Preparation of 4,6-Disubstituted α-Pyrones by Oxidative N-Heterocyclic Carbene Catalysis

Article abstract of DOI:10.1055/s-0036-1588336

An efficient synthesis of 4,6-disubstituted α-pyrones employing redox activation of enals using N-heterocyclic carbene catalysis is reported. The strategy uses aroyl-substituted nitromethanes and enals as substrates and reactions proceed through an additi

Full text of DOI:10.1055/s-0036-1588336

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
paper
A
S. Bera, A. Studer
Paper
Synthesis
Preparation of 4,6-Disubstituted α-Pyrones by Oxidative
N-Heterocyclic Carbene Catalysis
Srikrishna Bera
O
O
O
O
NHC, Cs2CO3
Armido Studer*
NO2
R1
H
R2
oxidant
– HNO2
R2
R1
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität,
Corrensstraße 40, 48149 Münster, Germany
studer@uni-muenster.de
R1, R2 = aryl, heteroaryl
16 examples
29–74% yield
Dedicated to Prof. Dieter Enders, a pioneer and driving force in
carbene catalysis, on the occasion of his 70th birthday
Received: 26.07.2016
Accepted after revision: 28.09.2016
Published online: 13.10.2016
gated their reactivity towards C–C bond formation.8c Later,
our group and other research groups further developed the
chemistry of in situ generated α,β-unsaturated acyl azoli-
um ions for the preparation of various important heterocy-
cles.8 However, the synthesis of substituted α-pyrones us-
ing N-heterocyclic carbene catalysis still remains unex-
plored. In 2014, Smith et al. demonstrated the synthesis of
substituted α-pyrones from (phenylthio)acetic acid and tri-
fluoromethyl enones via an isothiourea-catalyzed Michael
addition–lactonization–thiol elimination process (Scheme
1).9 However, this method is restricted to trifluoromethyl-
substituted enones where only the 4-aryl substituent can
be varied at the pyrone ring. Herein we report an organo-
cascade for the preparation of 4,6-disubstituted α-pyrones
starting from easily accessible aroyl-substituted nitrometh-
anes and enals by oxidative N-heterocyclic carbene cataly-
sis. We will show that 4,6-disubstituted α-pyrones bearing
two different substituents at the pyrone ring can be readily
accessed via a Michael addition–elimination–lactonization
sequence (Scheme 1). Notable, only few organocatalytic
methods have been reported for the synthesis of substitut-
ed α-pyrones to date.9,10
DOI: 10.1055/s-0036-1588336; Art ID: ss-2016-n0528-op
Abstract An efficient synthesis of 4,6-disubstituted α-pyrones em-
ploying redox activation of enals using N-heterocyclic carbene catalysis
is reported. The strategy uses aroyl-substituted nitromethanes and
enals as substrates and reactions proceed through an addition–elimina-
tion–lactonization sequence. On one hand the nitro group in the start-
ing ketone stabilizes the enolate and on the other hand it also acts as an
ionic leaving group. Products are obtained in moderate to good yields.
Key words α-pyrone, N-heterocyclic carbine, oxidative organocataly-
sis, NHC catalysis, elimination, lactonization
α-Pyrones1 belong to an important class of unsaturated
six-membered heterocycles present in many natural prod-
ucts that show biological activity such as antimicrobial,2a
antifungal,2b,c anti-HIV,2d and phytotoxic effects.2e Due to
their interesting biological activity and due to their valu-
able reactivity caused by the conjugated diene and lactone
functionalities, α-pyrones have drawn great attention in
synthesis.3 It is therefore not surprising that many methods
for the preparation of substituted α-pyrones have been dis-
closed.4 Despite great achievements in this area considering
the traditional methods and also modern transition-metal-
based processes, the development of novel approaches to-
wards α-pyrones is still of importance.
Over the past decade, N-heterocyclic carbene catalyzed
redox activation of enals for the synthesis of complex het-
erocycles has become increasingly more attractive.5,6 In
2010, our group8a demonstrated an organocascade where
1,3-diketones and in situ generated α,β-unsaturated acyl
azolium ions react to give dihydropyranones.7,8 Moreover,
Lupton and co-workers have studied the NHC-catalyzed
generation of α,β-unsaturated acyl azolium ions from the
corresponding acyl fluorides or acyl esters and have investi-
Previous work, Smith (2014)9
O
isothiourea
O
O
catalysis
O
PhS
Ar
CF3
OH
Ar
CF3
This work
O
oxidative NHC
catalysis
O
O
O
O2N
R1
H
R2
R1
R2
Scheme 1 Preparation of α-pyrones using organocatalysis
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
S. Bera, A. Studer
Paper
Synthesis
We began our investigations using trans-cinnamalde-
hyde (1a) and benzoylnitromethane (2a) as model sub-
strates. Diphenoquinone11 3 was chosen as an oxidant. We
delightfully found that with triazolium salt A12a as NHC pre-
catalyst (10 mol%) and DBU (1.2 equiv) as a base in THF at
room temperature, the targeted α-pyrone 4aa was formed
in 15% yield (Table 1, entry 1). Upon switching to NHC pre-
catalysts B12b and C,12b only a trace amount of the desired
pyrone 4aa was identified (Table 1, entries 2 and 3). With
Cs2CO3 (2.0 equiv) as the base the yield slightly improved
(20%) (Table 1, entry 4) and a worse result was achieved
with precatalysts D12c and E keeping Cs2CO3 as the base (Ta-
ble 1, entries 5 and 6). By using 2.0 equivalents of benzoyl-
nitromethane 2a, the yield increased from 20% to 40% (Ta-
ble 1, entry 7). Decreasing the amount of Cs2CO3 from 2.0 to
1.2 equivalents led to a further increase of the yield to 69%
(Table 1, entry 8). Notable, a catalytic amount of Cs2CO3
provided only a trace amount of the targeted product (Table
1, entry 9). Other solvents such as CH2Cl2, toluene, MeCN,
EtOAc, 1,2-dichloroethane, and DMF were tested, however,
in all cases a worse result was achieved (Table 1, entries 10–
15).
With optimized reaction conditions in hand, we started
to explore the generality and scope of our cascade (Scheme
2). Cinnamaldehyde derivatives bearing methyl, methoxy,
and dimethylamino substituents at the para position of the
aryl ring were tested in the reaction with nitro ketone 2a. In
all three cases the targeted products 4ba–da were ob-
tained. Whereas the methyl congener (see 4ba) provided
the same yield as the parent cinnamaldehyde, the electron-
rich methoxy- and dimethylamino-substituted enals af-
forded the pyrones 4ca and 4da in lower yields. Surprising-
ly, with electron-poorer cinnamaldehyde derivatives bear-
ing a bromo, fluoro, or nitro substituent at the para-posi-
tion, α-pyrone formation was not observed. Hence, the
reaction seems to show very strong effects on electronics
with best results being obtained for alkyl-substituted enals.
Along these lines, we found that a methyl group at the
meta-position of the arene ring of the enal is well tolerated
to give pyrone 4ea in 69% isolated yield. Electronic effects at
the meta-positions are not that pronounced and for both,
the meta-methoxy (see 4fa, 57%) and also the meta-chloro
derivative (see 4ga, 67%) the α-pyrone products were iso-
lated in good yields. The 2-furylenal 1h also gave the de-
sired pyrone 4ha in 50% isolated yield.
Table 1 Reaction Optimizationa
O
NHC (10 mol%)
O
O
base, 3
O
O2N
solvent, r.t., 24 h
Ph
Ph
H
N
Ph
Ph
1a
2a
4aa
N
tBu
tBu
tBu
Ar
N
N
Mes
O
N
Mes
X
Cl
O
A, Ar = Mes, X = BF4
B, Ar = C6H5, X = Cl
C, Ar = C6F5, X = BF4
E
tBu
3
D, Ar = 2,6-(MeO)2C6H3, X = Cl
Entry
Catalyst
Base (equiv)
Solvent
Yield (%)b
1
2
A
B
C
A
D
E
DBU (1.2)
THF
15
DBU (1.2)
THF
trace
trace
20
3
DBU (1.2)
THF
4
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (1.2)
Cs2CO3 (0.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
THF
5
THF
15
6
THF
15
7c
A
A
A
A
A
A
A
A
A
THF
40
8c,d
9c
THF
69
THF
trace
15
10c
11c
12c
13c
14c
15c
CH2Cl2
toluene
MeCN
EtOAc
DCE
20
15
11
22
DMF
<5
a All reactions were carried on a 0.1 mmol scale for 24 h.
b Determined by 1H NMR spectroscopy.
c 2a (2.0 equiv) was used.
d Yield of the isolated product.
tained in 52% yield. Hence, an electron-withdrawing group
seems to increase reaction efficiency. Indeed, with the
chloro and fluoro derivatives yield further improved and
the pyrones 4ae and 4af were obtained in 67% and 64%
yields, respectively. It was interesting to see that with the
meta-substituted halo-substituted congeners (2g and 2h)
the yield could be further improved (4ag: 68%; 4ah: 74%).
We were also pleased to find that the 2-naphthyl ketone
worked as a substrate providing the pyrone 4ai in 56% yield.
We also tested crotonaldehyde as a non-aromatic enal in
the reaction with 2a under the optimized reaction condi-
tions, but unfortunately only a trace amount of the desired
product was formed that was not isolated.
We further tested the scope by varying the α-nitro ke-
tone component keeping cinnamaldehyde as the reaction
partner. With the tolyl ketone a slightly lower yield of the
desired product 4ab was obtained as compared to the for-
mation of pyrone 4aa. As for the enal component, electronic
effects strongly influence reaction outcome. With p-meth-
oxyphenyl nitromethyl ketone 2c the yield significantly de-
creased and 4ac was isolated in 29% yield. However, with
para-bromo-substituted ketone 2d, the pyrone 4ad was ob-
Our suggested reaction mechanism for the formation of
the α-pyrones 4 is depicted in Scheme 3. Carbene A′, gener-
ated by deprotonation of precatalyst A, reacts with enal 1 to
provide the corresponding Breslow intermediate which is
immediately oxidized in situ by 3 to give acyl azolium ion 5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
S. Bera, A. Studer
Paper
Synthesis
O
A (10 mol%)
O
Cs2CO3 (1.2 equiv)
O
O
H
O
O
O2N
R1
H
R2
3 (1.2 equiv)
THF, r.t., 24 h
O
R1
N
R1
R2
R1
R2
1
N
Mes
4
N
1a–f
2a–i
4aa–fa
A´
3
R2
lactonization
N
O
O
O
O
O
O
O
N
R1
R1
N
N
N
5
N
Mes
R2
Mes
R
Michael
addition
7
R
4aa, R = H, 69%
4ba, R = Me, 69%
4ca, R = OMe, 50%
4ea, R = Me, 69%
4fa, R = OMe, 57%
4ga, R = Cl, 67%
O
elimination
O2N
O
HNO2
NO2
R2
O
4da, R = NMe2, 31%
N
N
2´
R1
N
O
O
O
O
Mes
6
Scheme 3 Plausible mechanism
O
R
reagents were purified according to standard procedures or were
used as received from Aldrich, Acros Organics, or Alfa Aesar. All α,β-
unsaturated aldehydes were either distilled or freshly prepared prior
to use. Catalysts A,12a B,12b and oxidant 311 were prepared according to
known literature procedures.
4ab, R = Me, 46%
4ac, R = OMe, 29%
4ad, R = Br, 52%
4ae, R = Cl, 67%
4af, R = F, 64%
4ha, 50%
1H and 13C NMR spectra were recorded on a Bruker DPX 300, Bruker
AV 300, or Bruker AV 400 at 300 K or a Varian 600 UNITY plus spec-
trometer at 299 K, relative to TMS [δ(1H) = 0.0, δ(13C) = 0.0]. The sol-
vents residual proton resonance and the respective carbon resonance
[CHCl3, δ(1H) = 7.26, δ(13C) = 77.0] were used for calibration. TLC:
Merck silica gel 60 F 254 plates; detection with UV light or by dipping
into a solution of KMnO4 [1.5 g; H2O (400 mL), NaHCO3 (5 g)] or a
solution of Ce(SO4)2·x H2O (10 g), phosphomolybdic acid hydrate (25
g), and concd H2SO4 (60 mL) in H2O (940 mL), followed by heating.
Flash column chromatography (FC): Merck or Acros Organics silica gel
60 (40–63 μm) at approx 0.4 bar. IR spectra were recorded on a Digi-
lab Varian 3100 FT-IR Excalibur Series. HRMS ESI (m/z) spectra were
recorded on a Bruker MicroTof or an Orbitrap LTQ XL(Nanospray) of
Thermo Scientific.
O
O
O
O
R
4ag, R = Br, 68%
4ah, R = Cl, 74%
4ai, 56%
Scheme 2 Scope of the reaction
Conjugative addition of deprotonated 2′ to the acyl azolium
ion 58f provides the enolate 6 which then undergoes HNO2
elimination affording enolate 7. Lactonization eventually
provides the product α-pyrone 4 thereby regenerating the
NHC catalyst A′.13
In summary, a novel method for the preparation of 4,6-
disubstituted α-pyrones from commercially available enals
and readily accessible aroyl-substituted nitromethanes via
oxidative N-heterocyclic carbene catalyzed addition–elimi-
nation–lactonization has been introduced. Reactions re-
ported are experimentally easy to perform by simply mix-
ing precatalyst, substrates and reagents at ambient tem-
perature providing the α-pyrones in moderate to good
yields.
α-Pyrones 4aa–4ah; General Procedure
To a heat gun dried Schlenk tube under an argon atmosphere, azoli-
um salt A (3.0 mg, 10 μmol), 3 (49 mg, 0.12 mmol, 1.2 equiv), Cs2CO3
(39 mg, 0.12 mmol, 1.2 equiv), 2a–i (0.2 mmol, 2 equiv), and THF (1
mL) were added and the resulting solution was stirred for 5 min at rt.
Then the enal 1a–h (0.1 mmol, 1.0 equiv) was added and stirring was
continued for 12 h at rt. After completion of the reaction (TLC moni-
toring), the crude mixture was directly subjected to flash column
chromatography (pentane/EtOAc).
4,6-Diphenyl-2H-pyran-2-one (4aa)
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 7:1) afforded α-pyrone 4aa (17 mg, 69%) as a white solid;
mp 136 °C.
All reactions involving air- or moisture-sensitive reagents or interme-
diates were carried out in heat gun dried glassware under an argon
atmosphere. THF was freshly distilled from potassium under argon.
CH2Cl2 was freshly distilled from P2O5. MeCN was freshly distilled
over CaH2. DCE was freshly distilled over CaH2. All other solvents and
FTIR (neat): 2253, 1708, 1629, 1539, 1495, 1078, 903, 722, 649 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.94–7.87 (m, 2 H), 7.69–7.61 (m, 2 H),
7.54–7.45 (m, 6 H), 6.97 (d, J = 1.5 Hz, 1 H), 6.48 (d, J = 1.5 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
S. Bera, A. Studer
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 162.8, 160.6, 155.7, 136.2, 131.7, 131.1,
130.8, 129.4 (× 2), 129.1 (× 2), 126.9 (× 2), 125.9 (× 2), 109.4, 101.5.
1H NMR (300 MHz, CDCl3): δ = 8.01–7.84 (m, 2 H), 7.70–7.27 (m, 7 H),
6.95 (d, J = 1.5 Hz, 1 H), 6.46 (d, J = 1.5 Hz, 1 H), 2.45 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H12NaO2: 271.0735; found:
271.0730.
13C NMR (75 MHz, CDCl3): δ = 162.7, 160.3, 155.7, 139.0, 136.1, 131.6,
131.4, 130.9, 129.1, 128.9 (× 2), 127.4, 125.8 (× 2), 123.9, 109.2, 101.5,
21.5.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14NaO2: 285.0891; found:
6-Phenyl-4-(p-tolyl)-2H-pyran-2-one (4ba)
285.0886.
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-4-
methylcinnamaldehyde (1b, 15 mg, 0.10 mmol, 1.0 equiv). FC (silica
gel, pentane/EtOAc 10:1) afforded α-pyrone 4ba (18 mg, 69%) as a
white solid; mp 134 °C.
4-(3-Methoxyphenyl)-6-phenyl-2H-pyran-2-one (4fa)
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-3-
methoxycinnamaldehyde (1f, 17 mg, 0.10 mmol, 1.0 equiv). FC (silica
gel, pentane/EtOAc 10:1) afforded α-pyrone 4fa (16 mg, 57%) as a yel-
lowish solid; mp 116 °C.
FTIR (neat): 2253, 2219, 1714, 1628, 1573, 1495, 903, 723, 649 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.96–7.84 (m, 2 H), 7.61–7.52 (m, 2 H),
7.50–7.44 (m, 3 H), 7.31 (d, J = 7.9 Hz, 2 H), 6.96 (d, J = 1.5 Hz, 1 H),
6.46 (d, J = 1.5 Hz, 1 H), 2.43 (s, 3 H).
FTIR (neat): 2253, 1714, 1629, 1537, 1495, 904, 726, 649 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 162.9, 160.4, 155.5, 141.3, 133.2, 131.8
(× 2), 131.0 (× 2), 130.1 (× 2), 129.1 (× 2), 126.8, 125.9, 108.7, 101.4,
21.5.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14NaO2: 285.0891; found:
285.0886.
1H NMR (300 MHz, CDCl3): δ = 7.96–7.83 (m, 2 H), 7.56–7.36 (m, 4 H),
7.22 (ddd, J = 7.7, 1.7, 0.9 Hz, 1 H), 7.15 (t, J = 2.1 Hz, 1 H), 7.05 (ddd,
J = 8.2, 2.6, 0.9 Hz, 1 H), 6.94 (d, J = 1.5 Hz, 1 H), 6.46 (d, J = 1.5 Hz, 1 H),
3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.8, 160.5, 160.3, 155.7, 137.7, 131.7,
131.1, 130.5, 129.1 (× 2), 125.9 (× 2), 119.2, 116.1, 112.6, 109.6, 101.6,
55.6.
4-(4-Methoxyphenyl)-6-phenyl-2H-pyran-2-one (4ca)
HRMS (ESI): m/z [M + Na]+ calcd for C18H14NaO3: 301.0841; found:
301.0835.
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-4-
methoxycinnamaldehyde (1c, 17 mg, 0.10 mmol, 1.0 equiv). FC (silica
gel, pentane/EtOAc 10:1) afforded α-pyrone 4ca (14 mg, 50%) as a yel-
lowish solid; mp 124 °C.
4-(3-Chlorophenyl)-6-phenyl-2H-pyran-2-one (4ga)
FTIR (neat): 2254, 2287, 1720, 1626, 1538, 1462, 903, 722, 650 cm–1
.
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-3-
chlorocinnamaldehyde (1g, 17 mg, 0.10 mmol, 1.0 equiv). FC (silica
gel, pentane/EtOAc 10:1) afforded α-pyrone 4ga (19 mg, 67%) as a yel-
lowish solid; mp 139 °C.
1H NMR (300 MHz, CDCl3): δ = 7.93–7.86 (m, 2 H), 7.69–7.59 (m, 2 H),
7.54–7.39 (m, 3 H), 7.07–6.99 (m, 2 H), 6.96 (d, J = 1.5 Hz, 1 H), 6.43
(d, J = 1.6 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.0, 162.0, 160.3, 155.0, 131.9, 131.0,
129.1 (× 2), 128.4 (× 2), 128.2, 125.9 (× 2), 114.8 (× 2), 107.8, 101.2,
55.6.
FTIR (neat): 2254, 1705, 1629, 1537, 1495, 1079, 903, 723, 649 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.95–7.84 (m, 2 H), 7.65–7.56 (m, 1 H),
7.57–7.38 (m, 6 H), 6.89 (d, J = 1.5 Hz, 1 H), 6.43 (d, J = 1.5 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H14NaO3: 301.0841; found:
13C NMR (75 MHz, CDCl3): δ = 162.3, 160.9, 154.3, 138.1, 135.5, 131.5,
301.0835.
131.2, 130.7, 130.7, 129.1 (× 2), 127.0, 125.9 (× 2), 125.0, 109.9, 101.1.
HRMS (ESI): m/z [M + Na]+ calcd for C17H11ClNaO2: 305.0345; found:
305.0340.
4-[4-(Dimethylamino)phenyl]-6-phenyl-2H-pyran-2-one (4da)
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-4-
(dimethylamino)cinnamaldehyde (1d, 18 mg, 0.10 mmol, 1.0 equiv).
FC (silica gel, pentane/EtOAc 5:1) afforded α-pyrone 4da (9 mg, 31%)
as a yellow solid; mp 145 °C.
4-(Furan-2-yl)-6-phenyl-2H-pyran-2-one (4ha)
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-3-
(furan-2-yl)acrylaldehyde (1h, 13 mg, 0.10 mmol, 1.0 equiv). FC (silica
gel, pentane/EtOAc 7:1) afforded α-pyrone 4ha (16 mg, 50%) as a
white solid; mp 139 °C.
FTIR (neat): 2185, 2043, 1710, 1606, 1522, 1202, 903, 722, 650 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.98–7.85 (m, 2 H), 7.67–7.55 (m, 2 H),
7.53–7.41 (m, 3 H), 7.00 (d, J = 1.6 Hz, 1 H), 6.84–6.73 (m, 2 H), 6.41
(d, J = 1.6 Hz, 1 H), 3.06 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 163.5, 159.8, 154.9, 152.2, 132.2, 130.7,
129.0 (× 2), 128.1 (× 2), 125.9 (× 2), 122.5, 112.3 (× 2), 105.4, 101.0,
40.3 (× 2).
FTIR (neat): 2256, 1708, 1633, 1534, 1167, 903, 723, 650 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.92–7.85 (m, 2 H), 7.63 (d, J = 1.8 Hz, 1
H), 7.48–7.44 (m, 3 H), 7.00 (d, J = 3.5 Hz, 1 H), 6.93 (d, J = 1.4 Hz, 1 H),
6.59 (dd, J = 3.5, 1.8 Hz, 1 H), 6.50 (d, J = 1.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 162.7, 160.7, 149.8, 145.9, 143.5, 131.7,
131.0, 129.1 (× 2), 125.9 (× 2), 112.8, 112.8, 104.4, 98.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H17NNaO2: 314.1157; found:
314.1151.
HRMS (ESI): m/z [M + Na]+ calcd for C15H10NaO3: 261.0528; found:
261.0522.
6-Phenyl-4-(m-tolyl)-2H-pyran-2-one (4ea)
According to GP with 2a (34 mg, 0.20 mmol, 2.0 equiv) and trans-3-
methylcinnamaldehyde (1e, 15 mg, 0.10 mmol, 1.0 equiv). FC (silica
gel, pentane/EtOAc 10:1) afforded α-pyrone 4ea (18 mg, 69%) as a
sticky oil.
4-Phenyl-6-(p-tolyl)-2H-pyran-2-one (4ab)
According to GP with 2b (36 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4ab (12 mg, 46%) as a yellowish
solid; mp 113 °C.
FTIR (neat): 2253, 2217, 1714, 1630, 1590, 1495, 903, 723, 649 cm–1
.
FTIR (neat): 2254, 2166, 1710, 1626, 1509, 1388, 903, 721, 649 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

E
S. Bera, A. Studer
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8.3 Hz, 2 H), 7.68–7.62 (m, 2
H), 7.54–7.49 (m, 3 H), 7.28 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 1.5 Hz, 1 H),
6.44 (d, J = 1.5 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.9, 160.8, 155.9, 141.6, 136.4, 130.7,
129.8 (× 2), 129.4 (× 2), 129.0, 126.9 (× 2), 125.9 (× 2), 109.0, 100.9,
21.6.
FTIR (neat): 2188, 1718, 1678, 1507, 1160, 903, 721, 650 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.96–7.86 (m, 2 H), 7.68–7.61 (m, 2 H),
7.55–7.49 (m, 3 H), 7.22–7.13 (m, 2 H), 6.90 (d, J = 1.5 Hz, 1 H), 6.47
(d, J = 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 166.1, 162.8, 162.6, 159.6, 155.8, 136.2,
130.9, 129.4, 128.1, 128.0, 126.9, 116.5, 116.2, 109.3, 101.3, 101.3.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14NaO2: 285.0891; found:
285.0886.
HRMS (ESI): m/z [M + Na]+ calcd for C17H11FNaO2: 289.0641; found:
289.0635.
6-(4-Methoxyphenyl)-4-phenyl-2H-pyran-2-one (4ac)
6-(3-Bromophenyl)-4-phenyl-2H-pyran-2-one (4ag)
According to GP with 2c (39 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 5:1) afforded α-pyrone 4ac (8 mg, 29%) as a yellowish sol-
id; mp 115 °C.
According to GP with 2g (49 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4ag (22 mg, 68%) as a yellowish
solid; mp 155 °C.
FTIR (neat): 2254, 1715, 1608, 1508, 1464, 1257, 903, 722, 650 cm–1
.
FTIR (neat): 2253, 2163, 1721, 1629, 1539, 1472, 903, 722, 650 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.92–7.82 (m, 2 H), 7.67–7.60 (m, 2 H),
7.55–7.47 (m, 3 H), 7.04–6.93 (m, 2 H), 6.85 (d, J = 1.5 Hz, 1 H), 6.41
(d, J = 1.5 Hz, 1 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.0, 162.0, 160.7, 156.1, 136.5, 130.7,
129.3 (× 2), 127.6 (× 2), 126.9 (× 2), 124.3, 114.6 (× 2), 108.3, 100.1,
55.6.
1H NMR (300 MHz, CDCl3): δ = 8.03 (t, J = 1.8 Hz, 1 H), 7.82 (dt, J = 7.9,
1.3 Hz, 1 H), 7.66–7.57 (m, 3 H), 7.55–7.48 (m, 3 H), 7.35 (t, J = 8.0 Hz,
1 H), 6.94 (d, J = 1.5 Hz, 1 H), 6.49 (d, J = 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 162.3, 158.8, 155.5, 135.9, 133.9, 133.6,
131.0, 130.6, 129.4 (× 2), 128.8, 126.8 (× 2), 124.4, 123.3, 110.1, 102.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H11BrNaO2: 348.9840; found:
348.9835.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14NaO3: 301.0841; found:
301.0835.
6-(3-Chlorophenyl)-4-phenyl-2H-pyran-2-one (4ah)
6-(4-Bromophenyl)-4-phenyl-2H-pyran-2-one (4ad)
According to GP with 2h (40 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4ah (21 mg, 74%) as a white sol-
id; mp 159 °C.
According to GP with 2d (49 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4ad (17 mg, 52%) as a yellowish
solid; mp 173 °C.
FTIR (neat): 2255, 2210, 1724, 1630, 1538, 1486, 903, 723, 650 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.82–7.72 (m, 2 H), 7.68–7.58 (m, 4 H),
7.56–7.49 (m, 3 H), 6.94 (d, J = 1.5 Hz, 1 H), 6.48 (d, J = 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 162.4, 159.4, 155.6, 136.0, 132.4 (× 2),
130.9, 130.6, 129.4 (× 2), 127.3 (× 2), 126.9 (× 2), 125.6, 109.8, 101.7.
HRMS (ESI): m/z [M + Na]+ calcd for C17H11BrNaO2: 348.9840; found:
348.9835.
FTIR (neat): 2256, 1694, 1628, 1536, 1428, 905, 762, 677 cm–1
.
.
1H NMR (300 MHz, CDCl3): δ = 7.88 (t, J = 1.9 Hz, 1 H), 7.78 (dt, J = 6.7,
1.9 Hz, 1 H), 7.68–7.61 (m, 2 H), 7.55–7.50 (m, 3 H), 7.47–7.36 (m, 2
H), 6.96 (d, J = 1.5 Hz, 1 H), 6.50 (d, J = 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 162.3, 158.9, 155.5, 135.9, 135.4, 133.4,
131.0, 131.0, 130.4, 129.4 (× 2), 126.9 (× 2), 126.0, 124.0, 110.1, 102.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H11ClNaO2: 305.0345; found:
305.0340.
6-(4-Chlorophenyl)-4-phenyl-2H-pyran-2-one (4ae)
6-(Naphthalen-2-yl)-4-phenyl-2H-pyran-2-one (4ai)
According to GP with 2e (40 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4ae (19 mg, 67%) as a white sol-
id; mp 170 °C.
According to GP with 2i (43 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4ai (17 mg, 56%) as a yellowish
solid; mp 148 °C.
FTIR (neat): 2254, 1719, 1628, 1540, 1491, 1094, 903, 723, 650 cm–1
.
FTIR (neat): 2252, 2159, 2067, 1725, 1624, 1533, 903, 722, 650 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.90–7.78 (m, 2 H), 7.68–7.60 (m, 2 H),
7.57–7.46 (m, 3 H), 7.48–7.43 (m, 2 H), 6.94 (d, J = 1.5 Hz, 1 H), 6.48
(d, J = 1.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 162.4, 159.4, 155.6, 137.2, 136.1, 130.9,
130.2, 129.4 (× 4), 127.1 (× 2), 126.9 (× 2), 109.7, 101.7.
1H NMR (300 MHz, CDCl3): δ = 8.49 (br s, 1 H), 8.03–7.80 (m, 4 H),
7.79–7.62 (m, 2 H), 7.64–7.46 (m, 5 H), 7.09 (d, J = 1.5 Hz, 1 H), 6.51
(d, J = 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 162.8, 160.5, 155.8, 136.3, 134.5, 133.2,
130.8, 129.4, 129.3, 129.2, 128.9, 128.7, 127.9, 127.2, 126.9, 126.9,
126.5, 122.3, 109.5, 101.9.
HRMS (ESI): m/z [M + Na]+ calcd for C17H11ClNaO2: 305.0345; found:
305.0340.
HRMS (ESI): m/z [M + Na]+ calcd for C21H14NaO2: 321.0891; found:
321.0886.
6-(4-Fluorophenyl)-4-phenyl-2H-pyran-2-one (4af)
According to GP with 2f (37 mg, 0.20 mmol, 2.0 equiv) and trans-cin-
namaldehyde (1a, 13.2 μL, 0.10 mmol, 1.0 equiv). FC (silica gel, pen-
tane/EtOAc 10:1) afforded α-pyrone 4af (17 mg, 64%) as a white solid;
mp 146 °C.
Acknowledgement
We acknowledge the WWU Münster and NRW Graduate School of
Chemistry for financial support.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
S. Bera, A. Studer
Paper
Synthesis
Supporting Information
F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307.
(m) Menon, R. S.; Biju, A. T.; Nair, V. Chem. Soc. Rev. 2015, 44,
5040.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588336.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(7) For recent reviews, see: (a) Knappke, C. E. I.; Imami, A.; von
Wangelin, A. J. ChemCatChem 2012, 4, 937. (b) De Sarkar, S.;
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5631.
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(13) It is also possible that the intermediate 6 may undergo intramo-
lecular proton transfer to give a ketone enolate which then lac-
tonizes to the corresponding dihydropyranone. Subsequent
double bond isomerization and HNO2 elimination will afford α-
pyrone 4 (Scheme 4). We thank a reviewer for this valuable sug-
gestion.
O
O
O
O
isomerization
R2
6
4
– HNO2
R2
R1
R1
NO2
NO2
Scheme 4
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F