Hydroalkylation leading to heterocyclic compounds. Part 1: New strategies for the synthesis of polysubstituted 2H-pyran-2-ones

Article abstract of DOI:10.1016/j.tet.2008.12.069

Polysubstituted 2H-pyran-2-ones and 5,6-dihydro-2H-pyran-2-ones were synthesized via the MCRs initiated by the hydroalkylation of alkynoates with activated methylenes. Under the optimized reaction conditions, the desired products were obtained in 47-88% i

Full text of DOI:10.1016/j.tet.2008.12.069

Tetrahedron 65 (2009) 2110–2115
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydroalkylation leading to heterocyclic compounds. Part 1: New strategies
for the synthesis of polysubstituted 2H-pyran-2-ones
*
Wei-Bing Liu, Huan-Feng Jiang , Chun-Li Qiao
State Key Laboratory for Pulp and Paper Engineering, School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road,
Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Polysubstituted 2H-pyran-2-ones and 5,6-dihydro-2H-pyran-2-ones were synthesized via the MCRs
initiated by the hydroalkylation of alkynoates with activated methylenes. Under the optimized reaction
conditions, the desired products were obtained in 47–88% isolated yields. The experimental results
showed that the groups on activated methylenes act important roles in the nucleophilic attack fashion.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 November 2008
Received in revised form 21 December 2008
Accepted 23 December 2008
Available online 27 December 2008
1. Introduction
activity12 and biological activity. They have been reported as plant
growth inhibitors, insect antifeedants,13 antibiotic, and antitumoral
In recent years, the rapid assembly of molecular diversity from
inexpensive available starting materials via multicomponent re-
actions (MCRs) is an important goal of synthetic organic chemis-
try.1–4 Interestingly, some of these methodologies have become
completely new tools to offer small heterocyclic molecules, which
are frequently found in various biologically active compounds and
potentially designed medicinal agents in medicinal chemistry.5 To
date, several groups have investigated MCRs for simple and
straightforward preparation of substituted heterocycles, such as
1,3-oxazinane-2,4-diones,6 polycyclic pyrrole-2-carboxylates,7 3-
(diarylmethylene)oxindoles,8 and so on. Thus, the exploration of
new synthetic methods and molecular diversity around heterocy-
cles remains a major challenge in modern organic synthesis.
In the context of our longstanding interest in the alkynes
chemistry,9 we employed alkynoates for MCRs to efficiently syn-
thesize novel six-membered heterocycles, 1,4,5,6-tetrahydropyr-
imidines, 2,5-dihydro-1,3-oxazin-6-ones, and 3,6-dihydro-2H-1,
3-oxazines, which were constructed via a domino hydroamination/
Mannich-type reaction/hydration–cyclization sequence (left side in
Scheme 1).10 In view of the convergent and modular nature of these
transformations, our attention is directed to a new type of MCRs:
hydroalkylation of alkynoates with activated methylenes to con-
struct different types of six-membered oxygen or nitrogen-con-
taining heterocyclic compounds (right side in Scheme 1). Among
these expectantly obtained heterocycles, 2H-pyran-2-ones and
their analogues are not only valuable materials in diverse organic
synthesis,11 but also possess a diverse range of pharmacological
agents.14–17 In this paper, we wish to report the synthesis of poly-
substituted 2H-pyran-2-ones and 5,6-dihydro-2H-pyran-2-ones
via the MCRs initiated by the hydroalkylation of alkynoates with
activated methylenes.
2. Results and discussion
At the outset of this work, our preliminary investigations began
with diethyl but-2-ynedioate (1a) with dibenzoylmethane (2a).
Ethyl 5-benzoyl-2-oxo-6-phenyl-2H-pyran-4-carboxylate (3aa)
was obtained in 87% GC yield when the reaction was carried out by
the aid of a stoichiometric amount of NaOH in dioxane at 80 ꢀC for
1 h (Table 1, entry 3). As shown in Table 1, various temperatures,
alkaline additives, and solvents were examined as the potential
base and solvent for the desired domino reaction. It is exciting that
the chosen bases and solvents, such as sodium hydroxide (NaOH),
sodium ethoxide (EtONa), potassium tert-butoxide (t-BuOK), ace-
tonitrile (CH3CN), toluene, and dichloromethane (CH2Cl2) are
suitable for the reactions (Table 1, entries 1–17). NaOH proves to be
the best base (Table 1, entry 4) and dioxane the best solvent (Table
1, entry 4). As a result, the best yield was obtained by the use of
0.25 mmol of 1a, 0.25 mmol of 2a, and 1 equiv of NaOH in dioxane
(2.0 mL) at 80 ꢀC for 2 h.
With the optimized conditions in hand, we turned our attention
to examine the scope of the reactions (Table 2). When several active
methylene compounds were employed, the reaction proceeded
smoothly and the desired trisubstituted 2H-pyran-2-ones were
afforded in satisfactory yields (Table 2, entries 1–4). It is delighted
that some less reactive carbon electrophiles such as alkynoates 1b
and 1c could serve as good substrates in this domino addition–
cyclization reaction (Table 2, entries 5–11). For examples, the
* Corresponding author. Tel.: þ86 20 22236518; fax: þ86 20 87112906.
E-mail address: jianghf@scut.edu.cn (H.-F. Jiang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.069

W.-B. Liu et al. / Tetrahedron 65 (2009) 2110–2115
2111
O
EtO2C
R
R2
O
N
R
R1
N
EWG
O
R1
O
CO2Et
CH2(EWG)2
H
R
R2
H
R
CO2Et
CH(EWG)2
H
R
CO2Et
NHR1
O
N
H2NR1
?
R
N
R3
R
R1
GWE EWG
O
EtO2C
R1
N
H
R
O
R
N
R2
GWE EWG
R1
Scheme 1. Synthesis of six-membered heterocycles based on alkynoates.
Table 1
Table 2
Optimization of reaction conditionsa
NaOH-induced domino synthesis of trisubstituted 2H-pyran-2-onesa
O
O
CO2Et
CO2R2
O
O
O
O
O
Base/Solvent
80 oC, 2 h
10 mol%NaOH/dioxane
80 oC, 2 h
O
+
+
R3
R4
Ph
Ph
R1
R3
EtO2C
Ph
R1
1
CO2Et
1a
R4
O
Ph
2a
O
2
3aa
3
Entry
Alkaline additive
Solvent
Reaction time (h)
1 (60 ꢀC)
1 (95 ꢀC)
Yieldb (%)
Entry
1
2
3 (Yield %)b
1
2
3
4
5
6
7
8
1a (R1¼CO2Et; R2¼Et)
2a (R3¼Ph; R4¼Ph)
3aa (85)
3ab (82)
3ac (65)
3ad (68)
3ba (88)
3bb (83)
3bc (70)
3bd (69)
3ca (84)
3cb (79)
3cc (59)
3cd (complex)
1
2
3
4
5
6
7
8
NaOH
NaOH
NaOH
NaOH
NaOH
Na2CO3
NaHCO3
CH3CO2Na
EtONa
t-BuOK
None
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CH3CN
DMF
DMSO
THF
CH2Cl2
Toluene
Dioxane
Dioxane
50
87
87
89
89
53
42
59
85
75
39
88
75
62
78
86
84
88
87
1a
1a
1a
2b (R3¼Ph; R4¼CH3)
2c (R3¼CH3; R4¼CH3)
1
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2d (R3¼CH3; R4¼OEt)
1b (R1¼Ph; R2¼Et)
2a
2b
2c
2d
2a
2b
2c
2d
1b
1b
1b
9
1c (R1¼n-C5H11; R2¼CH3)
9
10
11
12
13
14
15
16
17
18c
19d
10
11
12
1c
1c
1c
a
All reactions were carried out using 1.0 mmol of 1 and 1.0 mmol of 2 in dioxane
(2.0 mL) at 80 ꢀC.
b
Isolated yield.
employed, the reaction only gave trisubstituted 2H-pyran-2-ones
(3) even if formaldehyde was added beforehand.
a
The reaction was carried out using 0.25 mmol of 1a, 0.25 mmol of 2a, and
1 equiv of alkaline in solvent (2.0 mL) at 80 ꢀC for 2 h.
CO2Et
O
b
GC yield.
NaOH (10 mol %).
NaOH (0.5 equiv).
c
O
CO2Et
CO2Et
d
base/solvent
rt, 5h
+
HCHO
+
ð1Þ
CO2Et
EtO2C
4be
reactions of 1b or 1c with 2a afforded the corresponding products
3ba and 3ca with 88 and 84% isolated yields, respectively (Table 2,
entries 5 and 9). It is not clear why the reaction of 1c with 2d
generated a rather complicated mixture (Table 2, entry 12).
1b
2e
Representative optimization experiments were reported in
Table 3. Activated methylene dibenzoylmethane could not give the
5,6-dihydro-2H-pyran-2-one derivatives just as shown in entries 1,
5, and 9 of Table 3. When employing diethyl propanedioate the
reaction afforded the corresponding 5,6-dihydro-2H-pyran-2-ones
with satisfactory yields (Table 3, entries 2, 6, 10, and 13). The yields
were decreased to some extent along with the steric hindrance of
activated methylenes (Table 3, entries 4, 8, and 12).
The proposed mechanism of these MCRs could be depicted as
our hypothesis shown in Scheme 2. Our envisions all were initiated
by highly active carbon anions I formed from activated methylenes
2 in the presence of the alkaline during the reaction, and then
When ethyl 3-phenylprop-2-ynoate (1b) and diethyl propane-
dioate (2e) were used as the substrates, the reaction failed to afford
the expected product. But it is interesting that when formaldehyde
was added to the reaction mixture, another type of 2H-pyran-2-one
analogue, diethyl 6-oxo-4-phenyl-2H-pyran-3,3(6H)-dicarboxylate
(4be), was obtained in 82% isolated yield (Eq.1 and Table 2, entry 6).
This result showed clearly that the groups on activated methylenes
could lead to different structures of 5,6-dihydro-2H-pyran-2-ones.
When activated methylene such as dibenzoylmethane, 1-phenyl-
1,3-butanedione, 2,4-pentanedione, ethyl acetoacetate was

2112
W.-B. Liu et al. / Tetrahedron 65 (2009) 2110–2115
Table 3
Table 4
Synthesis of trisubstituted 5,6-dihydro-2H-pyran-2-onesa
Some data of 1,3-dicarbonyl compounds18
O
Entry
Compound
pKa
Content of enol (%)
CO2R2
1
2
3
4
CH3COCH2CO2Et
CH3COCH2COCH3
PhCOCH2COCH3
EtO2CCH2CO2Et
10.7
9
9.6
13
8.0
76.4
O
O
O
NaOH (20 %)
dioxane, rt, 5h
+
+ HCHO
R1
R3OC
R3
R4
89.2
R1
COR4
7.7ꢁ10ꢂ3
2
1
4
Entry
1
2
4 (Yield %)b
1
2
3
4
5
6
7
8
1a (R1¼CO2Et; R2¼Et)
2a (R3¼R4¼Ph)
4aa (trace)
4ae (88)
4af (83)
nucleophilic attack to formaldehyde to form intermediate VI. In
comparison the results between Table 2 and Table 3, we easily
found that the groups on activated methylenes act important roles
in the nucleophilic attack fashion.
1a
2e (R3¼R4¼OEt)
1a
1a
2f(R3¼OCH2Ph; R4¼OEt)
2g (R3¼R4¼OCH2Ph)
4ag (78)
4ba (trace)
4be (82)
4bf (70)
4bg (50)
4ca (trace)
4ce (80)
4cf (66)
1b (R1¼Ph; R2¼Et)
2a
2e
2f
2g
2a
2e
2f
1b
1b
1b
Table 4 listed pKa and content of enol of some dicarbonyl com-
pounds, which could help us to explain why different results are
obtained in the reaction system. The pKa value of 1,3-dicarbonyl
compounds indicated that the activated methylene C–H bond of
ethyl 3-oxobutanoate, pentane-2,4-dione, and 1-phenylbutane-1,3-
dione was more active than that of diethyl malonate. Due to the
difference of C–H bond activity of activated methylene and the
resonance phenomenon of keto–enol tautomerism in 1,3-dicar-
bonyl compounds, the pKa value directly related with the enol
content. For example, the enol content of 1-phenylbutane-1,3-
dione reached to 89.2%, while on the other hand, the enol content of
diethyl malonate was only 7.7ꢁ10ꢂ3%. These data implied that the
non-ester 1,3-dicarbonyl compounds were easily converted to enol
resonance structures than that of ester 1,3-dicarbonyl compounds.
The former favored directly oxygen nucleophilic attack to carbonyl
carbon to form product 3, and the latter favored carbon nucleo-
philic attack to formaldehyde to form intermediate VI, following
intramolecular oxygen nucleophilic attack to carbonyl carbon to
form product 4. These may explain our experimental phenomenon
that non- or single-ester dicarbonyl compounds react with alky-
noates leading to trisubstituted 2H-pyran-2-ones, and diester
malonate reacts with alkynoates leading to trisubstituted 5,6-
dihydro-2H-pyran-2-ones.
9
1c (R1¼n-C5H11; R2¼CH3)
10
11
12
13
1c
1c
1c
2g
2e
4cg (47)
4de (92)
1d (R1¼CH3; R2¼CH3)
a
All the reactions were carried out using 1 mmol of 1, 1 mmol of 2, 2 mmol of
formaldehyde, and 20% of NaOH in dioxane (6.0 mL) at room temperature for the
desired reaction time.
b
Isolated yield.
involved carbon nucleophilic attack on the carbon–carbon triple
bond of alkynoates to form intermediate II, which the process has
undergone base-induced intermolecular hydroalkylation of alky-
noates. Single regioisomers shown in Tables 2 and 3 indicated that
the nucleophilic attack of highly active carbon anions I on the
carbon–carbon triple bond in alkynoates 1 played a dominant role
on the regioselectivity.
Once intermediate II has been formed, it could exist in different
resonance structures, such as III, IV, and V. At this stage, the
presence of formaldehyde leads to two possible routes: oxygen
nucleophilic attack to carbonyl carbon to form product 3 or carbon
R
CO2Et
O
O
O
O
OEt
O
OEt
O
OEt
O
1
O
O
H
R3
R
R3
R3
R
R3
R
R
OEt
R2
O
R2
O
R2
O
R2
O
O
IV'
II
IV
3
R2
R3
I
Base
O
O
OEt
OH
O
OEt
O
O
R2
R3
R
R3
R
R3
2
R2
III
O
R2
O
V
R2=R3=OEt
O
O
OEt
O
O
OEt
O
O
R
R
O
O
OEt
O
O
R
OEt
R3
R2
VI
Scheme 2. Proposed mechanism for the synthesis of 2H-pyran-2-ones and 5,6-dihydro-2H-pyran-2-ones.
R3
R2
R2
O
HCHO
4
V'

W.-B. Liu et al. / Tetrahedron 65 (2009) 2110–2115
2113
3. Conclusion
4.2.2. Ethyl 5-acetyl-2-oxo-6-phenyl-2H-pyran-4-
carboxylate (3ab)
We have disclosed highly efficient methods for the synthesis
of polysubstituted 2H-pyran-2-ones and 5,6-dihydro-2H-pyran-
2-ones, which were formed via domino reactions all initiated by
the hydroalkylation of electron-deficient of alkynoates with
activated methylenes. These reactions offered a convenient entry
into several interesting heterocyclic structures, which will rep-
Yellow viscous oil; IR nmax (KBr): 2892, 2868, 1732, 1675, 1593,
1551, 1449, 1384, 1258, 1177, 1101, 917, 862, 783, 716 cmꢂ1; 1H NMR
(400 MHz, CD3COCD3):
d
ppm¼7.93–7.52 (m, 5H), 6.65 (s, 1H), 4.01
(q, 2H, J¼7.2 Hz), 2.15 (s, 3H), 1.01 (t, 3H, J¼7.2 Hz); 13C NMR
(100 MHz, CD3COCD3):
d
ppm¼192.7, 164.1, 163.9, 160.7, 146.1,
138.4, 134.4, 129.8, 129.7, 115.8, 115.6, 63.0, 18.9, 13.7; GC–MS m/z (%
rel inten.): 285.98 (Mþ, 41.13), 212.94 (100). Anal. Calcd for
C16H14O5: C, 67.13; H, 4.93. Found: C, 67.02; H, 5.28.
resent
a privileged medicinal scaffold. Armed with a clear
mechanistic understanding of this intriguing process, we are
pursuing further studies to uncover the reaction conditions
necessary for selective, high yielding synthesis of each one of
these corresponding products. It is reasonable to assume that, in
due course, other alkynoates, activated methylenes, aldehydes,
amines or related compounds that can find application in these
reactions would emerge. It is expected that this class of reactions
will attract the attention of synthetic organic chemists in the
near future.
4.2.3. Ethyl 5-acetyl-6-methyl-2-oxo-2H-pyran-4-
carboxylate (3ac)
Pale yellow viscous oil; IR nmax (KBr): 3081, 2986, 2875, 1741,
1699, 1625, 1446, 1381, 1363, 1259, 1096, 871, 807 cmꢂ1 1H NMR
;
(400 MHz, CD3COCD3):
d
ppm¼6.58 (s, 1H), 4.31 (q, 2H, J¼7.2 Hz),
2.39 (s, 3H), 2.29 (s, 3H), 1.32 (t, 3H, J¼7.2 Hz); 13C NMR (100 MHz,
CD3COCD3):
d
ppm¼198.8, 164.6, 162.9, 160.5, 145.3, 118.7, 115.5,
63.3, 31.6, 18.7, 14.0; GC–MS m/z (% rel inten.): 223.89 (Mþ, 23.65),
150.97 (100). Anal. Calcd for C11H12O5: C, 58.93; H, 5.39. Found: C,
58.82; H, 5.50.
4. Experimental
4.1. General
4.2.4. Diethyl 6-methyl-2-oxo-2H-pyran-4,5-dicarboxylate (3ad)
Pale yellow viscous oil; IR nmax (KBr): 2282, 1733, 1566, 1385,
All the reactions were carried out at 80 ꢀC in a round bottom
flask equipped with magnetic stir bar for 2 h. Solvents and all
reagents were used as received. 1H NMR spectra was recorded
in CD3COCD3 at 400 MHz and 13C NMR spectra were recorded
in CD3COCD3 at 100 MHz in the Guangzhou Institute of
Chemistry, Chinese Academy of Sciences. Respectively, the
chemical shifts (d) were referenced to TMS. GC–MS was
obtained using electron ionization (EI). IR spectra were
obtained as potassium bromide pellets or as liquid films be-
tween two potassium bromide pellets with a Brucker Vector 22
spectrometer. TLC was performed using commercially prepared
100–400 mesh silica gel plates (GF254) and visualization was
effected at 254 nm. All the other chemicals were purchased
from Aldrich Chemicals.
1263, 1082, 988, 859 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼1.27 (t, 3H, J¼7.2 Hz), 1.31 (t, 3H, J¼7.2 Hz), 4.24 (q, 2H,
J¼7.2 Hz), 4.31 (q, 2H, J¼7.2 Hz), 2.45 (s, 3H), 6.43 (s, 1H); 13C NMR
(100 MHz, CD3COCD3):
d
ppm¼168.1,165.1,164.8,160.0,147.4,113.8,
109.7, 63.0, 62.4, 19.3, 14.1; GC–MS m/z (% rel inten.): 253.90 (Mþ,
40.05), 180.88 (100). Anal. Calcd for C12H14O6: C, 56.69; H, 5.55.
Found: C, 56.81; H, 5.67.
4.2.5. 5-Benzoyl-4,6-diphenyl-2H-pyran-2-one (3ba)
Pale yellow needles crystals; IR nmax (KBr): 3058, 1742, 1659,
1596, 1581, 1508, 1449, 1389, 1370, 1262, 1174, 1058, 856, 828, 792,
745, 697 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.42–8.12
(m, 10H), 4.94 (s, 1H); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼196.30, 153.8, 142.9, 140.0, 138.3, 133.8, 133.5, 130.1, 129.5,
129.1, 129.0, 127.9, 123.7; GC–MS m/z (% rel inten.): 351.98 (Mþ,
49.24), 104.86 (100). Anal. Calcd for C24H16O3: C, 81.80; H, 4.58.
Found: C, 81.71; H, 4.65.
4.2. Typical procedure for the reaction of diethyl but-2-
ynedioate with dibenzoylmethane
A mixture of 1a (170 mg, 1 mmol), 2a (224 mg, 1 mmol),
and NaOH (4 mg, 0.1 mmol) in dioxane (2 mL) was heated
with stirring in a round bottom flask at 80 ꢀC for 2 h. After
cooling, the reaction was diluted with water and extracted
with diethyl ether. The ether layer was washed with saturated
salt water and dried with anhydrous MgSO4. The resulting
mixture was then analyzed by GC and GC–MS. Volatiles were
removed in vacuum and the crude product was subjected to
isolation by preparative TLC (GF254), eluted with a 10:2 pe-
troleum ether–diethyl ether mixture. Compound 3aa as pale
yellow solid was isolated in 296 mg (85%), after removal of the
solvent.
4.2.6. 5-Acetyl-4,6-diphenyl-2H-pyran-2-one (3bb)
Colorless crystals; mp: 141–142 ꢀC; IR nmax (KBr): 3047, 2822,
1721, 1663, 1620,1595,1578, 1493, 1446, 1386, 1372,1272,1094, 802,
749, 693 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.23–7.79
(m, 10H), 6.18 (s, 1H), 2.20 (s, 3H); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼194.6, 162.9, 161.0, 156.7, 138.4, 137.4, 134.5, 130.2, 130.1,
129.5, 129.3, 128.3, 118.4, 112.3, 18.90; GC–MS m/z (% rel inten.):
298.95 (Mþ, 100). Anal. Calcd for C19H14O3: C, 78.61; H, 4.86. Found:
C, 78.86; H, 4.71.
4.2.7. 5-Acetyl-6-methyl-4-phenyl-2H-pyran-2-one (3bc)
Colorless crystals; mp: 117–118 ꢀC; IR nmax (KBr): 3066, 2923,
2821, 1739, 1696, 1601, 1577, 1494, 1448, 1380, 1259, 1054, 835, 744,
4.2.1. Ethyl 5-benzoyl-2-oxo-6-phenyl-2H-pyran-4-
carboxylate (3aa)
699 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.37–7.53 (m,
5H), 6.12 (s, 1H), 2.29 (s, 3H), 1.84 (s, 3H); 13C NMR (100 MHz,
Pale yellow solid; IR nmax (KBr): 3060, 2989, 2939, 1742, 1732,
CD3COCD3):
d
ppm¼200.8, 162.8, 160.6, 155.7, 137.6, 130.8, 130.0,
1659, 1596, 1581, 1449, 1393, 1366, 1262, 1106, 792, 745, 697 cmꢂ1
;
128.1, 121.3, 112.2, 31.8, 18.6; GC–MS m/z (% rel inten.): 227.90 (Mþ,
82.11), 184.79 (100). Anal. Calcd for C14H12O3: C, 73.67; H, 5.30.
Found: C, 73.75; H, 5.12.
1H NMR (400 MHz, CD3COCD3):
d
ppm¼1.04 (t, 3H, J¼7.2 Hz), 4.10 (q,
2H, J¼7.2 Hz), 6.80 (1H), 7.30–7.87 (m, 10H); 13C NMR (100 MHz,
CD3COCD3):
d
ppm¼192.44, 163.51, 161.02, 159.94, 146.26, 137.17,
133.51, 131.74, 131.01, 129.25, 128.70, 128.55, 128.46, 115.75, 115.44,
62.36, 12.91; GC–MS m/z (% rel inten.): 347.87 (Mþ, 43.02),
104.87 (100). Anal. Calcd for C21H16O5: C, 72.41; H, 4.63. Found: C,
72.21; H, 4.92.
4.2.8. Ethyl 6-methyl-2-oxo-4-phenyl-2H-pyran-5-
carboxylate (3bd)
Colorless crystals; mp: 95–96 ꢀC; IR nmax (KBr): 3032, 2985,
2938, 1741, 1718, 1618, 1578, 1494, 1447, 1381, 1265, 1084, 831,

2114
W.-B. Liu et al. / Tetrahedron 65 (2009) 2110–2115
732, 681 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.33–7.47
4.3.2. 3-Benzyl 3,4-diethyl 6-oxo-2H-pyran-3,3,4(6H)-
tricarboxylate (4af)
(m, 5H), 6.12 (s, 1H), 3.98 (q, 2H, J¼7.2 Hz), 2.40 (s, 3H), 0.86 (t,
3H, J¼7.2 Hz); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼166.2,
Pale yellow viscous oil; IR nmax (KBr): 1731, 1640, 1371, 1237,
165.3, 160.4, 156.4, 138.2, 130.2, 129.4, 127.5, 113.2, 112.1, 61.9, 18.9,
13.7; GC–MS m/z (% rel inten.): 257.80 (Mþ, 87.89), 229.73 (100).
Anal. Calcd for C15H14O4: C, 69.76; H, 5.46. Found: C, 69.79; H,
5.62.
1090, 989 cmꢂ1; 1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.38–7.35
(m, 4H), 7.19–7.14 (m, 1H), 6.93 (s, 1H), 5.21 (s, 2H), 4.86 (s, 2H),
4.21–4.09 (m, 4H), 1.21 (m, 6H); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼168.6, 166.9, 164.8, 136.0, 131.0, 129.3, 129.2, 129.1, 114.7,
72.5, 68.9, 63.4, 62.0, 60.6, 14.2, 14.0; GC–MS m/z (% rel inten.):
376.69 (Mþ, 0.02), 91.0 (100). Anal. Calcd for C19H20O8: C, 60.63; H,
5.36. Found: C, 60.65; H, 5.40.
4.2.9. 5-Benzoyl-4-pentyl-6-phenyl-2H-pyran-2-one (3ca)
Pale yellow viscous oil; IR nmax (KBr): 1725, 1667, 1380, 1084,
986, 855 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.88–7.26
(m, 10H), 6.27 (s, 1H), 2.27 (t, 2H), 1.45 (q, 2H), 1.22 (m, 4H), 0.79 (q,
3H); 13C NMR (100 MHz, CD3COCD3):
4.3.3. 3,3-Dibenzyl 4-ethyl 6-oxo-2H-pyran-3,3,4(6H)-
tricarboxylate (4ag)
d
ppm¼195.0, 161.0, 159.2,
138.0, 134.8, 133.2, 121.5, 130.3, 130.1, 129.6, 129.4, 129.3, 129.1,
118.5, 112.9, 33.4, 32.1, 31.8, 28.7, 22.8, 14.0; GC–MS m/z (% rel
inten.): 346.04 (Mþ, 24.78), 104.87 (100). Anal. Calcd for C23H22O3:
C, 79.74; H, 6.40. Found: C, 79.63; H, 6.21.
Pale yellow viscous oil; IR nmax (KBr): 1370, 1645, 1460, 1378,
1238, 1090, 989, 741, 697 cmꢂ1 1H NMR (400 MHz, CD3COCD3):
;
d
ppm¼7.38–7.31 (m, 10H), 6.95 (s, 1H), 5.26–5.18 (q, 4H,
J¼12.4 Hz), 4.91 (s, 2H), 4.03–3.98 (q, 2H, J¼7.2 Hz), 1.14 (t, 3H,
J¼7.2 Hz); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼167.7, 165.9,
4.2.10. 5-Acetyl-4-pentyl-6-phenyl-2H-pyran-2-one (3cb)
163.9, 135.2, 130.2, 128.4, 128.3, 128.2, 128.0, 126.4, 71.7, 68.1, 61.2,
59.8, 13.2; GC–MS m/z (% rel inten.): 438.38 (Mþ, 0.01), 91.0 (100).
Anal. Calcd for C24H22O8: C, 65.75; H, 5.06. Found: C, 65.80; H,
5.28.
Pale yellow viscous oil; IR nmax (KBr): 1740, 1668, 1596, 1552,
1449, 1392, 1266, 1076, 982, 912, 858, 717 cmꢂ1; 1H NMR (400 MHz,
CD3COCD3):
d
ppm¼7.99–7.57 (m, 5H), 6.08 (s, 1H), 2.27 (t, 2H), 1.38
(m, 2H), 1.16 (m, 2H), 0.75 (t, 3H); 13C NMR (100 MHz, CD3COCD3)
d
ppm¼194.7, 161.3, 160.9, 158.8, 138.2, 135.2, 130.2, 130.1, 118.5,
4.3.4. Diethyl 6-oxo-4-phenyl-2H-pyran-3,3(6H)-
dicarboxylate (4be)
111.6, 33.4, 31.7, 22.7, 13.0, 14.0; GC–MS m/z (% rel inten.): 284.01
(Mþ, 56.77), 199.93 (100). Anal. Calcd for C18H20O3: C, 76.03; H, 7.09.
Found: C, 76.22; H, 7.11.
Yellow viscous oil; IR nmax (KBr): 1734, 1645, 1459, 1390, 1083,
1051, 856, 771, 699 cmꢂ1
;
1H NMR (400 MHz, CD3COCD3):
d
ppm¼7.57–7.55 (m, 2H), 7.44–7.43 (m, 3H), 6.24 (s, 1H), 4.88 (s,
4.2.11. 5-Acetyl-6-methyl-4-pentyl-2H-pyran-2-one (3cc)
2H), 4.15 (m, 4H), 1.10 (m, 6H); 13C NMR (100 MHz, CD3COCD3):
Pale yellow viscous oil; IR nmax (KBr): 1739, 1675, 1549, 1391,
d
ppm¼167.4, 162.4, 156.0, 136.9, 130.6, 129.2, 128.5, 119.9, 72.3,
1295, 1246, 1083, 987, 860 cmꢂ1
d
;
1H NMR (400 MHz, CD3COCD3):
63.6, 60.4, 14.0, 13.9; GC–MS m/z (% rel inten.): 317.91 (Mþ, 59.73),
171.89 (100). Anal. Calcd for C17H18O6: C, 64.14; H, 5.70. Found: C,
64.38; H, 5.79.
ppm¼5.99 (s, 1H), 2.49 (s, 3H), 2.23 (s, 3H), 2.38 (t, 2H), 1.52 (m,
2H), 1.29 (m, 4H), 0.84 (t, 3H); 13C NMR (100 MHz, CD3COCD3)
d
ppm¼201.1, 160.5, 159.3, 157.4, 121.0, 110.4, 32.5, 31.7, 31.1, 27.9,
22.0, 17.9, 13.2; GC–MS m/z (% rel inten.): 222 (Mþ, 8.49), 137.97
(100). Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.03; H,
8.10.
4.3.5. 3-Benzyl 3-ethyl 6-oxo-4-phenyl-2H-pyran-3,3(6H)-
dicarboxylate (4bf)
Pale yellow viscous oil; IR nmax (KBr): 1733, 1649, 1541, 1457,
1392, 1226, 1079, 989, 844, 696 cmꢂ1
;
1H NMR (400 MHz,
4.3. Typical procedure for the reaction of ethyl 3-phenylprop-
2-ynoate, diethyl propanedioate, and formaldehyde
CD3COCD3):
d
ppm¼7.54–7.52 (m, 2H), 7.43–7.33 (m, 6H), 7.27–7.26
(m, 2H), 6.25 (s, 1H), 5.15 (q, 2H), 4.91 (s, 2H), 4.12 (m, 2H), 1.01 (t,
3H, J¼7.2 Hz); 13C NMR (100 MHz, CD3COCD3):
ppm¼267.5, 167.3,
d
To a stirring mixture of ethyl 3-phenylprop-2-ynoate (1b, 174
mg, 1 mmol) and diethyl propanedioate (2e, 160 mg, 1 mmol), 6
mL dioxane and NaOH (8 mg, 0.2 mmol) were added succes-
sively. The mixture was stirred under air atmosphere in a round
bottom flask. The reaction was kept at air atmosphere for 4 h,
after which time 35% formaldehyde (171 mg, 2 mmol) was
added dropwise to the system to continue to react for 1 h. After
completion of the reaction, the solvent was diluted with water
and extracted with diethyl ether. The ether layer was washed
with saturated salt water and dried with anhydrous MgSO4. The
resulting mixture was then analyzed by GC and GC–MS. Vola-
tiles were removed under reduced pressure and the crude
product was subjected to isolation by PTLC (GF254), eluted with
a 10:1 petroleum ether–diethyl ether mixture to afford the de-
sired product diethyl 6-oxo-4-phenyl-2H-pyran-3,3(6H)-dicar-
boxylate (4be).
162.4, 155.8, 136.8, 135.8, 130.7, 129.3, 129.1, 128.5, 120.0, 72.3, 68.9,
63.4, 60.5, 13.8; GC–MS m/z (% rel inten.): 380.1 (Mþ, 0.24), 91.0
(100). Anal. Calcd for C22H20O6: C, 69.46; H, 5.30. Found: C, 69.58; H,
5.40.
4.3.6. Dibenzyl 6-oxo-4-phenyl-2H-pyran-3,3(6H)-
dicarboxylate (4bg)
Pale yellow viscous oil; IR nmax (KBr): 1725, 1645, 1451, 1366,
1220, 1080, 988, 874, 737, 692 cmꢂ1
;
1H NMR (400 MHz,
ppm¼7.49–7.38 (m, 3H), 7.35–7.31 (m, 8H), 7.22–7.19
CD3COCD3):
d
(m, 4H), 6.28 (s, 1H), 5.15 (q, 4H, J¼12.4 Hz), 4.96 (s, 2H); 13C NMR
(100 MHz, CD3COCD3):
d
ppm¼166.5, 161.7, 154.7, 135.7, 134.7,
129.9, 128.5, 128.4, 128.2, 127.5, 119.1, 71.5, 68.2, 59.6; GC–MS m/z (%
rel inten.): 441.91 (Mþ, 0.32), 91.0 (100). Anal. Calcd for C27H22O6: C,
73.29; H, 5.01. Found: C, 73.30; H, 5.05.
4.3.7. Diethyl 6-oxo-4-pentyl-2H-pyran-3,3(6H)-
dicarboxylate (4ce)
4.3.1. Triethyl 6-oxo-2H-pyran-3,3,4(6H)-tricarboxylate (4ae)
Yellow viscous oil; IR nmax (KBr): 2987, 1732, 1660, 1516, 1468,
Pale yellow viscous oil; IR nmax (KBr): 2964, 1736, 1641, 1462,
1376, 1233, 1096, 307, 859, 737 cmꢂ1
;
1H NMR (400 MHz,
1389, 1296, 1250, 1173, 1084, 994, 861 cmꢂ1 1H NMR (400 MHz,
;
CD3COCD3):
d
ppm¼6.92 (s, 1H), 4.86 (s, 2H), 4.21 (m, 6H), 1.21 (m,
CD3COCD3):
d
ppm¼5.93 (t, 1H, J¼1.6 Hz), 4.72 (s, 2H), 4.30–4.25
9H); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼168.7, 166.9, 164.8,
(q, 4H, J¼7.2 Hz), 2.37 (m, 2H), 1.58 (t, 2H, J¼7.6 Hz), 1.34 (m, 4H),
135.8, 130.9, 72.5, 63.3, 61.9, 53.3, 14.2, 14.0; GC–MS m/z (% rel
inten.): 314.28 (Mþ, 1.58), 167.79 (100). Anal. Calcd for C14H18O8: C,
53.50; H, 5.77. Found: C, 53.45; H, 5.69.
1.28 (m, 6H), 0.91 (t, 3H, J¼6.8 Hz); 13C NMR (100 MHz,
CD3COCD3):
d
ppm¼167.3, 162.5, 158.2, 118.1, 70.8, 63.3, 59.4, 33.8,
31.9, 26.9, 23.0, 14.2, 14.1; GC–MS m/z (% rel inten.): 311.96 (Mþ,

W.-B. Liu et al. / Tetrahedron 65 (2009) 2110–2115
2115
83.06), 28.94 (100). Anal. Calcd for C16H24O6: C, 61.52; H, 7.74.
References and notes
Found: C, 61.50; H, 7.74.
1. Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S. Org. Lett. 2006, 8, 899.
2. For recent examples on multicomponent reactions, see: (a) Bonne, D.; Dekhane,
M.; Zhu, J. P. Angew. Chem., Int. Ed. 2007, 46, 2485 and references therein; (b)
Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128,
11040; (c) Dondas, H. A.; Fishwick, C. W. G.; Gai, X.; Grigg, R.; Kilner, C.;
Dumrongchai, N.; Kongkathip, B.; Kongkathip, N.; Polysuk, C.; Sridharan, V.
Angew. Chem., Int. Ed. 2005, 44, 7570; (d) Pache, S.; Lautens, M. Org. Lett. 2003,
5, 4827; (e) Song, S. D.; Song, L. P.; Dai, B. F.; Yi, H.; Jin, G. F.; Zhu, S. Z.; Shao, M.
Tetrahedron 2008, 64, 5728; (f) Li, D. M.; Song, L. P.; Li, X. F.; Xing, C. H.; Peng,
W. M.; Zhu, S. Z. Eur. J. Org. Chem. 2007, 3520; (g) Li, X. F.; Song, L. P.; Xing, C. H.;
Zhao, J. W.; Zhu, S. Z. Tetrahedron 2006, 62, 2255.
3. For recent books, see: (a) Multicomponent Reactions; Zhu, J., Bienaym, H., Eds.;
Wiley-VCH: Weinheim, 2005; (b) Domino Reactions in Organic Synthesis; Tietze,
L. F., Brasche, G., Gericke, K., Eds.; Wiley-VCH: Weinheim, 2006.
4. Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295.
5. (a) Hansch, C.; Sammes, P. G.; Taylor, J. B. Comprehensive Medicinal Chemistry;
Pergamon: Oxford, 1990; Vol. 2, Chapter 7.1; (b) Erlanson, D. A.; McDowell, R.
S.; O’Brien, T. J. Med. Chem. 2004, 47, 3463.
4.3.8. 3-Benzyl 3-ethyl 6-oxo-4-pentyl-2H-pyran-3,3(6H)-
dicarboxylate (4cf)
Pale yellow viscous oil; IR nmax (KBr): 1735, 1643, 1516, 1481,
1390, 1250, 1171, 1083, 989, 853, 696 cmꢂ1 1H NMR (400 MHz,
;
CD3COCD3):
d
ppm¼7.41–7.36 (m, 5H), 5.93 (t,1H, J¼1.6 Hz), 5.29 (s,
2H), 4.75 (q, 2H, J¼12.4 Hz), 4.27–4.21 (m, 2H), 2.29 (m, 2H), 1.52
(m, 2H), 1.28 (m, 4H), 1.20 (t, 3H, J¼7.2 Hz), 0.89 (t, 3H, J¼6.8 Hz);
13C NMR (100 MHz, CD3COCD3):
d
ppm¼167.3, 162.5, 158.1, 136.0,
129.4, 129.3, 128.9, 118.2, 70.8, 68.8, 63.4, 59.5, 53.8, 33.9, 31.9, 26.9,
23.0, 14.2, 14.1; GC–MS m/z (% rel inten.): 374.18 (Mþ, 1.79), 91.0
(100). Anal. Calcd for C21H26O6: C, 67.36; H, 7.00. Found: C, 67.13; H,
7.05.
6. Church, T. L.; Byme, C. M.; Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2007,
129, 8156.
7. Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am. Chem. Soc. 2005,
127, 10804.
8. Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 3291.
9. For our early work on alkynes chemistry, see: (a) Wang, A.; Jiang, H. J. Am.
Chem. Soc. 2008, 130, 5030; (b) Huang, J.; Zhou, L.; Jiang, H. Angew. Chem., Int.
Ed. 2006, 45, 1945; (c) Jiang, H.; Tang, J.; Wang, A.; Deng, G.; Yang, S. Synthesis
2006, 1155; (d) Wang, Y.; Jiang, H.; Liu, H.; Liu, P. Tetrahedron Lett. 2005, 46,
3935; (e) Li, J.; Jiang, H.; Chen, M. J. Org. Chem. 2001, 66, 3627; (f) Li, J.; Jiang, H.
Chem. Commun. 1999, 2369; (g) Li, J.; Jiang, H.; Feng, A.; Jia, L. J. Org. Chem. 1999,
64, 5984.
4.3.9. Dibenzyl 6-oxo-4-pentyl-2H-pyran-3,3(6H)-
dicarboxylate (4cg)
Pale yellow viscous oil; IR nmax (KBr): 1731, 1643, 1460, 1384,
1230, 1082, 989, 849, 742, 694 cmꢂ1
;
1H NMR (400 MHz,
CD3COCD3):
d
ppm¼7.40–7.34 (m, 10H), 5.93 (t, 1H, J¼1.6 Hz), 5.27
(q, 4H, J¼12.4 Hz), 4.80 (s, 2H), 2.21 (m, 2H), 1.43 (m, 2H), 1.17 (m,
4H), 0.85 (t, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CD3COCD3):
d
ppm¼166.3, 161.8, 157.3, 135.0, 128.5, 128.4, 117.3, 69.9, 68.1, 58.8,
33.0, 30.9, 25.9, 22.0, 13.5; GC–MS m/z (% rel inten.): 435.88 (Mþ,
0.03), 91.0 (100). Anal. Calcd for C26H28O6: C, 71.54; H, 6.47. Found:
C, 71.55; H, 6.47.
10. (a) Zhang, M.; Jiang, H.; Liu, H.; Zhu, Q. Org. Lett. 2007, 9, 4111; (b) Zhang, M.;
Jiang, H. F.; Wang, A. Z. Synlett 2007, 3214; (c) Zhang, M.; Jiang, H.-F. Eur. J. Org.
Chem. 2008, 3519.
11. For recent examples to construct multiply substituted 5,6-2H-pyran-2-one rings,
see: (a) Gardner, S. C.; Kwon, O. Org. Lett. 2008, 10, 429; (b) Bartolo, G.; Raffaella,
M.; Giuseppe, S. J. Org. Chem. 2008, 73, 756; (c) Fang, D.; Cheng, J.; Gong, K.; Shi,
Q. R.; Liu, Z. L. Catal. Lett. 2008, 121, 255; (d) Lin, L. L.; Chen, Z. L.; Yang, X.; Liu,
X. H.; Feng, X. M. Org. Lett. 2008, 10, 1311; (e) Li, K. L.; Tunge, J. A. J. Comb. Chem.
2008, 10, 170; (f) Minoru, T.; Ken, O.; Mitsuru, K.; Hirohisa, K. Chem.dEur. J. 2007,
13, 9791; (g) Joerg, T. B.; Stefan, F. K.; Stefan, F. K. Chem. Commun. 2007, 4164.
12. (a) Leutbecher, H.; Williams, L. A. D.; Rosner, H.; Beifuss, U. Bioorg. Med. Chem.
Lett. 2007, 17, 978; (b) Chattapadhyay, T. K.; Dureja, P. J. Agric. Food Chem. 2006,
54, 2129; (c) Bellina, F.; Carpita, A.; Mannocci, L.; Rossi, R. Eur. J. Org. Chem.
2004, 2610.
13. Davies-Coleman, M. T.; Rivett, D. E. A. Prog. Chem. Org. Nat. Prod. 1989, 55, 1.
14. Christen, P. Pharm. Acta Helv. 1986, 61, 242.
15. Ramesh, S.; Franck, R. W. Tetrahedron: Asymmetry 1990, 1, 137.
16. Alkofahi, A.; Ma, W. W.; McKenzie, A. T.; Byrn, S. R.; McLaughlin, J. L. J. Nat. Prod.
1989, 52, 1371.
4.3.10. 3,3-Diethyl 4-methyl 6-oxo-2H-pyran-3,3,4(6H)-
tricarboxylate (4de)
Yellow viscous oil; IR nmax (KBr): 1738, 1646, 1516, 1439, 1373,
1338, 1241, 1096, 1012, 860 cmꢂ1 1H NMR (400 MHz, CD3COCD3):
;
d
ppm¼6.94 (s, 1H), 4.85 (s, 2H), 4.22 (m, 4H), 3.73 (s, 3H), 1.23 (t,
J¼7.2 Hz, 6H); 13C NMR (100 MHz, CD3COCD3):
ppm¼168.6, 167.0,
d
165.3, 136.1, 130.6, 72.5, 63.4, 60.6, 52.2, 14.0; GC–MS m/z (% rel
inten.): 300.93 (Mþ, 0.8), 195.74 (100). Anal. Calcd for C13H16O8: C,
52.00; H, 5.37. Found: C, 51.98; H, 5.36.
Acknowledgements
17. Duffield, P. H.; Jamieson, D. D.; Duffield, A. M. Arch. Int. Pharmacodyn. 1989,
301, 81.
18. The pKa value and content of enol, see: (a) Carey, F. A.; Sundberg, R. J. Advance
Organic Chemistry: Part B. Reaction and Synthesis; Plenum: New York, NY, 1977;
p 2; (b) March, J. Advance Organic Chemistry: Reactions, Mechanisms, Structure,
2nd ed.; McGraw-Hill: New York, NY, 1977; p 55.
The authors thank the National Natural Science Foundation of
China (Nos. 20772034, 20625205, 20572027, and 20332030) and
Guangdong Natural Science Foundation (No. 07118070) for finan-
cial support of this work.