (dq,
J = 15.6, 1.7 Hz, 1H), 2.52 (s, 3H), 2.01 (dd, J = 6.9, 1.7 Hz, 3H). 13C{1H} NMR (101 MHz,
chloroform-d): δC 163.3 (C), 159.0 (C), 147.7 (CH), 139.4 (CH), 128.2 (CH), 22.0 (CH3),
18.7 (CH3). ESI+-HRAM: m/z calculated for [C7H10N3]+ ([M+H]+) 136.086924, found
136.086793. IR (neat): 휈max 3043, 2917, 1655, 1548, 1356, 1283, 965. mp = 77–79 °C.
(E)-3-(prop-1-en-1-yl)-5-(trifluoromethyl)-1,2,4-triazine (1k).
Following the general procedure A from 3-methylthio-5-trifluoromethyl-1,2,4-triazine (512
mg, 2.62 mmol) and trans-1-propenylboronic acid pinacol ester (1.00 g, 5.77 mmol, 2.2
equiv) for 24 hours, the title compound (349 mg, 67% yield) was obtained as volatile bright-
yellow liquid after purification by column chromatography (dry loading, eluent = gradient
from pentane to 95:5 pentane/diethyl ether, Rf (95:5 petr. eth./Et2O) = 0.5). N.B.: the solution
obtained after column chromatography should not be heated on rotary evaporator for
concentration (volatile compound).
1H NMR (400 MHz, chloroform-d): δH 9.37 (s, 1H), 7.52 (dq, J = 15.6, 7.0 Hz, 1H), 6.89 (dq,
J = 15.6, 1.8 Hz, 1H), 2.09 (dd, J = 7.0, 1.8 Hz, 3H). 13C{1H} NMR (63 MHz, chloroform-d):
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(CH), 120.1 (q, JC-F = 276.2 Hz, CF3), 18.8 (CH3). ESI+-HRAM: m/z calculated for
[C7H7F3N3]+ ([M+H]+) 190.058658, found 190.058495. IR (neat): 휈max 3050, 2973, 2858,
1418, 1199, 1144.
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(E)-5,6-dimethyl-3-(prop-1-en-1-yl)-1,2,4-triazine (1l).
Following the general procedure A from 5,6-dimethyl-3-methylthio-1,2,4-triazine (407 mg,
2.62 mmol) and trans-1-propenylboronic acid pinacol ester (1.00 g, 5.77 mmol, 2.2 equiv) for
20 hours, the title compound (373 mg, 95% yield) was obtained as a beige solid after
purification by silica gel column chromatography (eluent = 8:2 pentane/ethyl acetate, Rf =
0.3).
1H NMR (250 MHz, chloroform-d): δH 7.23 (dq, J = 15.6, 7.0 Hz, 1H), 6.69 (dq, J = 15.6, 1.7
Hz, 1H), 2.63 (s, 3H), 2.49 (s, 3H), 1.99 (dd, J = 7.0, 1.7 Hz, 3H). C{1H} NMR (63 MHz,
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chloroform-d): δC 162.2 (C), 158.3 (C), 155.1 (C), 137.8 (CH), 128.2 (CH), 22.0 (CH3), 19.6
(CH3), 18.6 (CH3). ESI+-HRAM: m/z calculated for [C8H12N3]+ ([M+H]+) 150.102574, found
150.102505. IR (neat): 휈max 3012, 2935, 2858, 1653, 1541, 1517, 995. mp = 41-42 °C.
(E)-3-(prop-1-en-1-yl)-1,2,4-triazine (1m).
Following the general procedure A from 3-methylthio-1,2,4-triazine (333 mg, 2.62 mmol) and
trans-1-propenylboronic acid pinacol ester (1.00 g, 5.77 mmol, 2.2 equiv) for 20 hours, the
title compound (172 mg, 54% yield) was obtained as yellow crystals after purification by
silica gel column chromatography (eluent = 8:2 pentane/ethyl acetate, Rf = 0.4).
1H NMR (250 MHz, chloroform-d): δH 9.01 (d, J = 2.4 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.34
(dq, J = 15.6, 6.9 Hz, 1H), 6.77 (dq, J = 15.6, 1.7 Hz, 1H), 2.03 (dd, J = 6.9, 1.7 Hz, 3H).
13C{1H} NMR (63 MHz, chloroform-d): δC 164.4 (C), 148.6 (CH), 147.2 (CH), 140.1 (CH),
128.1 (CH), 18.8 (CH3). ESI+-HRAM: m/z calculated for [C6H8N3]+ ([M+H]+) 122.071274,
found 122.071296. IR (neat): 휈max 3050, 3034, 2966, 2943, 2915, 1655, 1550, 1527, 1432,
1409, 1553. mp = 67 °C.
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240 mL of a 5 M hydrochloric acid solution (1.2 mol, 10 equiv) in a water/methanol mixture,
obtained by mixing 100 mL of a 37% aqueous hydrochloric acid solution and 140 mL of
methanol, were added to stirred N-(tert-butoxycarbonyl)-N-(propargyl)methoxyamine (21.5 g,
116 mmol, prepared according to literature procedure).31 The mixture was subsequently
refluxed for 3 hours (TLC monitoring using ethyl acetate as eluent). Once cooled down to
room temperature, reactional mixture was diluted with 150 mL of distilled water and 150 mL
of dichloromethane. Layers were separated, aqueous layer was washed with dichloromethane
(150 mL) and ethyl acetate (150 mL) and finally evaporated on rotatory evaporator and dried
under vacuum. The title ammonium salt was obtained as a white crystalline solid (8.71 g, 61%
yield).
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N-methoxypropargylamine hydrochloride (4.95 g, 40.7 mmol) was introduced in a 250 mL
round bottom flask with 125 mL of diethyl ether. 90 mL (2.2 equiv) of a 1 M sodium
hydroxide aqueous solution were then added and the biphasic mixture was vigorously stirred
for 15 minutes. Layers were separated, aqueous phase was extracted with diethyl ether (2 × 50
mL). Gathered organic extracts were dried over magnesium sulfate and concentrated on rotary
evaporator in a 0-5 °C cold bath. 3.28 g (95% yield) of the expected
N-methoxypropargylamine were obtained as a colorless liquid.
1H NMR (250 MHz, chloroform-d): δH 5.56 (t, J = 6.8 Hz, 1H), 3.67 (dd, J = 6.8, 2.5 Hz, 2H),
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(CH), 62.1 (CH3), 41.1 (CH2). ESI+-HRAM: the compound is too volatile to be detected.
O-benzyl-N-(prop-2-yn-1-yl)hydroxylamine (2h).
A 5 M hydrochloric acid solution in a water/methanol mixture (obtained by diluting 3.2 mL
of 37% aqueous hydrochloric acid in 4.4 mL of methanol, 7.6 mL, 38 mmol, 10 equiv) was
slowly added to tert-butyl (benzyloxy)(prop-2-yn-1-yl)carbamate (1.00 g, 3.83 mmol,
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prepared according to literature procedure)31 and the mixture was stirred 24 hours at room
temperature (TLC monitoring, eluent = 9:1 petroleum ether/EtOAc, Rf = 0.5). 15 mL of
dichloromethane were then added into the flask. After 15 minutes of stirring, phases were
separated, and aqueous layer was washed with 25 mL of dichloromethane. 25 mL of sodium
bicarbonate saturated aqueous solution were added to the aqueous phase which was
subsequently extracted with dichloromethane (2 × 25 mL). The combined organic extracts
were dried over magnesium sulfate and concentrated on rotary evaporator at room
temperature, affording the spectroscopically pure propargylamine 2h (455 mg, 74% yield).
1H NMR (250 MHz, chloroform-d): δH 7.44 – 7.25 (m, 5H), 5.52 (br s, 1H), 4.77 (s, 2H), 3.66
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(s), 2.25 (t, J = 2.5 Hz, 1H). C{1H} NMR (63 MHz, chloroform-d): δC 137.8 (C), 128.6 (2
CH), 128.61 (2 CH), 128.55 (CH), 80.3 (C), 76.5 (CH2), 72.0 (CH), 41.5 (CH2). ESI+-HRAM:
m/z calculated for [C10H12NO]+ ([M+H]+) 162.091340, found 162.091115. IR (neat): 휈max
3288, 2915, 2859, 1545, 697, 636.
General procedure C for the aza-Michael reaction to 3-vinyl-1,2,4-triazine. The
alkoxyamine derivative 2 (1.5 equiv) was added to a solution of 3-vinyl-1,2,4-triazines 1 (0.1-
1 mmol, 0.1 M) and trifluoromethanesulfonimide E (20 mol%) in toluene. The mixture was
stirred at room temperature until a complete conversion of starting material 1 was observed by
TLC. A saturated aqueous solution of sodium bicarbonate was then added and the organic
phase was separated. The aqueous layer was extracted by dichloromethane (twice). The
combined organic layers were dried over anhydrous magnesium sulfate and concentrated on
rotary evaporator. The crude product was purified by silica gel column chromatography to
yield the desired adduct 3. If required the yield was also estimated on the crude product by 1H
NMR thanks to dibenzylether (0.25 equiv.) as an internal standard.
N-benzyl-N-methyl-2-(5-phenyl-1,2,4-triazin-3-yl)ethan-1-amine (3a).
N-methybenzylamine (97%, 20 µL, 18.8 mg, 0.15 mmol, 1.5 equiv) was added into a solution
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of 5 phenyl-3-vinyl-1,2,4-triazine (18.3 mg, 0.10 mmol) in 1 mL of methanol. The mixture
was stirred at 30 °C for 24 hours, concentrated on rotary evaporator and purified by column
chromatography (eluent = 1:4 petroleum ether/ethyl acetate, Rf = 0.3) to afford the tittle
product (31 mg, 0.10 mmol, quantitative yield) as a yellow oil.
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1H NMR (400 MHz, chloroform-d): δH 9.55 (s, 1H), 8.17 – 8.10 (m, 2H), 7.63 – 7.51 (m, 3H),
7.24 – 7.15 (m, 5H), 3.59 (s, 2H), 3.40 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.32 (s,
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3H). C{1H} NMR (100.7 MHz, chloroform-d) δC 169.0 (C), 155.2 (C), 144.3 (CH), 139.1
(C), 133.8 (C), 132.5 (CH), 129.5 (2 CH), 129.1 (2 CH), 128.3 (2 CH), 127.8 (2 CH), 127.0
(CH), 62.2 (CH2), 55.7 (CH2), 42.2 (CH3), 35.5 (CH2). ESI+-HRAM: m/z calculated for
[C19H21N4]+ ([M+H]+) 305.176073, found 305.176150. IR (neat): 휈max 3058, 3027, 2788,
1601, 1544, 1508, 1495, 1445, 1319, 1075, 1046, 738, 690.
N-Benzyl-O-methyl-N-(1-(5-phenyl-1,2,4-triazin-3-yl)propan-2-yl)hydroxylamine (3b).
Following the general procedure C from 5-phenyl-3-(prop-1-en-1-yl)-1,2,4-triazine 1b (19.7
mg, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in 24 hours,
the title compound (32.4 mg, 97% yield) was obtained as a yellow oil after purification by
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column chromatography (9:1 pentane/AcOEt, Rf = 0.3). H NMR (400 MHz, chloroform-d):
δH 9.55 (s, 1H), 8.16–8.08 (m, 2H), 7.64–7.51 (m, 3H), 7.26–7.16 (m, 5H), 3.98 (d, J = 13.0
Hz, 1H), 3.83 (d, J = 13.0 Hz, 1H), 3.76 (h, J = 6.8 Hz, 1H), 3.61 (dd, J = 6.8, 13.8 Hz, 1H),
3.28 (s, 3H), 3.22 (dd, J = 6.8, 13.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100.7
MHz, chloroform-d): δC 169.0 (C), 155.0 (C), 144.1 (CH), 138.2 (C), 133.8 (C), 132.5 (CH),
129.6 (2 CH), 129.5 (2 CH), 128.2 (2 CH), 127.7 (2 CH), 127.2 (CH), 61.7 (CH3), 59.3 (CH),
58.0 (CH2), 41.5 (CH2), 14.6 (CH3). ESI+-HRAM: m/z calculated for [C20H23N4O]+ ([M+H]+)
335.186638, found 335.186339. IR (neat): 휈max 2968, 2929, 2853, 1729, 1544, 1508, 1445,
1317, 1049, 762, 732, 691.
N-benzyl-O-methyl-N-(2-(5-phenyl-1,2,4-triazin-3-yl)propyl)hydroxylamine
(3c).
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Following the general procedure A from 5-phenyl-3-(prop-1-en-2-yl)-1,2,4-triazine 1c (19.7
g, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in 24 hours,
the title compound (25.9 g, 77% yield) was obtained as a yellow oil after purification by
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column chromatography (eluent = pentane/EtOAc, Rf = 0.3). H NMR (400 MHz,
chloroform-d): δH 9.55 (s, 1H), 8.14 – 8.01 (m, 2H), 7.64 – 7.48 (m, 3H), 7.19 – 7.14 (m, 5H),
3.93 (d, J = 12.8 Hz, 1H), 3.84 – 3.75 (m, 1H), 3.77 (d, 12.8 Hz, 1H), 3.37 (dd, J = 12.9, 9.5
Hz, 1H), 3.33 (s, 3H), 2.93 (dd, J = 12.7, 5.1 Hz, 1H), 1.41 (d, J = 7.0 Hz, 3H). 13C{1H} NMR
(101 MHz, chloroform-d): δC 172.7 (C), 155.2 (C), 144.3 (CH), 137.4 (C), 134.0 (C), 132.4
(CH), 129.5 (2 CH), 129.4 (2 CH) 128.2 (2 CH), 127.7 (2 CH), 127.3 (CH), 63.3 (CH2), 62.9
(CH2), 61.0 (CH3), 40.0 (CH), 18.6 (CH3). ESI+-HRAM: m/z calculated for [C20H23N4O]+
([M+H]+) 335.186638, found 335.186299. IR (neat): 휈max 3060, 2971, 2934, 1542, 1508,
1319, 1049, 769, 692.
2-(benzyl(methoxy)amino)-3-(5-phenyl-1,2,4-triazin-3-yl)propan-1-ol (3d). Following the
general procedure C from 3-(5-phenyl-1,2,4-triazin-3-yl)prop-2-en-1-ol 1d (21.3 mg, 0.10
mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in 24 hours, the title
compound (29.8 mg, 85% yield) was obtained as a dark-yellow oil after purification by
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column chromatography (eluent = 1:1 pentane/EtOAc, Rf = 0.4). H NMR (400 MHz,
chloroform-d): δH 9.56 (s, 1H), 8.16 – 8.07 (m, 2H), 7.65 – 7.51 (m, 3H), 7.32 – 7.20 (m, 5H),
4.11 (d, J = 13 Hz, 1H), 4.02 (d, J = 13 Hz, 1H), 3.91 – 3.78 (m, 2H), 3.71 (dd, J = 14, 5.5 Hz,
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1H), 3.68 – 3.60 (m, 1H), 3.37 (s, 3H), 3.29 (dd, J = 14, 7 Hz, 1H), 2.91 (br s, 1H). C{1H}
NMR (101 MHz, chloroform-d): δC 168.6 (C), 155.2 (C), 144.2 (CH), 137.2 (C), 133.5 (C),
132.7 (CH), 129.7 (2 CH), 129.5 (2 CH), 128.4 (2 CH), 127.7 (2 CH), 127.6 (CH), 64.6 (CH),
62.3 (CH2), 62.2 (CH3), 58.9 (CH2), 34.7 (CH2). ESI+-HRAM: m/z calculated for
[C20H23N4O2]+ ([M+H]+) 351.181552, found 351.181459. IR (neat): 휈max 3381, 3061, 3030,
2934, 2891, 1545, 1509, 1445, 1319, 1039, 1002, 907, 734, 691.
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N-benzyl-O-methyl-N-(1-(5-phenyl-1,2,4-triazin-3-yl)heptan-2-yl)hydroxylamine
(3e).
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Following the general procedure C from 3-(hept-1-en-1-yl)-5-phenyl-1,2,4-triazine 1e (25.3
mg, 0.10 mmol) N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in 72 hours, the
title compound (31 mg, 79% yield) was obtained as a yellow oil after purification by column
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chromatography (eluent = 9:1 pentane/EtOAc, Rf (8:2 petroleum ether/EtOAc)= 0.6). H
NMR (400 MHz, chloroform-d): δH 9.54 (s, 1H), 8.15 – 8.11 (m, 2H), 7.63 – 7.51 (m, 3H),
7.27 – 7.15 (m, 5H), 3.96 (d, J = 13.2 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.66 – 3.51 (m, 2H),
3.27 (dd, J = 12.8, 5.2 Hz, 1H), 3.24 (s, 3H), 1.89 – 1.74 (m, 1H), 1.59 – 1.47 (m, 2H), 1.47 –
1.38 (m, 1H), 1.28 (m, 4H), 0.87 (t, J = 6.8 Hz, 3H). C{1H} NMR (101 MHz, chloroform-
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d): δC 169.6 (C), 154.9 (C), 143.9 (CH), 138.5 (C), 133.9 (C), 132.4 (CH), 129.5 (2 CH),
129.4 (2 CH), 128.1 (2 CH), 127.7 (2 CH), 127.1 (CH), 63.7 (CH), 61.3 (CH3), 57.4 (CH2),
38.3 (CH2), 32.0 (CH2), 30.4 (CH2), 26.7 (CH2), 22.7 (CH2), 14.2 (CH3). ESI+-HRAM: m/z
calculated for [C24H31N4O]+ ([M+H]+) 391.249238, found 391.249002. IR (neat): 휈max 2930,
2857, 1544, 1508, 1496, 1318, 1047, 1001, 907, 758, 731, 690.
N-benzyl-N-(1-cyclopropyl-2-(5-phenyl-1,2,4-triazin-3-yl)ethyl)-O-
methylhydroxylamine (3f). Following the general procedure A from 3-(2-cyclopropylvinyl)-
5-phenyl-1,2,4-triazine 1f (22 mg, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15
mmol, 1.5 equiv) in 96 hours, the title compound (17 mg, 46% yield) was obtained as a
yellow oil after purification by silica gel column chromatography (eluent = 95:5
CH2Cl2/EtOAc, Rf = 0.4). 1H NMR (400 MHz, chloroform-d): δH 9.55 (s, 1H), 8.23 – 8.03 (m,
2H), 7.63 – 7.52 (m, 3H), 7.25 – 7.15 (m, 5H), 4.13 (d, J = 13.1 Hz, 1H), 4.01 (d, J = 13.1 Hz,
1H), 3.71 (dd, J = 13.7, 8.3 Hz, 1H), 3.44 (dd, J = 13.7, 6.1 Hz, 1H), 3.24 (s, 3H), 2.90 (ddd, J
= 9.7, 8.3, 6.1 Hz, 1H), 1.28 – 1.15 (m, 1H), 0.69 (m, 1H), 0.48 (m, 1H), 0.41 (m, 1H), -0.05 –
-0.14 (m, 1H). 13C{1H} NMR (101 MHz, chloroform-d): δC 169.2 (C), 154.8 (C), 143.9 (CH),
138.5 (C), 133.9 (C), 132.4 (CH), 129.44 (2 CH), 129.39 (2 CH), 128.1 (2 CH), 127.7 (2 CH),
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127.0 (CH), 69.4 (CH), 61.6 (CH3), 58.5 (CH2), 40.3 (CH2), 11.6 (CH), 5.8 (CH2), 2.8 (CH2).
ESI+-HRAM: m/z calculated for [C22H25N4O]+ ([M+H]+) 361.202288, found 361.202518.
IR (neat): 휈max 3030, 2939, 2895, 1543, 1507, 1319, 1027, 691.
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N-benzyl-O-methyl-N-(1-phenyl-3-(5-phenyl-1,2,4-triazin-3-yl)propan-2-yl)-
hydroxylamine (3g). Following the general procedure C from 5-phenyl-3-(3-phenylprop-1-
en-1-yl)-1,2,4-triazine 1g (27 mg, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15
mmol, 1.5 equiv) in 96 hours, the title compound (15.9 mg, 39% yield) was obtained as a
yellow oil after purification by silica gel column chromatography (eluent = 95:5
CH2Cl2/EtOAc, Rf = 0.3). 1H NMR (400 MHz, chloroform-d): δH 9.47 (s, 1H), 8.08 – 8.01 (m,
2H), 7.62 – 7.49 (m, 3H), 7.25 – 7.18 (m, 4H), 7.15 (s, 5H), 7.15 – 7.10 (m, 1H), 4.06 (d, J =
13.1 Hz, 1H), 4.02 – 3.92 (m, 1H), 3.95 (d, J = 13.1 Hz, 1H), 3.55 (dd, J = 14.2, 8.3 Hz, 1H),
3.34 (dd, J = 13.7, 4.9 Hz, 1H), 3.30 (s, 3H), 3.27 (dd, J = 14.2, 5.8 Hz, 1H), 2.85 (dd, J =
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13.7, 9.1 Hz, 1H). C{1H} NMR (101 MHz, chloroform-d): δC 169.1 (C), 154.7 (C), 143.9
(CH), 139.8 (C), 138.0 (C), 133.8 (C), 132.4 (CH), 129.44 (CH), 129.42 (CH), 129.37 (CH),
128.5 (CH), 128.2 (CH), 127.7 (2 CH), 127.2 (2 CH), 126.1 (2 CH), 65.1 (CH), 61.4 (CH3),
57.7 (CH2), 38.7 (CH2), 35.7 (CH2). ESI+-HRAM: m/z calculated for [C26H27N4O]+ ([M+H]+)
411.217938, found 411.218212. IR (neat): 휈max 3028, 2939, 2179, 1544, 1508, 691.
N-benzyl-O-methyl-N-(1-(5-methyl-1,2,4-triazin-3-yl)propan-2-yl)hydroxylamine
(3j).
Following the general procedure C from 5-methyl-3-(prop-1-en-1-yl)-1,2,4-triazine 1j (13.5
mg, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in 30 hours,
the title compound (19.9 mg, 73% yield) was obtained as a yellow oil after purification by
column chromatography (eluent = 1:1 pentane/EtOAc, Rf = 0.4). N.B.: the mixture turned
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from yellow to dark brown after 1–2 hours. H NMR (400 MHz, chloroform-d): δH 8.98 (s,
1H), 7.29 – 7.19 (m, 5H), 3.94 (d, J = 13.0 Hz, 1H), 3.79 (d, J = 13.0 Hz, 1H), 3.66 (h, J = 7.0
Hz, 1H), 3.50 (dd, J = 13.8, 7.0 Hz, 1H), 3.24 (s, 3H), 3.10 (dd, J = 13.8, 7.0 Hz, 1H,), 2.50
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(s, 3H), 1.21 (d, J = 7.0 Hz, 3H). C{1H} NMR (101 MHz, chloroform-d): δC 168.6 (C),
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159.0 (C), 147.9 (CH), 138.3 (C), 129.6 (2 CH), 128.1 (2 CH), 127.1 (CH), 61.7 (CH3), 59.4
(CH), 58.0 (CH2), 41.3 (CH2), 21.9 (CH3), 14.4 (CH3). ESI+-HRAM: m/z calculated for
[C15H21N4O]+ ([M+H]+) 273.170988, found 273.171000. IR (neat): 휈max 2971, 2937, 2895,
1604, 1548, 1530, 1359, 1035.
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N-benzyl-O-methyl-N-(1-(5-(trifluoromethyl)-1,2,4-triazin-3-yl)propan-2-yl)-
hydroxylamine (3k). Following the general procedure C from 5-trifluoromethyl-3-(prop-1-
en-1-yl)-1,2,4-triazine 1k (18.9 mg, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL,
0.15 mmol, 1.5 equiv) in 96 hours, the title compound (26 mg, 79% yield) was obtained as a
bright-yellow oil after purification by silica gel column chromatography (eluent = 95:5
pentane/Et2O, Rf = 0.3). 1H NMR (400 MHz, chloroform-d): δH 9.47 (s, 1H), 7.25 – 7.12 (m,
5H), 3.95 (d, J = 13.0 Hz, 1H), 3.76 (d, J = 13.0 Hz, 1H), 3.76 – 3.60 (m, 2H), 3.35 – 3.25 (m,
1H), 3.19 (s, 3H), 1.28 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d): δC 170.1
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3
(C), 147.3 (q, JC-F = 37.7 Hz, C), 142.7 (q, JC-F = 2.6 Hz, CH), 137.8 (C), 129.4 (2 CH),
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128.2 (2 CH), 127.3 (CH), 120.2 (q, JC-F = 276.0 Hz, CF3), 61.3 (CH3), 59.3 (CH), 57.8
(CH2), 41.4 (CH2), 14.4 (CH3). ESI+-HRAM: m/z calculated for [C15H18F3N4O]+ ([M+H]+)
327.142722, found 327.142697. IR (neat): 휈max 2976, 2937, 1334, 1199, 1143, 1036, 697.
N-benzyl-N-(1-(5,6-dimethyl-1,2,4-triazin-3-yl)propan-2-yl)-O-methylhydroxylamine
(3l). Following the general procedure C from 5,6-dimethyl-3-(prop-1-en-1-yl)-1,2,4-triazine
1l (14.9 mg, 0.10 mmol) and N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in
72 hours, the title compound (25 mg, 87% yield) was obtained as a yellow oil after
purification by column chromatography (eluent = 4:1 CH2Cl2/EtOAc, Rf = 0.3). 1H NMR (400
MHz, chloroform-d): δH 7.28 – 7.21 (m, 5H), 3.94 (d, J = 13.0 Hz, 1H), 3.80 (d, J = 13 Hz,
1H), 3.63 (h, J = 7 Hz, 1H), 3.46 (dd, J = 14, 7 Hz, 1H), 3.26 (s, 3H), 3.05 (dd, J = 14, 7 Hz,
1H), 2.66 (s, 3H), 2.47 (s, 3H), 1.20 (d, J = 7 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-
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d): δC 166.8 (C), 158.4 (C), 155.3 (CH), 138.4 (C), 129.6 (2 CH), 128.1 (2 CH), 127.1 (CH),
61.8 (CH3), 59.4 (CH), 58.1 (CH2), 40.8 (CH2), 21.8 (CH3), 19.5 (CH3), 14.5 (CH3). ESI+-
HRAM: m/z calculated for [C16H23N4O]+ ([M+H]+) 287.186638, found 287.186558. IR (neat):
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max 3297, 2972, 2935, 2899, 1398, 1039, 735, 698.
N-(1-(1,2,4-triazin-3-yl)propan-2-yl)-N-benzyl-O-methylhydroxylamine (3m). Following
the general procedure C from 3-(prop-1-en-1-yl)-1,2,4-triazine 1m (12.1 mg, 0.10 mmol) and
N-methoxybenzylamine 2d (19.8 µL, 0.15 mmol, 1.5 equiv) in 72 hours, the title compound
(10 mg, 39% yield) was obtained as a light-yellow oil after purification by silica gel column
chromatography (eluent = 4:1 pentane/EtOAc, Rf = 0.3). 1H NMR (400 MHz, chloroform-d):
δH 9.11 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.27 – 7.22 (m, 5H), 3.95 (d, J = 13.1
Hz, 1H), 3.79 (d, J = 13.1 Hz, 1H), 3.68 (h, J = 7 Hz, 1H), 3.56 (dd, J = 13.8, 7 Hz, 1H), 3.23
(s, 3H), 3.19 (dd, J = 13.8, 7 Hz, 1H), 1.23 (d, J = 7 Hz, 3H). C{1H} NMR (101 MHz,
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chloroform-d): δC 169.9 (C), 148.5 (C), 147.6 (CH), 138.2 (C), 129.6 (2 CH), 128.2 (2 CH),
127.2 (CH), 61.7 (CH3), 59.6 (CH), 58.1 (CH2), 41.4 (CH2), 14.7 (CH3). ESI+-HRAM: m/z
calculated for [C14H19N4O]+ ([M+H]+) 259.155338, found 259.155307. IR (neat): 휈max 3406,
2971, 2935, 2899, 1410, 1045, 735, 698.
O-methyl-N-(1-(5-phenyl-1,2,4-triazin-3-yl)propan-2-yl)-N-(prop-2-yn-1-yl)-
hydroxylamine (3n). Following the general procedure C from 5-phenyl-3-(prop-1-en-1-yl)-
1,2,4-triazine 1b (99 mg, 0.5 mmol) and N-methoxypropargylamine 2g (67 µL, 0.75 mmol,
1.5 equiv) in 24 hours, the title compound (127 mg, 90% yield) was obtained as a yellow oil
after purification by silica gel column chromatography (eluent = 4:1 pentane/EtOAc, Rf =
0.25). From 5-phenyl-3-(prop-1-en-1-yl)-1,2,4-triazine 1b (215 mg, 1.09 mmol) and N-
methoxypropargylamine 2g (150 µL, 1.69 mmol, 1.5 equiv) in 24 hours, the title compound
(270 mg, 88% yield) was obtained as a yellow oil after purification by silica gel column
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chromatography. H NMR (400 MHz, chloroform-d): δH 9.54 (s, 1H), 8.21 – 8.17 (m, 2H),
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7.62 – 7.51 (m, 3H), 3.88 (h, J = 7 Hz, 1H), 3.77 (dd, J = 17.0, 2.5 Hz, 1H), 3.62 (dd, J =
17.0, 2.5 Hz, 1H), 3.57 (s, 3H), 3.57 (dd, J = 14.0, 7.0 Hz, 1H), 3.21 (dd, J = 14.0, 7.0 Hz,
1H), 2.20 (t, J = 2.5 Hz, 1H), 1.19 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-
d): δC 168.5 (C), 155.0 (C), 144.2 (CH), 133.8 (C), 132.5 (CH), 129.5 (2 CH), 127.7 (2 CH),
79.1 (C), 72.4 (CH), 61.6 (CH3), 59.1 (CH), 43.2 (CH2), 41.6 (CH2), 15.7 (CH3). ESI+-
HRAM: m/z calculated for [C16H19N4O]+ ([M+H]+) 283.155338, found 283.155508. IR (neat):
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휈
max 3291, 2935, 1508, 1041, 690.
O-benzyl-N-(1-(5-phenyl-1,2,4-triazin-3-yl)propan-2-yl)-N-(prop-2-yn-1-yl)-
hydroxylamine (3o). Following the general procedure C from 5-phenyl-3-(prop-1-en-1-yl)-
1,2,4-triazine 1b (19.7 mg, 0.10 mmol) and O-benzyl-N-propargylhydroxylamine 2h (24 mg,
0.15 mmol, 1.5 equiv) in 24 hours, the title compound (29.2 mg, 81% yield) was obtained as a
yellow oil after purification by silica gel column chromatography (eluent = 4:1
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pentane/EtOAc, Rf = 0.3). H NMR (400 MHz, chloroform-d): δH 9.51 (s, 1H), 8.17 (dd, J =
8.1, 1.7 Hz, 2H), 7.64 – 7.49 (m, 3H), 7.38 – 7.24 (m, 5H), 4.83 (d, J = 10.7 Hz, 1H), 4.78 (d,
J = 10.7 Hz, 1H), 3.94 (h, J = 7 Hz, 1H), 3.76 (dd, J = 16.7, 2.5 Hz, 1H), 3.65 (dd, J = 16.7,
2.5 Hz, 1H), 3.60 (dd, J = 14.0, 7 Hz, 1H), 3.25 (dd, J = 14.0, 7 Hz, 1H), 2.20 (t, J = 2.5 Hz,
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1H), 1.23 (d, J = 7 Hz, 3H). C{1H} NMR (101 MHz, chloroform-d): δC 168.6 (C), 155.0
(C), 144.1 (CH), 137.3 (C), 133.8 (C), 132.5 (CH), 129.4 (2 CH), 128.9 (2 CH), 128.4 (2 CH),
128.0 (CH), 127.7 (2 CH), 79.5 (C), 76.3 (CH2), 72.4 (CH), 59.5 (CH), 43.8 (CH2), 41.4
(CH2), 15.7 (CH3). ESI+-HRAM: m/z calculated for [C22H23N4O]+ ([M+H]+) 359.186638,
found 359.186831. IR (neat): 휈max 3293, 2973, 2875, 1601, 1544, 1508, 691.
O-benzyl-N-(1-(5-phenyl-1,2,4-triazin-3-yl)propan-2-yl)hydroxylamine (3p). Following
the general procedure A from 5-phenyl-3-(prop-1-en-1-yl)-1,2,4-triazine 1b (19.7 mg, 0.10
mmol) and O-benzylhydroxylamine 2i (16 µL, 0.15 mmol, 1.5 equiv) in 24 hours, the title
compound (29.1 mg, 91% yield) was obtained as a yellow oil after purification by silica gel
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column chromatography (eluent = 65:35 petroleum ether/EtOAc, Rf = 0.3). H NMR (400
MHz, chloroform-d): δH 9.52 (s, 1H), 8.22 – 8.09 (m, 2H), 7.65 – 7.50 (m, 3H), 7.39 – 7.20
(m, 5H), 4.71 (s, 2H), 3.87 – 3.74 (m, 1H), 3.43 (dd, J = 14.5, 7.3 Hz, 1H), 3.24 (dd, J = 14.5,
5.5 Hz, 1H), 1.24 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, chloroform-d): δC 168.3 (C),
155.1 (C), 144.3 (CH), 138.0 (C), 133.7 (C), 132.6 (CH), 129.5 (2 CH), 128.40 (2 CH),
128.39 (2 CH), 127.8 (CH), 127.7 (2 CH), 76.7 (CH2), 55.5 (CH), 41.8 (CH2), 18.5 (CH3).
ESI+-HRAM: m/z calculated for [C19H21N4O]+ ([M+H]+) 321.170988, found 321.171098.
IR (neat): 휈max 2968, 2910, 1601, 1544, 1508.
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O-methyl-N-(2-(5-phenyl-1,2,4-triazin-3-yl)ethyl)-N-(prop-2-yn-1-yl)hydroxylamine (3q).
N-methoxypropargylamine hydrochloride 2g.HCl (845 mg, 6.96 mmol, 1.5 equiv) was added
into a mixture of 5-phenyl-3-vinyl-1,2,4-triazine 1a (850 mg, 4.64 mmol) and sodium
bicarbonate (585 mg, 6.96 mmol, 1.5 equiv) in 50 mL of tetrahydrofuran. The mixture was
stirred at room temperature for 24 hours (it turned brown after a few hours). 50 mL of a 0.3 M
sodium bicarbonate aqueous solution were then added, and the mixture was extracted with
dichloromethane (3 × 50 mL). The combined organic extracts were dried over magnesium
sulfate and concentrated on rotary evaporator. Purification by silica gel column
chromatography (eluent = 8:2 petroleum ether/EtOAc, Rf = 0.3) afforded the title compound
1
(960 mg, 3.58 mmol, 77% yield) as a yellow solid. H NMR (400 MHz, chloroform-d): δH
9.55 (s, 1H), 8.21 – 8.16 (m, 2H), 7.63 – 7.52 (m, 3H), 3.64 (d, J = 2.5 Hz, 2H), 3.56 (s, 3H),
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3.48 – 3.44 (m, 4H), 2.25 (t, J = 2.5 Hz, 1H). C{1H} NMR (101 MHz, chloroform-d): δC
168.4 (C), 155.0 (C), 144.2 (CH), 133.6 (C), 132.4 (CH), 129.4 (2 CH), 127.6 (2 CH), 78.4
(C), 73.0(CH), 61.1 (CH3), 55.4 (CH2), 46.5 (CH2), 35.3 (CH2). ESI+-HRAM: m/z calcd for
[C15H17N4O]+ ([M+H]+) 269.139688, found 269.139649 ; m/z calcd for [C15H16N4NaO]+
([M+Na]+) 291.121632, found 291.121608. IR (neat): 휈max 3263, 2931, 2859, 1552, 1517,
1319, 1044, 1032, 1000, 686, 667. mp = 57-59 °C.
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6-methoxy-2-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (4a). A solution of triazine 3q
(440 mg, 1.64 mmol) in 16 mL of α,α,α-trifluorotoluene was heated at 180 °C under
microwaves irradiation for 2 hours. The mixture was then concentrated on rotary evaporator
and the product was purified by silica gel column chromatography (eluent = 4:1 petroleum
ether/EtOAc, Rf = 0.4) to afford the expected tetrahydro-[1,6]-naphthyridine (320 mg, 81%
yield) as a beige solid. 1H NMR (250 MHz, dimethylsulfoxide-d6, 80 °C): δH 8.08 – 7.96 (m,
2H), 7.69 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.54 – 7.35 (m, 3H), 4.10 (s, 2H), 3.55
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(d, J = 0.4 Hz, 3H), 3.30 (t, J = 6.2 Hz, 2H), 3.04 (t, J = 6.2 Hz, 2H). C{1H} NMR (101
MHz, dimethylsulfoxide-d6): δC 153.9 (C), 153.5 (C), 138.6 (C), 135.9 (CH), 128.7 (CH),
128.6 (2 CH), 127.4 (C), 126.4 (2 CH), 117.7 (CH), 58.7 (CH3), 55.4 (CH2), 51.4 (CH2), 30.1
(CH2). ESI+-HRAM: m/z calculated for [C15H17N2O]+ ([M+H]+) 241.133540, found
241.133561. IR (neat): 휈max 2969, 2933, 2888, 2831, 2809, 1568, 1458, 1038, 774, 735, 694.
mp = 62-64 °C.
General procedure D for the one-pot synthesis of N-methoxytetrahydro-[1,6]-
naphthyridines (4). N-methoxy propargylamines 2g-h (1.5 equiv) were added to a solution of
3-vinyl-1,2,4-triazines 1a-l (0.3 mmol, 0.1 M) and trifluoromethanesulfonimide E (20 mol%)
in α,α,α-trifluorotoluene in a microwaves vial. The mixture was stirred at room temperature
until TLC monitoring revealed a complete transformation of starting material 1. Potassium
carbonate (1 equiv) was then added, the vial was sealed and heated at 180 °C under
microwaves irradiation (gradient temperature from room temperature to 180 °C over 5
minutes) for 2 hours. At room temperature, the reaction mixture was subsequently filtered
through cotton and purified by silica gel column chromatography to afford the expected
tetrahydronaphthyridine 4. Remark: NMR spectra for tetrahydro-[1,6]-naphthyridines were
carried out at 80 °C in dimethylsulfoxide-d6 in order to overcome the broad signal issues
observed for the aliphatic cycle. We considered the difference of chemical shifts values for
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tetramethylsilane between 25 and 80 °C insignificant.32 Chemical shifts were consequently
calibrated on dimethylsulfoxide signals (δ = 2.50 ppm for 1H and δ = 39.52 ppm for 13C).
6-Methoxy-7-methyl-2-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (4b). Following the
general procedure D from 5-phenyl-3-(prop-1-en-1-yl)-1,2,4-triazine 1b (59 mg, 0.30 mmol)
and N-methoxypropargylamine 2g (40 µL, 0.45 mmol, 1.5 equiv.) for 24 hours at room
temperature (TLC monitoring in 8:2 petroleum ether/AcOEt), the title compound was
obtained as a yellow solid (71 mg, 93%) after column chromatography (8:2 pentane/AcOEt,
Rf = 0.3). 1H NMR (250 MHz, dimethylsulfoxide-d6, 80 °C): δH 8.05–7.96 (m, 2H), 7.68 (d, J
= 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.51–7.39 (m, 3H), 4.32 (d, J = 16.0 Hz, 1H), 4.00 (d,
J = 16.0 Hz, 1H), 3.55 (s, 3H), 3.25 (dqd, J = 9.6, 6.3, 4.9 Hz, 1H), 2.97 (dd, J = 17.2, 4.9 Hz,
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1H), 2.82 (dd, J = 17.2, 9.6 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H). C{1H} NMR (63 MHz,
dimethylsulfoxide-d6, 80 °C): δC 153.7 (C), 153.4 (C), 138.5 (C), 135.0 (CH), 128.1 (CH),
128.1 (2 CH), 126.9 (C), 126.0 (2 CH), 117.2 (CH), 59.8 (CH3), 56.2 (CH), 53.8 (CH2), 36.4
(CH2), 18.0 (CH3). ESI+-HRAM: m/z calculated for [C16H19N2O]+ ([M+H]+) 255.149190,
found 255.149401. IR (neat): 휈max 2981, 2941, 2843, 1463, 1449, 1028, 776, 695. mp = 65–66
°C.
6-methoxy-8-methyl-2-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (4c). Following the
general procedure D from 5-phenyl-3-(prop-1-en-2-yl)-1,2,4-triazine 1c (59 mg, 0.30 mmol)
and N-methoxypropargylamine 2g (40 µL, 0.45 mmol, 1.5 equiv) for 24 hours at room
temperature (TLC monitoring in 4:1 petroleum ether/EtOAc), the title compound was
obtained as a brown oil (49 mg, 64% yield) after silica gel column chromatography (eluent =
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4:1 petroleum ether/Et2O, Rf = 0.2). H NMR (250 MHz, dimethylsulfoxide-d6, 80 °C): δH
8.12 – 7.99 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz 1H), 7.55 – 7.35 (m, 3H),
4.13 (d, J = 14.8 Hz, 1H), 4.04 (d, J = 14.8 Hz, 1H), 3.55 (s, 3H), 3.43 (dd, J = 11.0, 5.5 Hz,
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1H), 3.31 – 3.10 (m, 1H), 2.90 (dd, J = 11.0, 7.7 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H). C{1H}
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