Convenient MCRs synthesis of trifluoromethylated pyrano[4,3-b]pyrans and their further transformation

Article abstract of DOI:10.1055/s-0031-1289761

Ethyl 2-hydroxy-7-methyl-5-oxo-4-aryl-2-(trifluoromethyl)-3,4-dihydro-2H, 5H-pyrano[4,3-b]pyran-3-carboxylate derivatives were synthesized via a one-pot three-component reaction (MCR) promoted by ammonium acetate. The effect of ammonium acetate and the so

Full text of DOI:10.1055/s-0031-1289761

1686▌
PAPER
paper
Convenient MCRs Synthesis of Trifluoromethylated Pyrano[4,3-b]pyrans and
Their Further Transformation
Fluorinated Heterocycles
Wei Wang,a Jia Li,a Li Zhang,a Liping Song,*a,b Min Zhang,a Weiguo Cao,a Hongmei Deng,c Min Shaoc
a
Department of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200444, P. R. of China
Fax +86(21)66134594; E-mail: lpsong@shu.edu.cn
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. of China
c
Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, P. R. of China
Received: 20.03.2012; Accepted after revision: 11.04.2012
example, it can be reacted with diazonium compounds
Abstract: Ethyl
2-hydroxy-7-methyl-5-oxo-4-aryl-2-(trifluoro-
followed by ring-opening and ring-closure reactions to af-
ford 1-aryl-6-methyl-4-oxo-1,4-dihydropyridazine-3-car-
boxylic acids with potential antibacterial activity.10
methyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxylate de-
rivatives were synthesized via a one-pot three-component reaction
(MCR) promoted by ammonium acetate. The effect of ammonium
acetate and the solvent on the reaction efficiency was investigated. Tosylated and mesylated 4-hydroxy-6-methyl-2H-py-
Furthermore, treatment of the resultant products with thionyl chlo-
ride/pyridine in chloroform gave the corresponding dehydrated
products ethyl 4-aryl-7-methyl-5-oxo-2-(trifluoromethyl)-4H,5H-
lyzed Heck coupling reaction.11 9-Aryl-3,6-dimethyl-1,8-
pyrano[4,3-b]pyran-3-carboxylates and the unexpected defluorinat-
ed products ethyl 3-aryl-6-methyl-4-oxo-4H-furo[3,2-c]pyran-2-
rane-2-one derivatives can be reacted with electron-rich
olefins (vinyl ethers and amides) via a palladium-cata-
dioxo-2,7,10-trioxanthenes were effectively synthesized
by reaction of 4-hydroxy-6-methyl-2H-pyran-2-one with
aromatic aldehydes under microwave irradiation as cata-
lyst-free conditions.12 These different applications have
received considerable attention over the last few years.
carboxylates. The novel products are highly important for the syn-
thesis of related fluorinated fused heterocyclic compounds.
Key words: MCR, fluorinated heterocycle, ethyl trifluoroacetoace-
tate, dehydration
In order to evaluate the potential applications of multi-
component reactions in the field of organofluorine chem-
istry and to continue our ongoing study on the synthesis of
fluorine-containing heterocyclic compounds via multi-
component reactions based on trifluoromethyl-1,3-dicar-
Fluorine-containing compounds have attracted much in-
terest because of their unique chemical, physical, and
biological activity. In particular, fluorine-containing het-
erocycles are now widely recognized as important organic
molecules showing interesting biological activity with po-
tential for application in medicine and agriculture.1,2 As a
result, in recent years, the synthetic methodology for the
preparation of fluorinated heterocyclic compounds has re-
ceived much attention.3–5
bonyl compounds,
a
versatile fluorine-containing
building blocks, herein, we wish to report a one-pot, three-
component reaction for synthesis of ethyl 2-hydroxy-
7-methyl-5-oxo-4-aryl-2-(trifluoromethyl)-3,4-dihydro-
2H,5H-pyrano[4,3-b]pyran-3-carboxylate derivatives 4
via 4-hydroxy-6-methyl-2H-pyran-2-one,13,14 aromatic al-
dehyde, and ethyl trifluoroacetoacetate, together with fur-
ther dehydration of the α-hydroxy-dihydropyran moiety
to the corresponding 4H-pyran derivatives 5. Interesting-
ly, in the dehydration process, apart from the correspond-
ing dehydration products, the very unusual defluorinated
fused furo[3,2-c]pyran-4-one derivatives 6 were formed.
Multicomponent reactions (MCRs) are of great impor-
tance in synthetic organic chemistry, by virtue of their
convergence, productivity, facile execution, and generally
high yields of products, and they have attracted much at-
tention from the vantage point of combinatorial chemis-
try.6 In addition, the design of multicomponent reactions
for the production of elaborate active compounds has be-
come an important area of research in combinatorial and
medicinal chemistry. The reactions of fluorinated 1,3-di-
carbonyl compounds, as versatile fluorine-containing
building blocks and as components in multicomponent re-
actions, have been investigated extensively,7 and they are
well established as synthetic intermediates in heterocyclic
chemistry.8,9 4-Hydroxy-6-methyl-2H-pyran-2-one is a
potential 1,3-dicarbonyl compound with diverse synthetic
applications that have been extensively investigated. For
Initially, we carried out the one-pot, three-component re-
action of benzaldehyde (1a) and 4-hydroxy-6-methyl-2H-
pyran-2-one (2) with ethyl trifluoroacetoacetate (3) in the
presence of a catalytic amount of triethylamine in ethanol
at room temperature, however, no reaction occurred. Sub-
sequently, the resultant mixtures were heated to reflux, af-
ter stirring for 24 hours, TLC showed that the reaction
proceeded insufficiently and general workup gave the
product 4a in only 32% yield.
Based on the above results, the reaction conditions were
optimized to improve the yield by changing catalysts and
solvents. The effects of a variety of organic bases on the
reaction efficiency were firstly screened. As shown in
Table 1, when the reaction was performed in the absence
SYNTHESIS 2012, 44, 1686–1692
Advanced online publication: 08.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289761; Art ID: SS-2012-H0287-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fluorinated Heterocycles
1687
of base, 4a was not formed (entry 1). Other organic bases, smoothly and efficiently under the present conditions, af-
such as piperidine and pyridine, catalyzed the reaction fording the corresponding 3,4-dihydro-2H,5H-pyra-
giving almost the same reaction results in terms of reac- no[4,3-b]pyran-3-carboxylate derivatives 4 in moderate
tion time and yields (entries 2–4). Interestingly, when 0.5 to good yields. The reaction results are summarized in
equivalents of ammonium acetate were used as the cata- Table 2. Aldehydes with electron-withdrawing groups
lyst, the yield improved significantly (entry 5). A better gave higher yields than those bearing electron-donating
result was obtained when 1.0 equivalent of ammonium ac- groups (entries 1–11). On the other hand, the location of
etate was used as the promoter (entry 7), but higher the substituent, para or meta on the aromatic ring of the
amounts of ammonium acetate did not further improve the aromatic aldehyde, did not show a great effect on the yield
yield of 4a (entries 8 and 9). The solvent effect was the of product (entries 5, 10). It should be noted that the reac-
next considered factor. As shown in Table 1, generally, tion of aliphatic aldehydes, such as isobutyraldehyde,
better yields of 4a were obtained in polar protic solvents, failed; thin-layer chromatography of the reaction mixture
such as ethanol or methanol, than in polar aprotic sol- showed a mixture of starting materials and numerous
vents, even though the latter reactions were carried out for products. The reaction of non-fluorinated ethyl acetoace-
a prolonged reaction time. It should be noted that the re- tate was also investigated, unfortunately, the reaction also
action gave exclusively the O-heterocycle 4a, and the cor- failed and the starting materials were recovered.
responding N-heterocycles were not detected even though
Table 2 Results of the One-Pot, Three-Component Reactiona
the reaction was carried out in the presence of excess of
ammonium acetate (entries 8 and 9).
OH
O
Ar
CO2Et
O
O
NH4OAc
O
Table 1 Optimization of the One-Pot Reactiona
ArCHO
+
+
OH
EtOH, reflux
OEt
F3C
O
O
O
CF3
OH
O
Ph
O
1
2
3
4
CO2Et
O
O
cat.
O
+
+
PhCHO
Yieldb (%)
OH
Entry
Ar
Ph
Time (h) Product
solvent
F3C
OEt
O
O
CF3
1a
2
3
4a
1
2
24
24
12
12
8
4a
4b
4c
4d
4e
4f
70
63
76
78
81
69
61
75
73
83
71
4-MeC6H4
4-ClC6H4
Entry
Base
Solvent
Time
Yieldb
(%) of 4a
(equiv)
(h)
3
c
1
2
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
THF
48
24
24
24
24
24d
24
24
24
24
24
24
24
trace
32
4
4-BrC6H4
4-O2NC6H4
4-NCC6H4
4-MeOC6H4
3-ClC6H4
Et3N (0.25)
5
3
pyridine (0.25)
20
6
12
24
12
12
12
24
4
piperidine (0.25)
NH4OAc (0.5)
NH4OAc (1)
NH4OAc (1)
NH4OAc (10)
NH4OAc (30)
NH4OAc (1)
NH4OAc (1)
NH4OAc (1)
NH4OAc (1)
26
7
4g
4h
4i
5
52
8
6
trace
70
9
3-BrC6H4
3-O2NC6H4
4-HOC6H4
7
10
11
4j
8
70
4k
9
70
a Reaction conditions: 1 (1.0 mmol), 2 (1.0mmol), 3 (1.0 mmol),
NH4OAc (1.0 equiv), EtOH (15.0 mL), reflux.
b Isolated yield.
10
11
12
13
46
27
CH2Cl2
MeCN
36
The structures of compounds 4 were fully confirmed by
spectroscopic and elemental analysis. For instance, in the
1H NMR (CDCl3) spectra of 4a, characteristic were the
doublets at δ = 3.10 and 4.12 ppm with JH-H = 12.5 Hz for
H3 and H4, respectively, indicating the trans configura-
tion of the vicinal two hydrogen atoms. The CF3 group in
the 19F NMR spectrum appeared as a singlet peak at δ =
–84.13 ppm (s, 3 F), which indicated that the CF3 group
was bonded to a quaternary carbon atom. The structure of
4c was further confirmed by XRD analysis. This showed
unambiguously the trans relationship between the vicinal
six-membered ring protons (Figure 1).15
18
a Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), sol-
vent (15 mL).
b Isolated yield.
c Without base.
d The reaction was carried out at r.t.
With the optimal results in hand (Table 1, entry 7), we
next investigated the scope and limitation of this one-pot,
three-component reaction. Various aromatic aldehydes
with substituents of different electronic property reacted
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1686–1692

1688
W. Wang et al.
PAPER
drated derivatives 5 and the unexpected formation of
defluorinated products 6. Compounds 6 contain the fused
furo[3,2-c]pyran-4-one scaffold which appears in a large
number of naturally occurring and designed molecules en-
dowed with a wide array of biological properties.17
Investigations of the reaction scope revealed that various
substrates could be utilized in this protocol. Both electron-
withdrawing and electron-donating substituents on the
aromatic ring were well tolerated and did not have a great
influence on the yields of 5 and 6. The reaction results are
listed in Table 3. The structure identity of compounds 5
and 6 was fully supported by spectral and microanalytical
data. Moreover, the structure of 6a was further confirmed
by XRD analysis (Figure 2).15
Table 3 Reaction Results of Dehydration of 4 to 5 and 6a
Figure 1 X-ray crystal structure of compound 4c
O
Ar
O
Ar
O
O
SOCl2
pyridine
(5.0 equiv)
Ar
CO2Et
CO2Et
O
O
O
CO2Et
+
OH
Based on these results, a possible mechanism for the for-
mation of 4 is illustrated in Scheme 1. Firstly, intermedi-
ate A was formed via initial Knoevenagel condensation
reaction followed by Michael addition reaction, which
then underwent intramolecular cyclization reaction to af-
ford 4.
CHCl3
reflux
O
O
CF3
CF3
5
4
6
Entry
Ar
Ph
Time (h) Products [yieldb (%)]
1
2
3
4
5
12
12
12
12
12
5a [38]
5b [40]
5c [37]
5d [41]
5e [40]
6a [32]
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
6b [39]
6c [36]
6d [36]
6d [37]
O
O
OH
ArCHO
+
+
F3C
OEt
O
O
1
2
3
a Reactions conditions: 4 (1.0 mmol), SOCl2 (5.0 mmol), pyridine (5.0
mmol), CHCl3 (10 mL).
O
O
O
O
Ar
O
O
Ar
Ar
b Isolated yield.
EtO
O
3
2
OEt
CF3
O
F3C
O
HO
A
+
+
3
1
2
1
Ar
O
EtO2C
O
HO
F3C
O
4
Scheme 1 Plausible mechanism for formation of 4
Finally, we studied the dehydration of compounds 4. It
should be noted that the hemiketal moiety in 4 is stable; it
resists dehydration under the conditions for the formation
of 4 due to the strong electron-withdrawing effect of the
trifluoromethyl group on the six-membered ring.16 Thus,
the effects of different dehydration reagents were
screened, and reaction results showed that excess 4-tolu-
enesulfonic acid or phosphorus pentoxide were not effec-
tive even though the reaction was performed under reflux
in toluene. Using thionyl chloride/pyridine under reflux in
chloroform as the dehydration reagent gave smooth elim-
ination of water from 4 to afford the corresponding dehy-
Figure 2 X-ray crystal structure of compound 6a
In conclusion, we have demonstrated a simple and conve-
nient multicomponent protocol for the synthesis of a li-
brary of trifluoromethylated pyrano[4,3-b]pyrans from
readily available simple starting materials. Meanwhile,
The dehydration reaction afforded the corresponding de-
hydrated products and the unexpected defluorinated fused
furo[3,2-c]pyrans. The novel products obtained in this
Synthesis 2012, 44, 1686–1692
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fluorinated Heterocycles
MS (ESI): m/z = 433/435 [M + H]+.
1689
study may be considered as valuable synthons for further
elaboration into more complex heterocycles of biological
relevance.
Anal. Calcd for C19H16ClF3O6: C, 52.73; H, 3.73. Found: C, 52.52;
H, 3.71.
Ethyl 4-(4-Bromophenyl)-2-hydroxy-7-methyl-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4d)
Melting points were measured in Melt-Temp apparatus and were
1
uncorrected. H and 19F NMR spectra were recorded in CDCl3
White solid; yield: 372.0 mg (78%); mp 229–230 °C.
Bruker AM-500 instruments with TMS and CFCl3 (with upfield
negative) as the internal and external standards, respectively. IR
spectra were obtained with a Nicolet AV-360 spectrophotometer.
LR-MS were determined with Agilent 1100 LC/MSD SL instru-
ment using ESI technique. HRMS were run on Bruker Daltonics,
Inc. APEXIII 7.0 Tesla FTMS using ESI technique. Elemental anal-
yses were performed using a Vario EL III analyzer. All the solvents
were not purified before use. X-ray diffraction crystal structure
analysis was obtained on Bruker P4 instrument using graphite
monochromatized MoKα radiation (λ = 0.71073 Å) at 293(2) K.
IR (KBr): 3427, 3064, 2808, 1741, 1680, 1015, 997, 815 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.05 (t, J = 7.0 Hz, 3 H), 2.24 (s,
3 H), 3.02 (d, J = 12.0 Hz, 1 H), 4.06 (d, J = 12.0 Hz, 1 H), 4.06 (qd,
J1 = 7.0 Hz, 2J2 = 11.5 Hz, 2 H), 5.60 (s, 1 H), 5.96 (s, 1 H), 7.03 (d,
J = 8.5 Hz, 2 H), 7.10 (d, J = 8.5 Hz, 2 H).
19F NMR (470 MHz, CDCl3): δ = –84.05 (s, 3 F).
MS (ESI): m/z = 477/479 [M + H]+.
Anal. Calcd for C19H16BrF3O6: C, 47.82; H, 3.38. Found: C, 47.87;
H, 3.23.
Ethyl 2-Hydroxy-7-methyl-5-oxo-4-phenyl-2-(trifluoromethyl)-
3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxylate (4a);
Typical Procedure
Ethyl 2-Hydroxy-7-methyl-4-(4-nitrophenyl)-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4e)
To a mixture of benzaldehyde (1a, 106.0 mg, 1.0 mmol), 4-hy-
droxy-6-methyl-3,4-dihydro-2H-pyran-2-one (2, 126.0 mg, 1.0
mmol), and ethyl trifluoroacetoacetate (3, 184.0 mg, 1.0 mmol) in
EtOH (15 mL) was added NH4OAc (77.1 mg, 1.0 mmol). The resul-
tant mixture was stirred at reflux temperature for the time indicated
(Table 2). After completion of the reaction, the solvent was evapo-
rated and the residue was purified by column chromatography (sil-
ica gel, petroleum ether–EtOAc, 4:1) to afford pure 4a as a white
solid; yield: 279.0 mg (70%); mp 219–220 °C.
White solid; yield: 360.0 mg (81%); mp 233–234 °C.
IR (KBr): 3431, 3110, 3080, 2987, 2941, 1736, 1679, 1585, 1018,
995, 816 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.03 (t, J = 7.5 Hz, 3 H), 2.26 (s,
3 H), 3.05 (d, J = 11.5 Hz, 1 H), 4.07 (qd, J1 = 7.0 Hz, 2J2 = 13.5 Hz,
2 H), 4.24 (d, J = 11.5 Hz, 1 H), 5.52 (s, 1 H), 6.01 (s, 1 H), 7.34 (d,
J = 8.5 Hz, 2 H), 8.18 (d, J = 8.5 Hz, 2 H).
IR (KBr): 3434, 3067, 2984, 2939, 1740, 1680, 1017, 736, 715
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.01 (t, J = 7.0 Hz, 3 H), 2.26 (s,
3 H), 3.10 (d, J = 11.5 Hz, 1 H), 4.07 (q, J = 7.0 Hz, 2 H), 4.12 (d,
J = 11.5 Hz, 1 H), 5.68 (s, 1 H), 5.99 (s, 1 H), 7.12–7.36 (m, 5 H).
19F NMR (470 MHz, CDCl3): δ = –83.92 (s, 3 F).
MS (ESI): m/z = 444 [M + H]+.
Anal. Calcd for C19H16F3NO8: C, 51.48; H, 3.64; N, 3.16. Found: C,
51.48; H, 3.27, N, 3.31.
19F NMR (470 MHz, CDCl3): δ = –84.13 (s, 3 F).
MS (ESI): m/z = 399 [M + H]+.
Ethyl 4-(4-Cyanophenyl)-2-hydroxy-7-methyl-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4f)
Anal. Calcd for C19H17F3O6: C, 57.29; H, 4.30. Found: C, 57.21; H,
4.28.
White solid; yield: 293.0 mg (69%); mp 226–227 °C.
IR (KBr): 3410, 3072, 2989, 2941, 2849, 1736, 1680, 1018, 995,
817 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 2.26 (s,
3 H), 3.03 (d, J = 11.5 Hz, 1 H), 4.07 (qd, J1 = 7.0 Hz, 2J2 = 16.0 Hz,
2 H), 4.18 (d, J = 11.5 Hz, 1 H), 5.54 (s, 1 H), 6.00 (s, 1 H), 7.28 (d,
J = 8.5 Hz, 2 H), 7.62 (d, J = 8.5 Hz, 2 H).
Ethyl 2-Hydroxy-7-methyl-5-oxo-4-p-tolyl-2-(trifluoromethyl)-
3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxylate (4b)
White solid; yield: 260.0 mg (63%); mp 222–223 °C.
IR (KBr): 3427, 3033, 2981, 2925, 2868, 1744, 1680, 1021, 996,
814 cm–1.
19F NMR (470 MHz, CDCl3): δ = –83.93 (s, 3 F).
MS (ESI): m/z = 424 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 1.02 (t, J = 7.0 Hz, 3 H), 2.23 (s,
3 H), 2.30 (s, 3 H), 3.05 (d, J = 11.5 Hz, 1 H), 4.06 (qd, J1 = 7.0 Hz,
2J2 = 11.0 Hz, 2 H), 4.09 (d, J = 11.5 Hz, 1 H), 5.64 (s, 1 H), 5.96
(s, 1 H), 7.01 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 2 H).
19F NMR (470 MHz, CDCl3): δ = –80.66 (s, 3 F).
MS (ESI): m/z = 413 [M + H]+.
Anal. Calcd for C20H16F3NO6: C, 56.74; H, 3.81; N, 3.31. Found: C,
56.73; H, 3.82; N, 3.35.
Ethyl 2-Hydroxy-4-(4-methoxyphenyl)-7-methyl-5-oxo-2-(tri-
fluoromethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-car-
boxylate (4g)
Anal. Calcd for C20H19F3O6: C, 58.25; H, 4.64. Found: C, 58.19; H,
4.49.
White solid; yield: 262.0 mg (61%); mp 206–207 °C.
IR (KBr): 3437, 3002, 2938, 1742, 1681, 1375, 1018, 959, 821
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.04 (t, J = 7.0 Hz, 3 H), 2.23 (s,
3 H), 3.05 (d, J = 11.5 Hz, 1 H), 3.78 (s, 3 H), 4.06 (q, J = 7.0 Hz, 2
H), 4.07 (d, J = 11.5 Hz, 1 H), 5.63 (s, 1 H), 5.96 (s, 1 H), 6.84 (d,
J = 6.5 Hz, 2 H), 7.06 (d, J = 6.5 Hz, 2 H).
Ethyl 4-(4-Chlorophenyl)-2-hydroxy-7-methyl-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4c)
White solid; yield: 329.0 mg (76%); mp 216–217 °C.
IR (KBr): 3434, 3067, 3005, 2939, 1740, 1680, 1017, 995, 814
cm–1.
19F NMR (470 MHz, CDCl3): δ = –84.15 (s, 3 F).
MS (ESI): m/z = 429 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 1.05 (t, J = 7.5 Hz, 3 H), 2.24 (s,
3 H), 3.02 (d, J = 11.0 Hz, 1 H), 4.07 (qd, J1 = 7.5 Hz, 2J2 = 11.5 Hz,
2 H), 4.08 (d, J = 11.0 Hz, 1 H), 5.56 (s, 1 H), 5.97 (s, 1 H), 7.08 (d,
J = 8.5 Hz, 2 H), 7.28 (d, J = 8.5 Hz, 2 H).
Anal. Calcd for C20H19F3O7: C, 56.03; H, 4.47. Found: C, 55.64; H,
4.44.
19F NMR (470 MHz, CDCl3): δ = –84.08 (s, 3 F).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1686–1692

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W. Wang et al.
PAPER
Ethyl 4-(3-Chlorophenyl)-2-hydroxy-7-methyl-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4h)
Ethyl 7-Methyl-5-oxo-4-phenyl-2-(trifluoromethyl)-4H,5H-py-
rano[4,3-b]pyran-3-carboxylate (5a) and Ethyl 6-Methyl-4-oxo-
3-phenyl-4H-furo[3,2-c]pyran-2-carboxylate (6a); Typical Pro-
cedure
White solid; yield: 325.0 mg (75%); mp 214–215 °C.
To a stirred soln of CHCl3 (10.0 mL) containing 4a (398.0 mg, 1.0
mmol) and pyridine (395.0 mg, 5.0 mmol) was added dropwise
SOCl2 (595.0 mg, 5.0 mmol) at r.t. When the addition was com-
plete, the resultant mixture was heated at reflux (62 °C) for the time
indicated Table 3 until completion (TLC monitoring). After cool-
ing, the mixture was poured into H2O (100 mL). The aqueous layer
was extracted with CHCl3 (2 × 20 mL). The combined organic lay-
ers were washed with H2O (2 × 20 mL) and brine (2 × 20 mL), and
concentrated under reduced pressure. The residue was purified by
column chromatography (petroleum–EtOAc, 8:1) to afford pure 5a
and 6a.
IR (KBr): 3072, 2939, 2798, 1740, 1678, 1018, 995, 789, 696 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.05 (t, J = 7.0 Hz, 3 H), 2.25 (s,
3 H), 3.02 (d, J = 11.0 Hz, 1 H), 4.08 (qd, J1 = 7.0 Hz, 2J2 = 11.5 Hz,
2 H), 4.12 (d, J = 11.0 Hz, 1 H), 5.61 (s, 1 H), 5.98 (s, 1 H), 7.03–
7.27 (m, 1 H), 7.11 (s, 1 H), 7.23–7.26 (m, 2 H).
19F NMR (470 MHz, CDCl3): δ = –84.05 (s, 3 F).
MS (ESI): m/z = 433/435 [M + H]+.
Anal. Calcd for C19H16ClF3O6: C, 52.73; H, 3.73. Found: C, 52.68;
H, 3.79.
Ethyl 7-Methyl-5-oxo-4-phenyl-2-(trifluoromethyl)-4H,5H-py-
rano[4,3-b]pyran-3-carboxylate (5a)
Ethyl 4-(3-Bromophenyl)-2-hydroxy-7-methyl-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4i)
White solid; yield: 144.0 mg (38%); mp 82–83 °C.
White solid; yield: 348.0 mg (73%); mp 222–223 °C.
IR (KBr): 3434, 3033, 2976, 2925, 1738, 1141, 980, 759, 701 cm–1.
IR (KBr): 3428, 3059, 2939, 2852, 1740, 1679, 1017, 995, 786, 696
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.05 (t, J = 7.0 Hz, 3 H), 2.26 (s,
3 H), 3.01 (d, J = 11.5 Hz, 1 H), 4.07 (d, J = 12.0 Hz, 1 H), 4.11 (qd,
J1 = 7.0 Hz, 2J2 = 11.5 Hz, 2 H), 5.61 (s, 1 H), 5.98 (s, 1 H), 7.08–
7.09 (m, 1H), 7.18–7.21 (m, 1 H), 7.26 (s, 1 H), 7.40–7.42 (m, 1 H).
19F NMR (470 MHz, CDCl3): δ = –84.05 (s, 3 F).
MS (ESI) m/z = 477/479 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 1.10 (t, J = 7.0 Hz, 3 H), 2.20 (s,
3 H), 4.10 (q, J = 7.0 Hz, 2 H), 4.81 (s, 1 H), 6.00 (s, 1 H), 7.25–7.32
(m, 5 H).
19F NMR (470 MHz, CDCl3): δ = –67.01 (s, 3 F).
MS (ESI): m/z = 381 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H16F3O5: 381.0950; found:
381.0948.
Ethyl 6-Methyl-4-oxo-3-phenyl-4H-furo[3,2-c]pyran-2-carbox-
ylate (6a)
White solid; yield: 96.0 mg (32%); mp 139–141 °C.
Anal. Calcd for C19H16BrF3O6: C, 47.82; H, 3.38. Found: C, 48.03;
H, 3.53.
IR (KBr): 3461, 2921, 1706, 1620, 982, 758, 699 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.0 Hz, 3 H), 2.40 (s,
3 H), 4.30 (q, J = 7.0 Hz, 2 H), 6.52 (s, 1 H), 7.45–7.55 (m, 5 H).
Ethyl 2-Hydroxy-7-methyl-4-(3-nitrophenyl)-5-oxo-2-(trifluo-
romethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-carboxyl-
ate (4j)
White solid; yield: 369.0 mg (83%); mp 214–215 °C.
MS (ESI): m/z = 299 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H15O5: 299.0920; found:
IR (KBr): 3427, 3095, 2983, 2850, 1738, 1677, 1591, 1018, 994,
739, 688 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.00 (t, J = 7.0 Hz, 3 H), 2.27 (s,
3 H), 3.06 (d, J = 11.5 Hz, 1 H), 4.06 (qd, J1 = 7.5 Hz, 2J2 = 13.5 Hz,
2 H), 4.24 (d, J = 11.5 Hz, 1 H), 5.58 (s, 1 H), 6.02 (s, 1 H), 7.49–
7.49–7.53 (m, 2 H), 8.00–8.01 (m, 1 H), 8.15–8.17 (m, 1 H).
19F NMR (470 MHz, CDCl3): δ = –83.91 (s, 3 F).
MS (ESI): m/z = 444 [M + H]+.
299.0914.
Ethyl 4-(4-Chlorophenyl)-7-methyl-5-oxo-2-(trifluoromethyl)-
4H,5H-pyrano[4,3-b]pyran-3-carboxylate (5b)
White solid; yield: 166.0 mg (40%); mp 80–82 °C.
IR (KBr): 3431, 2984, 1741, 1077, 979, 836 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.12 (t, J = 7.5 Hz, 3 H), 2.22 (s,
3 H), 4.11 (q, J = 7.5 Hz, 2 H), 4.78 (s, 1 H), 6.01 (s, 1 H), 7.24 (d,
J = 8.0 Hz, 2 H), 7.28 (d, J = 8.0 Hz, 2 H).
Anal. Calcd for C19H16F3NO8: C, 51.48; H, 3.64; N, 3.16. Found: C,
51.38; H, 3.56; N, 3.33.
19F NMR (470 MHz, CDCl3): δ = –66.95 (s, 3 F).
MS (ESI) m/z = 415/417 [M + H]+.
Ethyl 2-Hydroxy-4-(4-hydroxyphenyl)-7-methyl-5-oxo-2-(tri-
fluoromethyl)-3,4-dihydro-2H,5H-pyrano[4,3-b]pyran-3-car-
boxylate (4k)
Anal. Calcd for C19H14ClF3O5: C, 55.02; H, 3.40. Found: C, 54.83;
H, 3.57.
White solid; yield: 295.0 mg (71%); mp 198–199 °C.
IR (KBr): 3431, 3100, 2789, 1702, 1659, 1609, 1520, 1496, 1457,
1418, 1360, 1077, 729 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.02 (t, J = 7.0 Hz, 3 H), 2.24 (s,
3 H), 3.03 (d, J = 11.0 Hz, 1 H), 4.03 (d, J = 11.0 Hz, 1 H), 4.05 (qd,
J1 = 7.0 Hz, 2J2 = 12.5 Hz, 2 H), 5.59 (s, 1 H), 6.61 (d, J = 8.5 Hz, 2
H), 6.94 (d, J = 8.5 Hz, 2 H).
19F NMR (470 MHz, CDCl3): δ = –84.14 (s, 3 F).
MS (ESI): m/z = 415 [M + H]+.
Ethyl 6-Methyl-4-oxo-3-(4-chlorophenyl)-4H-furo[3,2-c]pyran-
2-carboxylate (6b)
White solid; yield: 130.0 mg (39%); mp 169–171 °C.
IR (KBr): 3468, 2996, 1719, 1618, 962, 823 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.28 (t, J = 7.0 Hz, 3 H), 2.40 (s,
3 H), 4.32 (q, J = 7.0 Hz, 2 H), 6.52 (s, 1 H), 7.43 (d, J = 7.0 Hz, 2
H), 7.51 (d, J = 7.0 Hz, 2 H).
MS (ESI): m/z = 333/335 [M + H]+.
Anal. Calcd for C19H16F3NO8·H2O: C, 52.78; H, 4.43. Found: C,
52.77; H, 4.46.
Anal. Calcd for C17H13ClO5: C, 61.36; H, 3.94. Found: C, 61.49; H,
4.05.
Ethyl 7-Methyl-5-oxo-4-p-tolyl-2-(trifluoromethyl)-4H,5H-py-
rano[4,3-b]pyran-3-carboxylate (5c)
White solid; yield: 146.0 mg (37%); mp 93–95 °C.
Synthesis 2012, 44, 1686–1692
© Georg Thieme Verlag Stuttgart · New York

PAPER
Fluorinated Heterocycles
1691
IR (KBr): 3432, 2960, 2851, 1740, 1647, 1070, 978, 826 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.0 Hz, 3 H), 2.38 (s,
3 H), 4.30 (d, J = 7.0 Hz, 2 H), 6.49 (s, 1 H), 7.41 (d, J = 8.5 Hz, 2
H), 7.56 (d, J = 8.5 Hz, 2 H).
1H NMR (500 MHz, CDCl3): δ = 1.15 (t, J = 7.5 Hz, 3 H), 2.24 (s,
3 H), 2.32 (s, 3 H), 4.14 (q, J = 7.5 Hz, 2 H), 4.79 (s, 1 H), 6.01 (s,
1 H), 7.14 (d, J = 7.5 Hz, 2 H), 7.20 (d, J = 7.5 Hz, 2 H).
MS (ESI): m/z = 377/379 [M + H]+.
19F NMR (470 MHz, CDCl3): δ = –66.97 (s, 3 F).
MS (ESI) m/z = 395 [M + H]+.
Anal. Calcd for C17H13BrO5: C, 54.13; H, 3.47. Found: C, 54.14; H,
3.37.
HRMS (ESI) m/z [M + Na]+ calcd for C20H17F3NaO5: 417.0926;
found: 417.0921.
Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (NNSFC) (Nos. 21072128, 20772080),
Leading Academic Discipline Project of Shanghai Municipal Edu-
cation Commission (No. J50102), and Key Laboratory of Orga-
nofluorine Chemistry, Shanghai Institute of Organic Chemistry.
Ethyl 6-Methyl-4-oxo-3-p-tolyl-4H-furo[3,2-c]pyran-2-carbox-
ylate (6c)
White solid; yield: 113.0 mg (36%); mp 155–156 °C.
IR (KBr): 3462, 2993, 1712, 1619, 1143, 982, 800 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.26 (t, J = 7.0 Hz, 3 H), 2.38 (s,
3 H), 2.41 (s, 3 H), 4.30 (d, J = 7.0 Hz, 2 H), 6.49 (s, 1 H), 7.25 (d,
J = 8.5 Hz, 2 H), 7.43 (d, J = 8.5 Hz, 2 H).
Supporting Information for this article is available online at
MS (ESI) m/z = 313 [M + H]+.
http://www.thieme-connect.com/ejournals/toc/synthesis. SnufpgIorpi
o
nmitSartunpIoofprimntgirat
Anal. Calcd for C18H16O5: C, 69.22; H, 5.16. Found: C, 69.17; H,
5.05.
References
Ethyl 7-Methyl-4-(4-nitrophenyl)-5-oxo-2-(trifluoromethyl)-
4H,5H-pyrano[4,3-b]pyran-3-Carboxylate (5d)
(1) Filler, R.; Banks, R. E. Organofluorine Chemicals and Their
Industrial Applications; Ellis Horwood: Chichester, 1979.
(2) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Frezza, M.;
Balestrino, D.; Soulère, L.; Reverchon, S.; Queneau, Y.;
Forestier, C.; Doutheau, A. Eur. J. Org. Chem. 2006, 4731.
(c) Leroux, F.; Lefebvre, O.; Schlosser, M. Eur. J. Org.
Chem. 2006, 3147. (d) Buscemi, S.; Pace, A.; Piccionello,
A.; Macaluso, G.; Vivona, N. J. Org. Chem. 2005, 70, 3288.
(3) (a) Hiyama, T. Organofluorine Compounds; Springer:
Berlin, 2000. (b) Hudlicky, M. Chemistry of Organic
Fluorine Compounds; Ellis Harwood: Chichester, 1976.
(4) (a) Welch, J. T. Fluorine in Bioorganic Chemistry;
Eswarakrishnan, S., Ed.; Wiley: New York, 1991.
White solid; yield: 175.0 mg (41%); mp 79–80 °C.
IR (KBr): 3445, 2921, 2850, 1735, 1650, 979, 828 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.14 (t, J = 7.0 Hz, 3 H), 2.27 (s,
3 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.94 (s, 1 H), 6.07 (s, 1 H), 7.51 (d,
J = 9.0 Hz, 2 H), 8.20 (d, J = 9.0 Hz, 2 H).
19F NMR (470 MHz, CDCl3): δ = –66.83 (s, 3 F).
MS (ESI) m/z = 426 [M + H]+.
HRMS (ESI) m/z [M + H]+ calcd for C19H15F3NO7: 426.0801;
found: 426.0807.
Ethyl 6-Methyl-3-(4-nitrophenyl)-4-oxo-4H-furo[3,2-c]pyran-
2-carboxylate (6d)
(b) Prabhakaran, J.; Underwood, M. D.; Parsey, R. V.;
Arango, V.; Majo, V. J.; Simpson, N. R.; Heertum, R. V.;
Mann, J. J.; Kumar, J. S. D. Bioorg. Med. Chem. 2007, 15,
1802.
White solid; yield: 123.0 mg (36%); mp 177–178 °C.
IR (KBr): 3458, 2919, 1761, 1624, 1129, 965, 852 cm–1.
(5) (a) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of
Fluorine Chemistry; Kodansha & Elsevier Biomedical:
Tokyo, 1982. (b) Filler, R.; Kobayashi, Y.; Yagupolskii, L.
M. Organofluorine Compounds in Medical Chemistry and
Biomedical Application; Elsevier: Amsterdam, 1993.
(6) (a) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Suresh Babu, A. R.; Raghunathan, R. Tetrahedron
Lett. 2006, 47, 9221.
(7) (a) Yi, H.; Song, L. P.; Wang, W.; Liu, J. N.; Zhu, S. Z.;
Deng, H. M.; Shao, M. Chem. Commun. 2010, 46, 6941.
(b) Wang, P. Y.; Song, L. P.; Yi, H.; Zhang, M.; Deng, H.
M.; Shao, M. Tetrahedron Lett. 2010, 51, 3975. (c) Song, L.
P.; Li, X. F.; Xing, C. H.; Li, D. M.; Zhu, S. Z.; Deng, H. M.;
Shao, M. Synlett 2010, 830. (d) Dai, B. F.; Song, L. P.;
Wang, P. Y.; Yi, H.; Jin, G. F.; Zhu, S. Z.; Shao, M. Synlett
2009, 1842. (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, D. M.;
Song, L. P.; Song, S. D.; Zhu, S. Z. J. Fluorine Chem. 2007,
128, 952. (h) Li, X. F.; Song, L. P.; Xing, C. H.; Zhao, J. W.;
Zhu, S. Z. Tetrahedron 2006, 62, 2255.
1H NMR (500 MHz, CDCl3): δ = 1.25 (t, J = 7.5 Hz, 3 H), 2.40 (s,
3 H), 4.31 (d, J = 7.5 Hz, 2 H), 6.53 (s, 1 H), 7.71 (d, J = 8.5 Hz, 2
H), 8.30 (d, J = 8.5 Hz, 2 H).
MS (ESI) m/z = 344 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd For C17H14NO7: 344.0770; found:
344.0764.
Ethyl 4-(4-Bromophenyl)-7-methyl-5-oxo-2-(trifluoromethyl)-
4H,5H-pyrano[4,3-b]pyran-3-carboxylate (5e)
White solid; yield: 184.0 mg (40%); mp 66–67 °C.
IR (KBr): 3433, 2982, 2922, 1741, 1651, 979, 835 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.14 (t, J = 7.0 Hz, 3 H), 2.24 (s,
3 H), 4.12 (q, J = 7.0 Hz, 2 H), 4.78 (s, 1 H), 6.02 (s, 1 H), 7.19 (d,
J = 8.5 Hz, 2 H), 7.45 (d, J = 8.5 Hz, 2 H).
19F NMR (470 MHz, CDCl3): δ = –66.91 (s, 3 F).
MS (ESI) m/z = 459/461 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H14BrF3NaO5: 480.9874;
found: 480.9854.
Ethyl 3-(4-Bromophenyl)-6-methyl-4-oxo-4H-furo[3,2-c]py-
ran-2-carboxylate (6e)
White solid; yield: 139.0 mg (37%); mp 167–168 °C.
(8) Atkinson, R. S.; Barker, E.; Edwards, P. J.; Thomson, G. A.
J. Chem. Soc., Perkin Trans. 1 1995, 1533.
IR (KBr): 3466, 3093, 1719, 1618, 1146, 961, 822 cm–1.
(9) (a) Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.;
Matsui, M.; Muramatsu, H.; Shibata, K. Synthesis 1997,
1321. (b) Amii, H.; Obayashi, K. T.; Terasawa, H.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1686–1692

1692
W. Wang et al.
PAPER
Uneyama, K. Org. Lett. 2001, 3, 3103. (c) Xing, C. H.; Zhu,
S. Z. J. Org. Chem. 2004, 69, 6486.
(14) Sagar, R.; Park, J. M.; Koh, M.; Park, S. B. J. Org. Chem.
2009, 74, 2171.
(10) Rahul, R. N.; Vijay, V. K.; Sachin, S. B.; Devanand, B. S.
Eur. J. Med. Chem. 2005, 40, 1325.
(11) Hansen, A. L.; Skrydstrup, T. Org. Lett. 2005, 7, 5585.
(12) Gao, Y.; Tu, S. J.; Shi, F.; Wang, Q.; Zhu, X. T.; Shi, D. Q.
Synth. Commun. 2007, 37, 1603.
(15) CCDC-860235 (4c) and CCDC-860236 (6a) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(13) (a) de March, P.; Moreno-Mañas, M.; Casado, J.; Pleixats,
R.; Roca, J. L.; Trius, A. J. Heterocycl. Chem. 1984, 21, 85.
(b) de March, P.; Moreno-Mañas, M.; Casado, J.; Pleixats,
R.; Roca, J. L.; Trius, A. J. Heterocycl. Chem. 1984, 21,
1369.
(16) Zhu, S. Z.; Song, L. P.; Jin, G. F.; Dai, B. F.; Hao, J. Curr.
Org. Chem. 2009, 13, 1015.
(17) (a) Cadierno, V.; Díez, J.; Gimeno, J.; Nebra, N. J. Org.
Chem. 2008, 73, 5852. (b) Conreaux, D.; Belot, S.;
Desbordes, P.; Monteiro, N.; Balme, G. J. Org. Chem. 2008,
73, 8619; and references cited therein.
Synthesis 2012, 44, 1686–1692
© Georg Thieme Verlag Stuttgart · New York