Divergent NHC-catalyzed oxidative transformations of 3-bromoenal: Selective synthesis of 2H-pyran-2-ones and chiral dihydropyranones

Article abstract of DOI:10.1021/jo400950j

A selective synthesis of either 2H-pyran-2-ones (4) or chiral dihydropyranones (6) from the same substrates of 3-bromoenals and 1,3-dicarbonyl compounds upon oxidative N-heterocyclic carbene catalysis is presented. It is shown that the oxidative transformation of 3-bromoenals under NHC catalyst can be well controlled to proceed through two pathways, i.e., elimination of reducible β-bromide or by an external oxidant 3, allowing the selective generation two sorts of unsaturated acyl azoliums, respectively.

Full text of DOI:10.1021/jo400950j

Article
pubs.acs.org/joc
Divergent NHC-Catalyzed Oxidative Transformations of
3‑Bromoenal: Selective Synthesis of 2H‑Pyran-2-ones and Chiral
Dihydropyranones
Gang Wang, Xia Chen, Gaohan Miao, Weijun Yao, and Cheng Ma*
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, China
S
* Supporting Information
ABSTRACT: A selective synthesis of either 2H-pyran-2-ones (4) or chiral dihydropyranones (6) from the same substrates of 3-
bromoenals and 1,3-dicarbonyl compounds upon oxidative N-heterocyclic carbene catalysis is presented. It is shown that the
oxidative transformation of 3-bromoenals under NHC catalyst can be well controlled to proceed through two pathways, i.e.,
elimination of reducible β-bromide or by an external oxidant 3, allowing the selective generation two sorts of unsaturated acyl
azoliums, respectively.
acyl azoliums III or I, respectively (Scheme 2b). Moreover,
both of these resultant species are efficient partners in the
cyclization reaction with 1,3-dicarbonyl nucleophiles, resulting
in selective formation of either 2H-pyran-2-ones11 or chiral
dihyropyranones from same substrates with ease.12
INTRODUCTION
■
Over the past decade, N-heterocyclic carbene (NHC) catalysis
has developed into a powerful tool for chemical synthesis.1
Recently, combinations of nucleophilic NHC catalysis and
oxidative reactions for exploring sequential umpolung proce-
dures2 with more diverse substrates have received enormous
interest and emerged as an active research area.3 In this context,
α,β-unsaturated acyl azoliums I, generated in situ from carbonyl
derivatives upon treatment with NHCs, represent a distinct
reactive intermediate for esterifications,4 amidations,5 Michael
additions,6 and Claisen rearrangements7 (Scheme 1). Signifi-
cant progress has been made by these reactions; however, to
our knowledge, the generation of unsaturated acyl azoliums
containing embedded functional groups, which may be
exploited for further conversion, is yet to be investigated.
We have previously demonstrated that the combination of
NHC catalysts with 3-haloenals 1 may generate β-halogen
substituted Breslow intermediates II,8 which can act as a
masked β-acylvinyl anion9 to cyclize with electrophilic carbonyl,
diazene, or nitroso compounds, resulting in the formation of
several sorts of furan-2-one analogies after subsequent
elimination of the halogen, respectively.10 Notably, in the
case of nitrosoarenes,10b 3-chloroacrylic acids are competitively
formed possibly through the oxidative hydrolysis of the reactive
intermediate II (Scheme 2a). Triggered by these results, we
have focused our attention on the oxidative transformation of
substituted 3-haloenals in the presence of NHC catalysts; as a
result, we report herein that these transformations could be
controlled to proceed via two pathways by employing an
external organic oxidant or not, providing access to unsaturated
RESULTS AND DISCUSSION
■
Our initial experiments explored the reaction of 3-bromo-3-
phenyl-2-propenal (1a) with acetyl acetone (2a) in the
presence of an NHC precursor C, oxidant 3 (3,3′,5,5′-tetra-
tert-butyl-[1,1′-bi(cyclohexane)]-2,2′,5,5′-tetraene-4,4′-dione),
and base in THF at 25 °C. As shown in Table 1, using DBU
(1.5 equiv) as the base, triazolium salt C1 gave 2H-pyran-2-one
4a in 30% yield along with dieneone 5a, arising from a
competitive aldol-dehydration reaction between 1a and 2a; in
contrast, while otherwise identical, triazolium C2 failed to
afford any annulation products (Table 1, entries 1 and 2).
Moreover, other two azolium salts of C3 and C4 produced 4a
in diminished yield (entries 3 and 4). On the other hand, when
employing C1 as the carbene precursor, the base played a
marked influence on this reaction. Switching the base to Et3N
led to 4a in an improved yield of 43% with a small amount of
byproduct 5a (Table 1, entry 5). To our delight, when a set of
inorganic bases such as K2CO3, tBuOK, and NaH were used,
the side reaction to byproduct 5a was completely suppressed
(Table 1, entries 6−8). Still, the use of NaH in THF at 50 °C
provided optimal reaction efficiency to afford 4a in 72% yield,
Received: May 2, 2013
Published: June 5, 2013
© 2013 American Chemical Society
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Scheme 1. Generation of α,β-Unsaturated Acyl Azolium Intermediates I
Scheme 2. NHC-Catalyzed Transformations of 3-Haloenals: Homoenolate II versus α,β-Unsaturated Acyl Azolium Ions I and
III
while lowering the reaction temperature to −20 °C would lead
to a sluggish conversion and reduced yield (entries 9 and 10).
Under the optimal conditions, the 3-chloro counterpart of 1a
also produced 4a but in a lower yield (34%). Interestingly, in
the absence of oxidant 3, a control entry with Et3N as the base
furnished dihydropyranone 6a instead of 4a in 65% yield
(Table 1, entry 11), whereas that of strong base like NaH only
gave trace amounts of 6a in addition to 5a (entry 12). These
results implicate that an uncovered route to α,β-unsaturated
acyl azoliums I from enals with a reducible group at the β-
position is likely involved, as a complement to those of α-
reducible aldehydes.6f,13
Subsequently, the substrates scope for the synthesis of 2H-
pyran-2-ones 4 was evaluated using a range of 1,3-dicarbonyl
compounds (Table 2). Symmetrical 1,3-diketones with aliphatic
and aromatic substituents rendered the corresponding products
4a−d in reasonably good yields. Gratifyingly, unsymmetrical
1,3-diketones only afforded single product regioisomers.
Presumably for electronic effect reasons, the keto function
next to the aromatic substituent preferably acted as the
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a
a
Table 1. Optimization of the Reaction Conditions for 4a
Table 2. Scope of the NHC-Catalyzed Reaction toward 4
b
b
b
entry
C
base
T (°C)
4a (%)
5a (%)
6a (%)
1
2
C1
C2
C3
C4
C1
C1
C1
C1
C1
C1
C1
C1
DBU
DBU
DBU
DBU
Et3N
K2CO3
tBuOK
NaH
NaH
NaH
Et3N
NaH
25
25
30
−
20
31
13
15
9
−
−
−
−
−
−
−
−
−
3
25
17
17
43
21
60
63
4
25
5
25
6
25
−
−
−
−
−
−
20
7
25
8
25
9
−20
50
48
c
10
72 (34)
−
65
d
11
25
−
−
d
12
25
trace
a
Reaction conditions: 1a (0.75 mmol), 2a (0.5 mmol), catalyst C (10
mol %), base (0.75 mmol), and oxidant 3 (0.75 mmol) in THF (10
a
b
c
Reaction conditions: C1 (10 mol %), NaH (1.5 equiv), and oxidant 3
mL) under N2. Isolated yield. Yield of 4a using 3-chloro-3-phenyl-2-
propenal instead of 1a in parentheses. In the absence of 3. DBU =
d
(0.75 mmol) in THF (10 mL) under N2, and then 1a (0.75 mmol), 2a
(0.5 mmol) was added at 50 °C. Yield refers to isolated product.
Solutions of the corresponding substrates 1 and 2 in THF (2 mL)
1,8-diazabicyclo[5.4.0]undec-7-ene.
b
each were simultaneously added via syringe pumps for 1 h.
nucleophile in the cyclization reaction to give the stable isomers
(4e, 4r, and 4t). Moreover, β-keto esters were also found to be
good substrates, allowing efficient formation of pyran-2-ones
4f−j and 4u. Next, variation in enal partner was examined.
Electron-rich and electron-poor aromatic, as well as hetero-
aromatic 3-bromoenals all reacted smoothly to produce the
desired products 4k−t. The placement of o-substituted phenyl
and 1-naphthyl in the β-position of enals 1 was tolerated to
provide 4k and 4p in 79 and 61% yield, respectively, indicating
that steric nature in the aromatic moiety of 1 has no negative
effects on this reaction. In addition, alkenyl-substituted enal
also underwent the reaction to give pyranone 4s. However,
alkyl-substituted 3-bromoenals could not achieve this cycliza-
tion reaction under the current reaction conditions.
Next, an asymmetric variation of the aforementioned
cyclization of 1a and 2a in the absence of oxidant 3 toward
dihydropyranone 6a was explored using a set of chiral NHC
precursors instead of C1 as the catalyst (Table 3). After
assessing three chiral azolium salts, we were delighted to find
that triazolium catalyst C5, developed by Enders,14 was the
most effective to afford product 6a in 53% ee albeit in very low
yield (Table 3, entries 2−4). Using C5 as the catalyst, key
results of our optimization (Table 3, entries 5−11) included a
sharp improvement in yield when 1,4-diazabicyclo[2.2.2]octane
(DABCO) was used as the base to generate the carbene (39%
ee, entry 8) and the observation that a mixture of Tol/tBuOH
(v/v = 10/1) was the choice of solvent to furnish the product
6a in 81% yield and 85% ee (entry 11). Moreover, the addition
of LiCl (10 mol %) further improved both the yield and ee
value of product 6a (94% yield, 92% ee, entry 12), indicating
that NHC/Lewis acid co-operative catalysis15 was beneficial for
this enantioselective cyclization reaction.16
A variety of aromatic 3-bromoenals with electron-donating
and electron-withdrawing groups reacted easily with acetyl
acetone, generating the corresponding products 6b−e in
moderate to good yields with consistently good enantioselecti-
vites (Table 4). Sterically hindered enal with a methyl group at
the ortho position was also tolerated to afford compound 6d in
moderate yield still with 90% ee. Heteroaromatic substrates like
3-bromo-3-(thiophen-2-yl)acrylaldehyde were also successful in
yielding the expected product 6f with high stereocontrol. Upon
replacing the β-aryl group of enals with an alkenyl substituent,
decreased yield and stereoinduction was observed for the
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a
Table 3. Optimization of the Enantioselective Formation of
6a
Table 4. Enantioselective Formation of 6
a
b
c
entry
C
base/additive
solvent
yield (%) ee (%)
1
C1
C5
C6
C7
C5
C5
C5
C5
C5
C5
C5
C5
Et3N
THF
THF
THF
THF
THF
THF
THF
THF
65
12
−
53
−
2
Et3N
3
DABCO
tBuOK
0
4
24
7
5
NaH
0
6
DIPEA
K2CO3
trace
trace
72
7
8
DABCO
DABCO
DABCO
DABCO
DABCO/LiCl
39
80
9
toluene
32
10
11
12
DMF
44
−17
85
Tol/tBuOH = 10/1
Tol/tBuOH = 10/1
81
94
92
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10 mol
%), additive (10 mol %), and base (0.3 mmol) in solvent (2 mL) at 25
b
c
°C. Isolated yield. Determined by chiral HPLC analysis.
desired product 6g. Several 1,3-dicarbonyl compounds were
also tested in the reaction with 1a. Symmetrical 1,3-diketones
as well as β-ketoesters could serve as suitable nucleophiles for
this reaction (6h−l); nevertheless, possibly due to steric effects,
those containing large alkyl groups or aromatic ring substrates
provided products (6h and 6l) with slightly lower ee values.
Finally, the absolute configuration of (S)-6f was established by
X-ray analysis; others were assigned by analogy.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), C5 (10 mol %),
LiCl (10 mol %), DABCO (1.5 equiv) in toluene/tBuOH (v/v = 10:1,
2 mL) at 25 °C. Yield refers to isolated product. The ee values were
b
determined by chiral HPLC analysis. At 0 °C.
To gain insights into the mechanism, H2O was used as the
nucleophile instead of 1,3-carbonyl compounds 2 to interrupt
the current NHC-catalyzed diverse transformations of 3-
bromoenals, giving access to cinnamic acid and 3-bromo-3-
phenylacrylic acid (7) in 71 and 75% yield, respectively
(Scheme 3). Moreover, (E)-2-hydroxyphenyl 3-phenylacrylate
(8) could also be isolated in 80% yield from 1a and
pyrocatechol. These results indicated that the unsaturated
acylazolium ions I and III could be formed under these reaction
conditions.
On the basis of these experimental results, a postulated
catalytic cycle is depicted in Scheme 4. Thus, the addition of in
situ generated carbene to 3-bromoenals initially gives
conjugated β-bromo Breslow intermediates II and II′. Upon
treatment with an external oxidant, β-bromo unsaturated acyl
azoliums III are thereby formed. Attacked by deprotonated 1,3-
dicarbonyl compounds 2′, presumably via 1,4-adducts IV,17 the
intermediates III undergo subsequent cyclization and elimi-
nation of the bromide to furnish 2H-pyran-2-ones 4 with
liberation of carbene catalyst. On the other hand, in the absence
of external oxidants, proton transfer of homoenolate II′ by a
weak base like DABCO would yield ester enolates V, which
afford azoliums I after elimination of bromide. Subsequently,
the Michael addition of 1,3-carbonyl compounds onto I
followed by ring-closure to provide the annulation product 6
and regenerate the catalyst.
CONCLUSION
■
In summary, we have presented a flexible protocol for the
selective synthesis of either chiral dihydropyranones or 2H-
pyran-2-ones from the same starting materials of 3-bromoenals
and 1,3-dicarbonyl compounds upon controlled and divergent
NHC-catalyzed oxidative transformations. Mechanistically,
taking advantage of the embedded β-reducible halogen, the
oxidative transformation of 3-bromoenals under NHC catalysis
can be well controlled to proceed through either internal or
external pathways, allowing the selective generation two sorts of
unsaturated acyl azoliums I or III, respectively. The current
research on the reactivity of β-bromoenal constitutes a
complement to those of α-reducible aldehydes in NHC
catalysis.
EXPERIMENTAL SECTION
General Methods. All reactions were performed under a nitrogen
atmosphere, with dry, freshly distilled solvents in anhydrous
■
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Scheme 3. Interruption of the NHC-Catalyzed Oxidative Conversions of 1a
brine, the organic phase was dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel (300−400 mesh) to afford the
corresponding compounds 1.
Scheme 4. Proposed Catalytic Cycle
3-Bromo-3-phenylacrylaldehyde (1a).18 The title compound
was obtained according to the general procedure described above after
flash column chromatography (eluting with n-hexane/EtOAc 30/1) as
a yellow oil (0.85 g, 81%): 1H NMR (400 MHz, CDCl3) δ 10.07 (d, J
= 6.8 Hz, 1H), 7.72−7.69 (m, 2H), 7.49−7.41 (m, 3H), 6.79 (d, J =
6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.6, 189.6, 145.0,
137.4, 131.7, 128.8, 128.1, 127.5.
3-Bromo-3-(o-tolyl)acrylaldehyde (1b). The title compound
was obtained according to the general procedure described above after
flash column chromatography (eluting with n-hexane/EtOAc 30/1) as
a yellow oil (0.86 g, 76%): 1H NMR (400 MHz, CDCl3) δ 10.05, 9.13
(d, J = 7.2 Hz, 1H), 7.34−7.24 (m, 4H), 6.79, 6.39 (d, J = 7.2 Hz, 1H),
2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.4, 189.4, 149.4,
144.1, 139.1, 136.2, 135.7, 135.4, 134.9, 131.0, 130.8, 130.8, 130.3,
130.1, 128.9, 128.2, 126.0, 19.9, 19.5; IR (thin film) ν 3062, 2846,
1682, 1609, 1250, 1116, 854, 757 cm−1; HRMS (EI) calculated for
C10H9BrO, [M]+, 223.9837, found 223.9845.
3-Bromo-3-(4-nitrophenyl)acrylaldehyde (1c). The title com-
pound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 30/1) as a yellow solid (0.91 g, 71%): mp 57−59 °C (EtOAc/
n-hexane); 1H NMR (400 MHz, CDCl3) δ 10.08 (d, J = 6.0 Hz, 1H),
8.31 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 192.7, 149.3, 143.3, 141.0,
129.9, 129.0, 124.0; IR (KBr) ν 3017, 2853, 1679, 1590, 1518, 1348,
1124, 841 cm−1; HRMS (EI) calculated for C9H6BrNO3, [M]+,
254.9531, found 254.9536.
3-Bromo-3-(thiophen-2-yl)acrylaldehyde (1d). The title com-
pound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 30/1) as a yellow solid (0.74 g, 68%): mp 50−52 °C (EtOAc/
n-hexane); 1H NMR (400 MHz, CDCl3) δ 10.00 (d, J = 6.4 Hz, 1H),
7.68 (d, J = 3.2 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.15 (t, J = 4.0 Hz,
1H), 6.78 (d, J = 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.1,
141.1, 135.3, 131.9, 131.2, 128.4, 124.2; IR (KBr) ν 3130, 2876, 1663,
1383, 1218, 1069, 876, 652 cm−1; HRMS (EI) calculated for
C7H5BrOS, [M]+, 215.9244, found 215.9238.
conditions. Column chromatography was conducted on silica gel
(300−400 mesh) using compound-appropriate mixtures of n-hexane
and EtOAc as eluent. Infrared spectra were recorded as thin films on
NaCl plates unless otherwise indicated and are reported in cm−1.
1
HRMS data was collected using a TOF mass spectrometer. H NMR
(400 or 500 MHz) and 13C NMR (100 or 125 MHz) spectra were
recorded in deuterated solvents and are reported in ppm relative to
tetramethylsilane (TMS).
3-Bromo-3-(furan-2-yl)acrylaldehyde (1e). The title compound
was obtained according to the general procedure described above after
flash column chromatography (eluting with n-hexane/EtOAc 30/1) as
A variety of substituted 3-bromoenals (1) were synthesized from
the corresponding ketones with Vilsmeier−Haack according to the
literature.10,18 All other chemicals were obtained from commercial
sources and used without further purification.
1
a yellow solid (0.69 g, 69%): mp 68−70 °C (EtOAc/n-hexane); H
Preparation of 3-Bromoenals. A solution of DMF (15 mmol, 3.0
equiv) in CHCl3 (10 mL) was cooled to 0 °C, followed by the
addition of PBr3 (13.5 mmol, 2.7 equiv) over 15 min. The reaction
mixture was stirred for another 1 h at room temperature; during this
time, yellow solid precipitated in the solution. Ketone (5 mmol, 1.0
equiv) was added, and the mixture was then stirred overnight. The
resulting mixture was poured into ice water, neutralized with K2CO3 to
pH = 8, and extracted with Et2O (30 mL × 3). After washing with
NMR (400 MHz, CDCl3) δ 10.00−9.96 (m, 1H), 7.61−7.60 (m, 1H),
7.12−7.11 (m, 1H), 6.91−6.87 (m, 1H), 6.57−6.56 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ = 192.8, 192.8, 150.2, 146.7, 129.1, 122.6,
122.6, 118.0, 113.1; IR (KBr) ν 3118, 2869, 1655, 1588, 1468, 1125,
949, 767 cm−1; HRMS (EI) calculated for C7H5BrO2, [M]+, 199.9473,
found 199.9470.
(4E)-3-Bromo-5-phenylpenta-2,4-dienal (1f). The title com-
pound was obtained according to the general procedure described
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above after flash column chromatography (eluting with n-hexane/
EtOAc 30/1) as a yellow solid (0.83 g, 70%): mp 75−78 °C (EtOAc/
n-hexane); 1H NMR (400 MHz, CDCl3) δ 10.12−9.96 (m, 1H),
7.74−7.39 (m, 6H), 6.87 (d, J = 5.6 Hz, 1H), 6.61−6.48 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 193.5, 187.0, 144.2, 142.1, 141.9, 134.9,
131.3, 130.3, 130.2, 129.1, 128.9, 128.2, 128.1, 126.4, 121.4; IR (KBr)
ν 3024, 2848, 1665, 1610, 1567, 1155, 953, 751 cm−1; HRMS (EI)
calculated for C11H9BrO, [M]+, 235.9837, found 235.9841.
3-Bromo-3-(4-bromophenyl)acrylaldehyde (1g). The title
compound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 30/1) as a yellow solid (1.18 g, 82%): mp 89−92 °C (EtOAc/
n-hexane); 1H NMR (400 MHz, CDCl3) δ 10.05 (d, J = 6.8 Hz, 1H),
7.58 (s, 4H), 6.78 (d, J = 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
193.3, 143.3, 136.3, 132.1, 129.4, 127.7, 126.3; IR (KBr) ν 3030, 2861,
1685, 1526, 1127, 849, 753, 694 cm−1; HRMS (EI) calculated for
C9H6Br2O, [M]+, 287.8785, found 287.8789.
stirring for 5 min, cyclohexane-1,3-dione (56 mg, 0.5 mmol, in 2 mL
THF) and 3-bromo-3-phenylacrylaldehyde (158.3 mg, 0.75 mmol, in 2
mL THF) were simultaneously added using syringe pumps for 1 h.
The mixture was stirred for additional 30 min and then was neutralized
by aqueous solution of HCl (1.2 M), extracted with CH2Cl2 (5 mL ×
3). After washing with brine (10 mL), the organic phase was dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel
(300−400 mesh) with n-hexane/EtOAc 4:1 as an eluent to afford 4d
(69.6 mg, 58%) as a pale yellow solid: mp 166−168 °C (EtOAc/n-
1
hexane); H NMR (500 MHz, CDCl3) δ 7.41−7.37 (m, 3H), 7.20−
7.18 (m, 2H), 6.08 (s, 1H), 2.94 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5
Hz, 2H), 2.19−2.14 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 193.1,
174.8, 159.4, 156.6, 137.3, 128.9, 127.9, 127.0, 114.4, 114.2, 38.2, 29.2,
19.8; IR (KBr) ν 3052, 2946, 1759, 1682, 1533, 1393, 1293, 1016
cm−1; HRMS (EI) calculated for C15H12O3, [M]+, 240.0786, found
240.0782.
General Procedure for the Synthesis of 2H-Pyran-2-one (4).
NaH (60%, 30 mg, 0.75 mmol) was added to a suspension of
triazolium salt C1 (13 mg, 0.05 mmol) in anhydrous THF (4 mL)
under N2. The mixture was stirred for 5 min, followed by the addition
of 1,3-dicarbonyl compounds 2 (0.5 mmol, 1.0 equiv) and 3,3′,5,5′-
tetra-tert-butyldiphenoquinone (3, 306.5 mg, 0.75 mmol). After
stirring for 5 min, a solution of 3-haloenals 1 (0.75 mmol, 1.5
equiv) in THF (1 mL) was added. The mixture was stirred at 50 °C
until complete consumption of 2; the reaction was neutralized by
aqueous solution of HCl (1.2 M) and extracted with CH2Cl2 (5 mL ×
3). After washing with brine (10 mL), the combined organic phase was
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by column chromatography to
afford compounds 4.
5-Benzoyl-6-methyl-4-phenyl-2H-pyran-2-one (4e). The title
compound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 4/1) as a white solid (130.9 mg, 90%): mp 137−139 °C
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.68−7.65 (m,
2H), 7.48−7.44 (m, 1H), 7.32 (t, J = 6.8 Hz, 2H), 7.22−7.18 (m, 5H),
6.24 (s, 1H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.0,
162.1, 161.1, 156.3, 137.0, 136.0, 133.7, 129.6, 129.1, 128.6, 127.3,
117.9, 111.6, 18.8; IR (KBr) ν 3062, 1736, 1664, 1622, 1543, 1287,
1166, 917 cm−1; HRMS (EI) calculated for C19H14O3, [M]+, 290.0943,
found 290.0951.
Ethyl 6-cyclopropyl-2-oxo-4-phenyl-2H-pyran-5-carboxy-
late (4f). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 3/1) as a yellow solid (96.6 mg, 68%): mp
126−128 °C (EtOAc/n-hexane); 1H NMR (500 MHz, CDCl3) δ
7.43−7.40 (m, 3H), 7.31−7.27 (m, 2H), 6.06 (s, 1H), 3.97 (q, J = 7.5
Hz, 2H), 2.39−2.36 (m, 1H), 1.35−1.32 (m, 2H), 1.11−1.08 (m, 2H),
0.84 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 168.3, 166.2,
160.3, 158.4, 137.5, 129.4, 128.7, 126.6, 111.9, 110.3, 61.5, 13.4, 12.6,
10.1; IR (KBr) ν 3069, 2984, 1721, 1607, 1390, 1254, 1165, 1068
cm−1; HRMS (EI) calculated for C17H16O4, [M]+, 284.1049, found
284.1047.
5-Acetyl-6-methyl-4-phenyl-2H-pyran-2-one (4a). The title
compound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 3/1) as a yellow solid (82.2 mg, 72%): mp 120−122 °C
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.50−7.44 (m,
3H), 7.34−7.29 (m, 2H), 6.19 (s, 1H), 2.36 (s, 3H), 1.83 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 200.7, 162.3, 160.8, 155.1, 136.4, 130.3,
129.4, 127.1, 120.9, 111.8, 31.8, 18.6; IR (KBr) ν 3067, 1740, 1697,
1538, 1389, 1288, 772, 700 cm−1; HRMS (EI) calculated for
C14H12O3, [M]+, 228.0786, found 228.0783.
Ethyl 2-oxo-4,6-diphenyl-2H-pyran-5-carboxylate (4g). The
title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 4/1) as a white solid (139.3 mg, 87%): mp 112−114
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.66−7.64 (m,
2H), 7.50−7.41 (m, 6H), 7.38−7.36 (m, 2H), 6.28 (s, 1H), 3.93 (q, J
= 7.2 Hz, 2H), 2.46 (s, 3H), 0.86 (t, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 165.9, 161.0, 160.5, 156.1, 136.3, 131.7, 131.1, 129.7, 128.7,
128.6, 128.2, 127.0, 113.6, 112.8, 61.9, 13.3; IR (KBr) ν 3060, 2984,
1735, 1618, 1534, 1382, 1263, 1001 cm−1; HRMS (EI) calculated for
C20H16O4, [M]+, 320.1049, found 320.1053.
5-Hexanoyl-6-pentyl-4-phenyl-2H-pyran-2-one (4b). The title
compound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 6/1) as a yellow solid (105.6 mg, 62%): mp 32−33 °C
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.47−7.42 (m,
3H), 7.31−7.30 (m, 2H), 6.17 (s, 1H), 2.51 (t, J = 6.8 Hz, 2H), 2.00
(t, J = 7.2 Hz, 2H), 1.76−1.72 (m, 2H), 1.36−1.29 (m, 6H), 1.10−
1.05 (m, 2H), 0.99−0.89 (m, 5H), 0.76 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ = 203.8, 165.1, 161.2, 155.1, 136.5, 130.1, 129.3,
127.3, 120.4, 111.8, 44.7, 32.0, 31.5, 30.9, 27.7, 23.5, 22.3, 22.1,13.9,
13.8; IR (KBr) ν 3061, 2954, 2930, 2861, 1732, 1693, 1539, 1383
cm−1; HRMS (EI) calculated for C22H28O3, [M]+, 340.2038, found
340.2046.
Methyl 6-methyl-2-oxo-4-phenyl-2H-pyran-5-carboxylate
(4h). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 4/1) as a yellow solid (83.0 mg, 68%): mp 81−
5-Benzoyl-4,6-diphenyl-2H-pyran-2-one (4c). The title com-
pound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 4/1) as a yellow solid (137.4 mg, 78%): mp 180−182 °C
1
83 °C (EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.43−7.41
(m, 3H), 7.29−7.27 (m, 2H), 6.17 (s, 1H), 3.51 (s, 3H), 2.45 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 166.4, 164.5, 160.7, 155.9, 137.0,
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0
129.6, 128.7, 126.5, 112.6, 111.8, 52.3, 19.1 ppm; IR (KBr) ν 3065,
2951, 1713, 1630, 1546, 1443, 1293, 1086 cm−1; HRMS (EI)
calculated for C14H12O4, [M]+, 244.0736, found 244.0733.
Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.31−7.28
(m,1H), 7.26−7.19 (m, 9H), 6.36 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 193.8, 160.9, 160.3, 157.2, 137.1, 135.9, 133.7, 131.5, 131.0,
129.5, 129.3, 129.2, 128.7, 128.6, 128.5, 127.5, 117.9, 113.3; IR (KBr)
ν 3060, 1724, 1664, 1448, 1372, 1259, 1007, 911 cm−1; HRMS (EI)
calculated for C24H16O3, [M]+, 352.1099, found 352.1095.
4-Phenyl-7,8-dihydro-2H-chromene-2,5(6H)-dione (4d). NaH
(60%, 30 mg, 0.75 mmol) was added to a suspension of triazolium salt
C1 (13 mg, 0.05 mmol) in anhyd. THF (4 mL) under N2. The
mixture was heated to 50 °C, followed by the addition of 3,3′,5,5′-
tetra-tert-butyl-diphenoquinone (3, 306.5 mg, 0.75 mmol). After
Methyl 6-isopropyl-2-oxo-4-phenyl-2H-pyran-5-carboxylate
(4i). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
1
with n-hexane/EtOAc 4/1) as a pale yellow oil (99.3 mg, 73%): H
NMR (400 MHz, CDCl3) δ 7.43−7.40 (m, 3H), 7.31−7.29 (m, 2H),
6.16 (s, 1H), 3.52 (s, 3H), 3.19−3.09 (m, 1H), 1.32 ppm (d, J = 6.8
Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 170.5, 166.4, 160.9, 155.8,
136.8, 129.7, 128.8, 126.6, 111.8, 111.4, 52.4, 31.5, 20.2 ppm; IR (thin
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film) ν 3062, 2926, 1719, 1629, 1544, 1439, 1270, 1081 cm−1; HRMS
(EI) calculated for C16H16O4, [M]+, 272.1049, found 272.1043.
Methyl 2-oxo-6-pentyl-4-phenyl-2H-pyran-5-carboxylate
(4j). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 6/1) as a colorless oil (91.6 mg, 61%): 1H NMR
(400 MHz, CDCl3) δ 7.43−7.41 (m, 3H), 7.30−7.28 (m, 2H), 6.17 (s,
1H), 3.51 (s, 3H), 2.68 (t, J = 8.0 Hz, 2H), 1.79−1.73 (m, 2H), 1.37−
1.34 (m, 4H), 0.91 ppm (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.7, 166.4, 160.8, 155.8, 136.9, 129.6, 128.7, 126.6, 112.5,
111.7, 52.3, 32.4, 31.3, 27.4, 22.3, 13.9 ppm; IR (thin film) ν 3059,
2965, 2926, 2857, 1730, 1623, 1534, 1369 cm−1; HRMS (EI)
calculated for C18H20O4, [M]+, 300.1362, found 300.1364.
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.96−7.90 (m,
2H), 7.80 (d, J = 8.0 Hz, 1H), 7.55−7.50 (m, 3H), 7.35 (d, J = 7.2 Hz,
1H), 6.29 (s, 1H), 2.42 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 199.7, 163.0, 160.5, 154.3, 134.0, 133.6, 130.3, 129.9, 128.7,
127.5, 127.0, 126.0, 125.3, 124.7, 122.1, 113.8, 31.2, 19.1; IR (KBr) ν
3062, 1736, 1686, 1524, 1283, 1247, 1055, 890 cm−1; HRMS (EI)
calculated for C18H14O3, [M]+, 278.0943, found 278.0948.
5-Acetyl-6-methyl-4-(thiophen-2-yl)-2H-pyran-2-one (4q).
The title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 4/1) as a yellow solid (72.6 mg, 62%): mp 94−96 °C
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.52−7.50 (m,
1H), 7.16−7.11 (m, 2H), 6.27 (s, 1H), 2.31 (s, 3H), 2.08 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 201.1, 161.3, 160.6, 147.1, 137.0, 129.4,
129.0, 128.7, 120.2, 110.8, 32.0, 18.5; IR (KBr) ν 3097, 1728, 1689,
1544, 1382, 1247, 889, 743 cm−1; HRMS (EI) calculated for
C12H10O3S, [M]+, 234.0351, found 234.0359.
5-Acetyl-6-methyl-4-o-tolyl-2H-pyran-2-one (4k). The title
compound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 4/1) as a yellow solid (95.7 mg, 79%): mp 127−129 °C
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 7.6
5-Acetyl-4-(furan-2-yl)-6-phenyl-2H-pyran-2-one (4r). The
title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 4/1) as a yellow solid (100.8 mg, 72%): mp 170−172
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 6.8
Hz, 2H), 7.62 (t, J = 6.8 Hz, 2H) 7.48 (t, J = 6.8 Hz, 1H), 7.37 (s, 1H),
6.59 (d, J = 6.8 Hz, 1H), 6.56 (s, 1H), 6.34−6.33 (m, 1H), 2.15 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 194.1, 161.6, 160.8, 147.3,
145.4, 142.2, 136.7, 134.4, 129.3, 129.1, 114.8, 114.4, 112.7, 106.0,
18.8; IR (KBr) ν 3133, 3117, 1713, 1664, 1624, 1579, 1298, 1023
cm−1; HRMS (EI) calculated for C17H12O4, [M]+, 280.0736, found
280.0734.
(E)-5-Benzoyl-6-phenyl-4-styryl-2H-pyran-2-one (4s). The
title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 4/1) as a yellow solid (85.1 mg, 45%): mp 171−174
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.80−7.78 (m,
2H), 7.54−7.52 (m, 2H), 7.46−7.44 (m, 1H), 7.35−7.29 (m, 9H),
7.27−7.22 (m, 2H); 6.71 (d, J = 16.0 Hz, 1H), 6.62 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 194.5, 161.4, 159.9, 152.0, 137.9, 137.0, 135.3,
134.2, 131.6, 131.0, 129.7, 129.5, 128.8, 128.8, 128.7, 128.5, 127.6,
121.6, 117.0, 107.5; IR (KBr) ν 3069, 1713, 1659, 1597, 1492, 1447,
1382, 959 cm−1; HRMS (EI) calculated for C26H18O3, [M]+, 378.1256,
found 378.1262.
5-Acetyl-4,6-bis(4-bromophenyl)-2H-pyran-2-one (4t). The
title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 3/1) as a yellow solid (104.8 mg, 47%): mp 181−183
°C (EtOAc/n-hexane); 1H NMR (500 MHz, CDCl3) δ 7.56−7.50 (m,
4H), 7.38−7.36 (m, 2H), 7.06−7.04 (m, 2H), 6.21 (s, 1H), 2.25 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 192.8, 162.6, 160.6, 154.8,
135.7, 134.7, 132.3, 132.1, 130.6, 129.6, 128.8, 124.5, 117.1, 112.0,
19.0; IR (KBr) ν 3060, 1741, 1666, 1625, 1549, 1294, 1171, 924 cm−1;
HRMS (EI) calculated for C19H12Br2O3, [M]+, 445.9153, found
445.9151.
Hz, 1H), 7.28−7.24 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 6.08 (s, 1H),
2.36 (s, 3H), 2.25 (s, 3H), 1.75 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 199.9, 162.7, 160.6, 155.4, 136.1, 134.7, 131.1, 129.7, 127.9, 126.4,
121.7, 112.8, 31.3, 19.8, 19.0; IR (KBr) ν 3070, 1755, 1686, 1538,
1382, 1287, 873, 769 cm−1; HRMS (EI) calculated for C15H14O3,
[M]+, 242.0943, found 242.0948.
5-Acetyl-6-methyl-4-p-tolyl-2H-pyran-2-one (4l). The title
compound was obtained according to the general procedure described
above after flash column chromatography (eluting with n-hexane/
EtOAc 4/1) as a yellow solid (82.4 mg, 68%): mp 134−136 °C
1
(EtOAc/n-hexane); H NMR (400 MHz, CDCl3) δ 7.28−7.21 (m,
4H), 6.17 (s, 1H), 2.41 (s, 3H), 2.34 (s, 3H), 1.85 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 200.9, 162.0, 160.8, 155.0, 140.6, 133.4, 130.0,
127.0, 120.8, 111.3, 31.8, 21.3, 18.5 ppm; IR (KBr) ν 3061, 1732,
1615, 1537, 1382, 1285, 897, 816 cm−1; HRMS (EI) calculated for
C15H14O3, [M]+, 242.0943, found 242.0940.
5-Acetyl-4-(4-methoxyphenyl)-6-methyl-2H-pyran-2-one
(4m). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 4/1) as a yellow solid (91.7 mg, 71%): mp
115−117 °C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.27
(d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.15 (s, 1H), 3.86 (s,
3H), 2.34 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
201.1, 162.0, 161.4, 161.0. 154.7, 128.7, 128.5, 120.9, 114.8, 110.9,
55.4, 31.9, 18.6; IR (KBr) ν 3067, 1732, 1682, 1610, 1514, 1252, 899,
849 cm−1; HRMS (EI) calculated for C15H14O4, [M]+, 258.0892,
found 258.0893.
5-Acetyl-6-methyl-4-(4-nitrophenyl)-2H-pyran-2-one (4n).
The title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 3/1) as a yellow solid (81.3 mg, 68%): mp 150−152
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0
Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 6.15 (s, 1H), 2.31 (s, 3H), 1.85 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 198.5, 162.1, 158.8, 151.6,
147.7, 141.5, 127.3, 123.5, 119.1, 112.0, 31.1, 17.9; IR (KBr) ν 3059,
1740, 1669, 1615, 1542, 1291, 1154, 923 cm−1; HRMS (EI) calculated
for C14H11NO5, [M]+, 273.0637, found 273.0631.
5-Acetyl-4-(4-fluorophenyl)-6-methyl-2H-pyran-2-one (4o).
The title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 4/1) as a yellow solid (75.0 mg, 61%): mp 127−128
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.36−7.29 (m,
2H), 7.19−7.15 (m, 2H), 6.16 (s, 1H), 2.35 (s, 3H), 1.87 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 200.6, 163.9 (JC−F = 249.8 Hz),
162.4, 160.6, 154.0, 132.4 (JC−F = 3.9 Hz), 129.2 (JC−F = 8.3 Hz),
120.7, 116.6 (JC−F = 21.1 Hz), 111.9, 31.9, 18.6 ppm; IR (KBr) ν 3059,
1736, 1699, 1508, 1287, 1225, 850, 841 cm−1; HRMS (EI) calculated
for C14H11FO3, [M]+, 246.0692, found 246.0687.
Methyl 4-(3,4-dimethoxyphenyl)-2-oxo-6-(3,4,5-trimethoxy-
phenyl)-2H-pyran-5-carboxylate (4u). The title compound was
obtained according to the general procedure described above after
flash column chromatography (eluting with n-hexane/EtOAc 3/1) as a
yellow solid (191.7 mg, 84%): mp 100−102 °C (EtOAc/n-hexane);
1H NMR (400 MHz, CDCl3) δ 6.96−6.91 (m, 5H), 6.27 (s, 1H), 3.93
(s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.88 (s, 6H), 3.54 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.0, 160.5, 160.1, 155.5, 153.1, 150.4,
149.0, 140.5, 128.4, 126.6, 119.8, 113.1, 111.7, 111.1, 110.0, 105.4,
60.9, 56.1, 55.8, 52.8 ; IR (KBr) ν 2943, 2840, 1729, 1583, 1513, 1422,
1352, 1130 cm−1; HRMS (EI) calculated for C24H24O9, [M]+,
456.1420, found 456.1424.
(Z)-3-(3-Bromo-3-phenylallylidene)pentane-2,4-dione (5a).
The title compound was obtained as a byproduct of 4a when DBU
was used as base after flash column chromatography (eluting with n-
hexane/EtOAc 3/1) as a yellow solid (29.3 mg, 20%): mp 104−106
°C (EtOAc/n-hexane); 1H NMR (400 MHz, CDCl3) δ 7.66−7.64 (m,
2H), 7.58 (d, J = 10.8 Hz, 1H), 7.40−7.37 (m, 3H), 7.21 (d, J = 10.8
5-Acetyl-6-methyl-4-(naphthalen-1-yl)-2H-pyran-2-one (4p).
The title compound was obtained according to the general procedure
described above after flash column chromatography (eluting with n-
hexane/EtOAc 3/1) as a yellow solid (84.8 mg, 61%): mp 167−169
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Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
202.9, 197.5, 143.6, 139.5, 139.0, 138.5, 130.6, 128.7, 128.2, 123.9,
31.7, 26.5; IR (KBr) ν 3059, 2924, 1663, 1599, 1247, 1183, 1154, 761
cm−1; HRMS (EI) calculated for C14H13BrO2, [M]+ 292.0099, found
292.0097.
1H), 2.45 (s, 3H), 2.40 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 196.9, 164.6, 159.5, 136.2, 133.7, 130.4, 126.9, 124.5, 116.3,
34.5, 34.0, 28.3, 18.2, 18.0; IR (thin film) ν 2926, 1686, 1676, 1615,
1597, 1443, 1332, 1171 cm−1; HRMS (EI) calculated for C15H16O3,
[M]+, 244.1099, found 244.1101. The ee value was determined by
HPLC with Chiralpack OD−H column at 254 nm (hexane/iPrOH =
85:15, flow rate = 0.8 mL/min), tR = 17.23 min (minor), tR = 18.46
min (major).
(R)-5-Acetyl-6-methyl-4-p-tolyl-3,4-dihydro-2H-pyran-2-one
(6e). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 5/1) as a white solid (31.7 mg, 65%, 90% ee):
[α]D20 = −43.2 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.13
(d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 4.10 (d, J = 6.8 Hz, 1H),
2.94 (dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1H), 2.81 (J1 = 15.6 Hz, J2 = 2.8
Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 198.1, 165.8, 160.1, 137.7, 136.7, 130.1, 126.6, 117.4,
38.5, 37.3, 29.7, 21.0, 19.1; IR (thin film) ν 2923, 1784, 1692, 1514,
1420, 1359, 1171, 1114 cm−1; HRMS (EI) calculated for C15H16O3,
[M]+, 244.1099, found 244.1100. The ee value was determined by
HPLC with Chiralpack OD−H column at 254 nm (hexane/iPrOH =
85:15, flow rate = 0.8 mL/min), tR = 15.84 min (minor), tR = 19.44
min (major).
(S)-5-Acetyl-6-methyl-4-(thiophen-2-yl)-3,4-dihydro-2H-
pyran-2-one (6f). The title compound was obtained according to the
general procedure described above after flash column chromatography
(eluting with n-hexane/EtOAc 5/1) as a white solid (33 mg, 70%, 90%
ee): [α]D20 = −19.8 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.17 (d, J = 5.2 Hz, 1H), 6.92−6.89 (m, 1H), 6.82 (d, J = 3.6 Hz,1H),
4.53 (d, J = 6.4 Hz, 1H), 3.76 (s, 3H), 3.01 (dd, J1 = 16.0 Hz, J2 = 2.0
Hz, 1H), 2.93 (dd, J1 = 16.0 Hz, J2 = 6.8 Hz, 1H) 2.44 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.1, 165.8, 162.1, 143.5, 127.1, 124.7,
124.1, 110.3, 52.0, 36.5, 32.9, 19.0; IR (thin film) ν 2922, 1784, 1689,
1609, 1379, 1277, 1145, 1115 cm−1; HRMS (EI) calculated for
C12H12O3S, [M]+, 236.0507, found 236.0502. The ee value was
determined by HPLC with Chiralpack OD−H column at 254 nm
(hexane/iPrOH = 85:15, flow rate = 0.8 mL/min), tR = 17.13 min
(minor), tR = 20.79 min (major).
General Procedure for the Synthesis of 3,4-Dihydro-2H-
pyran-2-one (6). DABCO (34.8 mg, 0.3 mmol) was added to a
mixture of 3-bromoenals 1 (0.2 mmol), 1,3-dicarbonyl compounds 2
(0.3 mmol, 1.5 equiv), chiral triazolium salt C5 (7.7 mg, 0.02 mmol),
and LiCl (0.85 mg, 0.02 mmol) in toluene/tBuOH (2 mL, v/v = 10:1)
in a Schlenk tube under N2 at 25 °C. The reaction mixture was stirred
for 1 h until complete consumption of 1 (detected by TLC). The
reaction was then quenched with H2O (5 mL) and extracted with
CH2Cl2 (5 mL × 3). After washing with brine (10 mL), the combined
organic phase was dried over anhydrous Na2SO4 and concentrate
under reduced pressure. The residue was purified by column
chromatography on silica gel (300−400 mesh) to afford compounds 6.
(R)-5-Acetyl-6-methyl-4-phenyl-3,4-dihydro-2H-pyran-2-one
(6a). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 5/1) as a white solid (43.2 mg, 94%, 92% ee):
20
1
[α]D = −116.1 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.36−7.32 (m, 2H), 7.29−7.27 (m, 1H), 7.16−7.14 (m, 2H), 4.15 (d, J
= 6.0 Hz, 1H), 2.97 (dd, J1 = 16.0 Hz, J2 = 7.6 Hz, 1H), 2.83 (dd, J1 =
16.0 Hz, J2 = 2.8 Hz, 1H), 2.43 (s, 3H), 2.12 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 197.9, 165.6, 160.3, 139.7, 129.4, 128.0, 126.7, 117.3,
38.8, 37.2, 29.8, 19.1; IR (thin film) ν 3029, 1783, 1690, 1493, 1360,
1173, 1115, 1026 cm−1; HRMS (EI) calculated for C14H14O3, [M]+,
230.0943, found 230.0939. The ee value was determined by HPLC
with Chiralpack OD−H column at 254 nm (hexane/iPrOH = 85:15,
flow rate = 0.8 mL/min), tR = 15.34 min (minor), tR = 19.56 min
(major).
(R)-5-Acetyl-4-(4-fluorophenyl)-6-methyl-3,4-dihydro-2H-
pyran-2-one (6b). The title compound was obtained according to
the general procedure described above after flash column chromatog-
raphy (eluting with n-hexane/EtOAc 5/1) as a pale yellow solid (36.2
mg, 74%, 90% ee): [α]D20 = −120.6 (c = 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.14−7.11 (m, 2H), 7.05−7.00 (m, 2H), 4.16 (d, J =
6.4 Hz, 1H), 2.96 (dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1H), 2.81 (dd, J1 =
15.6 Hz, J2 = 2.4 Hz, 1H) 2.43 (s, 3H), 2.14 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 197.6, 165.4, 162.3 (JC−F = 246.3 Hz), 160.5, 135.5
(JC−F = 3.2 Hz), 128.4 (JC−F = 7.9 Hz), 117.4, 116.4 (JC−F = 22 Hz),
38.1, 37.2, 29.8, 19.2; IR (thin film) ν 2923, 1784, 1690, 1606, 1509,
1360, 1225, 1115 cm−1; HRMS (EI) calculated for C14H13FO3, [M]+,
248.0849, found 248.0846. The ee value was determined by HPLC
with Chiralpack OD−H column at 254 nm (hexane/iPrOH = 85:15,
flow rate = 0.8 mL/min), tR = 14.33 min (minor), tR = 18.91 min
(major).
(R,E)-5-Acetyl-6-methyl-4-styryl-3,4-dihydro-2H-pyran-2-
one (6g). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 5/1) as a white solid (25.4 mg, 47%, 66% ee):
20
1
[α]D = −12.8 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.34−7.29 (m, 4H), 7.26−7.25 (m, 1H), 6.44 (d, J = 12.8 Hz, 1H),
6.10 (dd, J1 = 12.8 Hz, J2 = 6.8 Hz, 1H), 3.76−3.75 (m, 1H), 2.83−
2.81 (m, 2H), 2.38 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 192.3, 160.8, 155.1, 130.7, 126.8, 123.4, 122.8, 121.6, 121.3,
111.9, 30.4, 29.4, 24.7, 14.1; IR (thin film) ν 2929, 1795, 1687, 1523,
1419, 1365, 1177, 1113 cm−1; HRMS (EI) calculated for C16H16O3,
[M]+, 256.1099, found 256.1097. The ee value was determined by
HPLC with Chiralpack OD−H column at 254 nm (hexane/iPrOH =
85:15, flow rate = 0.8 mL/min), tR = 24.24 min (minor), tR = 33.61
min (major).
(R)-5-Acetyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydro-2H-
pyran-2-one (6c). The title compound was obtained according to the
general procedure described above after flash column chromatography
(eluting with n-hexane/EtOAc 2/1) as a yellow solid (46.2 mg, 84%,
20
1
93% ee): [α]D = −176.2 (c = 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ = 8.15 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.55 (t, J = 8.0 Hz,
1H), 7.50 (d, J = 7.6 Hz, 1H), 4.37 (d, J = 6.8 Hz, 1H), 3.04 (dd, J1 =
15.6 Hz, J2 = 7.2 Hz, 1H), 2.88 (J1 = 15.6 Hz, J2 = 2.4 Hz, 1H), 2.49 (s,
3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.7, 164.9,
161.5, 148.9, 142.1, 132.7, 130.6, 123.1, 122.0, 117.0, 38.2, 36.6, 30.3,
19.6; IR (thin film) ν 2924, 1785, 1654, 1529, 1348, 1113, 1050, 944
cm−1; HRMS (EI) calculated for C14H13NO5, [M]+, 275.0794, found
275.0790. The ee value was determined by HPLC with Chiralpack
OD−H column at 254 nm (hexane/iPrOH = 70:30, flow rate = 0.8
mL/min), tR = 17.91 min (minor), tR = 26.91 min (major).
(R)-5-Butyryl-4-phenyl-6-propyl-3,4-dihydro-2H-pyran-2-
one (6h). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 5/1) as a colorless oil (39.0 mg, 68%, 78% ee):
20
1
[α]D = −99.7 (c = 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ
7.35−7.32 (m, 2H), 7.29−7.26 (m, 1H), 7.16−7.14 (m, 2H), 4.12−
4.11 (m, 1H), 2.94 (dd, J1 = 16.0 Hz, J2 = 7.5 Hz, 1H), 2.81 (dd, J1 =
16.0 Hz, J2 = 3.5 Hz, 1H), 2.72−2.63 (m, 2H), 2.45−2.40 (m, 1H),
2.23−2.16 (m, 1H), 1.76−1.72 (m, 2H), 1.52−1.44 (m, 2H), 1.02 (t, J
= 7.5 Hz, 3H), 0.76 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 200.8, 166.0, 162.2, 139.7, 129.4, 127.9, 126.7, 117.5, 43.3, 38.8, 37.4,
33.5, 20.8, 17.3, 13.8, 13.6; IR (thin film) ν 2963, 2874, 1783, 1688,
1608, 1454, 1170, 1115 cm−1; HRMS (EI) calculated for C18H22O3,
[M]+, 286.1569, found 286.1572. The ee value was determined by
HPLC with Chiralpack OD−H column at 254 nm (hexane/iPrOH =
85:15, flow rate = 0.8 mL/min), tR = 10.61 min (minor), tR = 13.28
min (major).
(R)-5-Acetyl-6-methyl-4-o-tolyl-3,4-dihydro-2H-pyran-2-one
(6d). The title compound was obtained according to the general
procedure described above after flash column chromatography (eluting
with n-hexane/EtOAc 5/1) as a white solid (25.4 mg, 52%, 90% ee):
20
1
[α]D = −165.4 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
7.20−7.13 (m, 3H), 6.98−6.96 (m, 1H), 4.35 (d, J = 7.2 Hz, 1H), 2.93
(dd, J1 = 15.6 Hz, J2 = 7.2 Hz, 1H), 2.72 (J1 = 15.6 Hz, J2 = 2.6 Hz,
6230
dx.doi.org/10.1021/jo400950j | J. Org. Chem. 2013, 78, 6223−6232

The Journal of Organic Chemistry
Article
(R)-Methyl 6-methyl-4-(3-nitrophenyl)-2-oxo-3,4-dihydro-
2H-pyran-5-carboxylate (6i). The title compound was obtained
according to the general procedure described above after flash column
chromatography (eluting with n-hexane/EtOAc 5/1) as a colorless oil
(43.7 mg, 75%, 92% ee): [α]D20 = −237.7 (c = 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.13 (m, 1H), 8.03 (m, 1H), 7.54−7.46 (m,
2H), 4.39 (d, J = 6.8 Hz, 1H), 3.71 (s, 3H), 3.03 (dd, J1 = 16.4 Hz, J2 =
127.1, 122.4, 121.0, 118.0, 116.3; HRMS (EI) calculated for C15H12O2,
[M]+, 224.0837, found 224.0832.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C spectra for all new compounds, HPLC
8.0 Hz, 1H), 2.86 (dd, J1 = 16.4 Hz, J2 = 2.0 Hz, 1H), 2.53 (s, 3H); 13
C
spectra of chiral products 6; X-ray crystallographic data (in CIF
format) for compound (S)-6f. This material is available free of
charge via the Internet at http://pubs.acs.org.
NMR (100 MHz, CDCl3) δ 164.9, 164.1, 162.0, 147.7, 141.6, 131.6,
129.2, 121.8, 121.0, 107.6, 51.2, 36.6, 35.1, 18.1 ppm; IR (thin film) ν
2953, 1787, 1719, 1648, 1530, 1351, 1118, 1077 cm−1; HRMS (EI)
calculated for C14H13NO6, [M]+, 291.0743, found 291.0750. The ee
value was determined by HPLC with Chiralpack OD−H column at
254 nm (hexane/iPrOH = 70:30, flow rate = 0.8 mL/min), tR = 14.86
min (minor), tR = 39.78 min (major).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mcorg@zju.edu.cn.
(R)-Ethyl 6-methyl-2-oxo-4-phenyl-3,4-dihydro-2H-pyran-5-
carboxylate (6j). The title compound was obtained according to the
general procedure described above after flash column chromatography
(eluting with n-hexane/EtOAc 8/1) as a colorless oil (37.5 mg, 72%,
Notes
The authors declare no competing financial interest.
20
1
91% ee): [α]D = −151.3 (c = 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.31−7.23 (m, 3H), 7.14 (d, J = 7.2 Hz, 2H), 4.26 (d, J = 7.2
Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 2.95 (dd, J1 = 16.0 Hz, J2 = 7.2 Hz,
1H), 2.82 (dd, J1 = 16.0 Hz, J2 = 2.0 Hz, 1H), 2.47 (s, 3H), 1.19 (t, 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 166.0, 161.3, 140.7,
129.0, 127.5, 126.6, 110.0, 60.9, 37.8, 36.4, 18.9, 14.1; IR (thin film) ν
2983, 1787, 1713, 1454, 1369, 1244, 1148, 1029 cm−1; HRMS (EI)
calculated for C15H16O4, [M]+, 260.1049, found 260.1053. The ee
value was determined by HPLC with Chiralpack OD−H column at
254 nm (hexane/iPrOH = 90:10, flow rate = 0.8 mL/min), tR = 11.05
min (minor), tR = 18.95 min (major).
(R)-tert-Butyl 6-methyl-2-oxo-4-phenyl-3,4-dihydro-2H-
pyran-5-carboxylate (6k). The title compound was obtained
according to the general procedure described above after flash column
chromatography (eluting with n-hexane/EtOAc 8/1) as a colorless oil
(51.9 mg, 90%, 93% ee): [α]D20 = −146.9 (c = 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.31−7.22 (m, 3H), 7.14−7.12 (m, 2H), 4.18−
4.16 (m, 1H), 2.94 (dd, J1 = 15.6 Hz, J2 = 7.6 Hz, 1H), 2.79 (dd, J1 =
15.6 Hz, J2 = 3.2 Hz, 1H), 2.43 (s, 3H), 1.35 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 166.3, 165.1, 160.1, 140.9, 128.8, 127.3, 126.5, 111.3,
81.3, 38.2, 36.3, 27.9, 18.6; IR (thin film) ν 2977, 1787, 1709, 1652,
1368, 1249, 1172, 1116 cm−1; HRMS (EI) calculated for C17H20O4,
[M]+, 288.1362, found 288.1366. The ee value was determined by
HPLC with Chiralpack OD−H column at 254 nm (hexane/iPrOH =
85:15, flow rate = 0.8 mL/min), tR = 9.44 min (minor), tR = 15.05 min
(major).
ACKNOWLEDGMENTS
■
Financial support from NSFC (No. 21072166), the Program
for New Century Excellent Talents in University, and the
Zhejiang Provincial Natural Science Foundation of China (No.
R4110055) is gratefully acknowledged.
REFERENCES
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boxylate (6l). The title compound was obtained according to the
general procedure described above after flash column chromatography
(eluting with n-hexane/EtOAc 6/1) as a pale yellow oil (40.1 mg, 65%,
20
1
76% ee): [α]D = −54.7 (c = 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.52−7.50 (m, 2H), 7.44−7.39 (m, 3H), 7.34−7.31 (m,
2H), 7.27−7.23 (m, 3H), 4.41−4.39 (m, 1H), 3.45 (s, 3H), 3.08 (dd,
J1 = 16.0 Hz, J2 = 7.5 Hz, 1H), 2.92 (dd, J1 = 16.0 Hz, J2 = 3.5 Hz, 1H),
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130.2, 129.2, 128.5, 128.0, 127.8, 126.7, 112.3, 51.9, 38.8, 36.3; IR
(thin film) ν 2951, 1783, 1710, 1653, 1494, 1350, 1116, 1068 cm−1;
HRMS (EI) calculated for C19H16O4, [M]+, 308.1049, found 308.1045.
The ee value was determined by HPLC with Chiralpack OD−H
column at 254 nm (hexane/iPrOH = 85:15, flow rate = 0.8 mL/min),
tR = 19.42 min (minor), tR = 22.89 min (major).
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MHz, CDCl3) δ 10.79 (b, 1H), 7.67−7.65 (m, 2H), 7.44−7.38 (m,
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MHz, CDCl3) δ 7.91 (d, J = 15.6 Hz, 1H), 7.58−7.57 (m, 2H), 7.43−
7.42 (m, 3H), 7.16−7.11 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.94 (t, J =
8.0 Hz, 1H), 6.66 (d, J = 15.6 Hz, 1H), 5.75 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 165.4, 147.8, 147.2, 138.7, 133.9, 131.0, 129.0, 128.5,
6231
dx.doi.org/10.1021/jo400950j | J. Org. Chem. 2013, 78, 6223−6232

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