Facile one-pot three-component reaction to synthesize trifluoromethylated cyclopenta[b]pyran derivatives and their further transformation

Article abstract of DOI:10.1016/j.tetlet.2012.03.023

A series of trifluoromethylated cyclopenta[b]pyran derivatives were synthesized efficiently from 1,3-cyclopentanedione, arylaldehydes, and ethyl 4,4,4-trifluoro-3-oxobutanoate via one-pot multi-component reaction catalyzed by NH₄OAc. This one-p

Full text of DOI:10.1016/j.tetlet.2012.03.023

Tetrahedron Letters 53 (2012) 2469–2472
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile one-pot three-component reaction to synthesize trifluoromethylated
cyclopenta[b]pyran derivatives and their further transformation
Jianning Liu a, Jia Li a, Li Zhang a, Liping Song a,b, , Min Zhang a, Weiguo Cao a, Shizheng Zhu b,
⇑
⇑
,
Hongmei Deng c, Min Shao c
a Department of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
c Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of trifluoromethylated cyclopenta[b]pyran derivatives were synthesized efficiently from 1,3-
cyclopentanedione, arylaldehydes, and ethyl 4,4,4-trifluoro-3-oxobutanoate via one-pot multi-compo-
nent reaction catalyzed by NH4OAc. This one-pot multi-component process comprises an initial Michael
addition and a subsequent intramolecular cyclization reaction. The effect of catalysts and solvents on the
reaction efficiency and the yield were investigated. The structure of product 4f was further confirmed by
XRD analysis. Meanwhile, further transformation of hemi-ketal moiety to the corresponding dehydrated
product is also studied. In addition, a possible mechanism of this reaction is proposed herein.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 13 January 2012
Revised 27 February 2012
Accepted 6 March 2012
Available online 11 March 2012
Keywords:
One-pot three-component reactions
1,3-Cyclopentanedione
Trifluoromethylated cyclopenta[b]pyrans
Synthesis
Multicomponent reactions (MCRs) have proved to be one of the
most powerful and efficient methods for the preparation of bioac-
tive heterocyclic compounds because of its atom economy, simple
experimentation, and high yields of the products.1 MCRs, such as
the Biginelli,2 Passerini,3 Ugi,4 and Hantzsch, provide a wide variety
of methods to synthesize important heterocycles.5 Hence, such
reactions have constituted increasingly valuable approaches for
preparing products with complex structure and libraries in recent
years.6
Fluorine-containing heterocycles are widely recognized as
important organic molecules showing interesting biological
activities with potential for applications in the medicinal and
agricultural fields.7 Introduction of trifluoromethyl groups into
heterocycles can bring about remarkable changes in the physical,
chemical, and biological properties.8 Thus, trifluoromethyl-substi-
tuted heterocycles are becoming increasingly important for the
development of new agrochemicals and medicines. The reactions
of trifluoromethyl-1,3-dicarbonyl compounds, as fluorine-contain-
ing building blocks, have been investigated extensively,9 and are
well established as synthetic intermediates in heterocyclic chemis-
try.10 In recent years, the synthesis of fluorinated O-heterocyclic or
N-heterocyclic compounds have received much attention.11 With
this aim, we reported the synthesis of a variety of trifluoromethyl
containing heterocycles based on the fluorinated building block
strategy.
4H-Pyran moiety is a constituent of many natural products,
showing important biological and pharmacological activities.12
Due to their important use in organic synthesis, the synthetic meth-
odology for cyclopenta[b]pyrans have been studied for many
years.13 Recently, Tu et al. presented a methodology to synthesize
a series of 4-aryl-cyclopenta[b]pyran derivatives from aromatic
aldehyde, 1,3-cyclopentanedione and malononitrile or ethyl
cyanoacetate via multi-component reaction under solvent-free
and catalyst-free conditions.14 The cyclopenta[b]pyrans could also
be constructed by ruthenium/TFA-catalyzed coupling of activated
secondary propargylic alcohols with cyclic 1,3-diones.15 However,
the synthesis of the corresponding trifluoromethylated cyclo-
penta[b]pyrans is scarcely documented or not investigated thor-
oughly in the literature. In addition, in order to evaluate the
potential applications of MCRs in the field of organofluorine
chemistry and to continue our ongoing study on the synthesis of
fluorine-containing heterocyclic compounds via MCRs based on
the trifluoromethyl-1,3-dicarbonyl compounds,
a
versatile
fluorine-containing building block, herein, we wish to report a
one-pot, three-component reaction to synthesize the ethyl 4-aryl-
2-hydroxy-5-oxo-2-(trifluoromethyl)-2,3,4,5,6,7-hexahydrocyclo-
penta[b]pyran-3-carboxylate derivatives, and their further
dehydration reaction.
Initially, we carried out the one-pot, three-component reaction
of benzaldehyde 1a, 1,3-cyclopentanedione 2, and ethyl 4,4,4-tri-
fluoro-3-oxobutanoate 3 as model reaction. To a solution of 1a
(1 mmol), 2 (1 mmol), and 3 (1 mmol) in ethanol (15.0 mL) was
added a catalytic amount of Et3N (25 mol %). The mixture was then
⇑
Corresponding authors. Tel.: +86 21 6613 4846; fax: +86 21 6613 4594.
E-mail address: lpsong@shu.edu.cn (L. Song).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.023

2470
J. Liu et al. / Tetrahedron Letters 53 (2012) 2469–2472
Table 1
Optimization of the one-pot reaction under various conditionsa
Ph
O
O
O
O
CO2Et
Base
PhCHO
+
+
OH
F3C
OC2H5
O
CF3
solvent
O
4a
1a
3
2
Entry
Base/equiv
Solvent
Time/T
Yield of 4ab (%)
c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
—
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
THF
24/rt
24/rt
8/reflux
24/rt
24/reflux
8/rt
24/reflux
8/rt
8/rt
24/rt
24/reflux
8/rt
Trace
Trace
35
26
31
67
59
54
64
Trace
20
57
27
40
Et3N/0.25
Et3N/0.25
Piperidine/0.25
Piperidine/0.25
NH4OAc/1.00
NH4OAc/1.00
NH4OAc/0.50
NH4OAc/2.00
Pyridine/0.25
DABCO/0.25
NH4OAc/1.00
NH4OAc/1.00
NH4OAc/1.00
NH4OAc/1.00
NH4OAc/1.00
24/rt
24/rt
24/rt
24/rt
CH2Cl2
CH3CN
DME
18
Trace
a
b
c
Reaction and conditions: 1a (1 mmol), 2 (1 mmol), 3 (1 mmol), solvent:15 mL.
Isolated yield.
Without catalyst.
Table 2
One-pot synthesis of product 4a,17,18
Ar
O
O
O
O
CO2Et
NH4OAc,1 equiv.
EtOH, r.t.
ArCHO
+
+
OH
F3C
OC2H5
O
CF3
O
1 (a-k)
2
3
4 (a-k)
Entry
Ar
Time/h
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
p-FC6H4
p-ClC6H4
8
8
8
8
8
8
8
8
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
67
77
64
62
63
56
59
66
60
61
24
—
p-BrC6H4
p-O2NC6H4
p-NCC6H4
p-CH3C6H4
m-ClC6H4
m-BrC6H4
m-O2NC6H4
p-CH3OC6H4
o-ClC6H4
8
4j
4k
—
24
24
24
2,4-Cl2C6H4
—
—
a
Reaction and conditions: aryldehyde 1(a–k) (1.5 mmol), 1,3-cyclopentanedione
2 (1.5 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate 3
(1.5 mmol), NH4OAc (1.0 equiv.), EtOH (15.0 mL), room temperature.
b
Isolated yield.
stirred at room temperature for 24 h, however, this reaction failed
to occur and the starting materials were recovered. Hence, the
mixture was heated to reflux, after stirring for 8 h, TLC analysis
showed that the reaction did not proceed efficiently. General work-
up afforded the product 4a only in 35% yield as a white solid (entry
3, Table 1).
Based on the above results, the reaction conditions were opti-
mized to improve the yield by changing bases and solvents. The
effects of a variety of organic bases and the amount on the reaction
efficiency and yield were first screened. As shown in Table 1, when
the reaction was performed in the absence of base, no product was
obtained (entry 1, Table 1). It was observed that the reaction took
much longer time to give 4a in 26% yield when piperidine was
utilized as catalyst (entry 4, Table 1). Other organic bases such as
DABCO and Pyridine used in place of Et3N resulted in lower yields
of 4a (entries 10–11, Table 1). Surprisingly, the yield was improved
significantly when 1 equiv of NH4OAc was used (entry 6, Table 1).
It should be indicated that the reaction exclusively gave the O-het-
erocycles 4a, and no corresponding N-heterocycles were detected
even though the reaction was carried out in the presence of excess
of NH4OAc (entry 9, Table 1). The above reaction results indicated
that NH4OAc, served as soft brønsted acid, played a unique role in
the one-pot, three-component reaction, other than a reactant.16
With the optimal results in hand as shown in Table 1, entry 6,
we investigated the scope and limitation of this one-pot,
three-component reaction. A variety of aromatic aldehydes with

J. Liu et al. / Tetrahedron Letters 53 (2012) 2469–2472
2471
Table 3
Reaction results of dehydration of 4a,b,20,21
Ar
Ar
O
O
CO2Et
CF3
CO2Et
OH
CF3
p-TsOH(4 equiv.)
Toluene, reflux
O
O
5
4
Entry
Ar
Time/h
Product
Yieldb (%)
4a
4c
4g
C6H5
p-ClC6H4
m-ClC6H4
12
12
12
5a
5b
5c
70
72
71
a
Reaction and conditions: 4 (1.0 mmol), p-TsOH (4.0 mmol, 4.0 equiv), solvent:
toluene (15.0 mL), reflux.
b
Isolated yields.
Figure 1. X-Ray crystal structure of compound 4f.
crystal X-ray analysis to support our speculation on structures of
these products (Fig. 1).19
electron-withdrawing or electron-donating groups were employed
as substrates and the reactions afforded the corresponding
products in moderate to good yields. As shown in Table 2, it was
clear that the product yield was influenced by both electronic
and steric effects of the substituting groups on the aromatic alde-
hydes. The aromatic aldehydes with strong electron-donating
groups afforded lower yield of the corresponding products with
prolonged time (entry 11, Table 2). Furthermore, the effect of steric
hindrance on the aromatic aldehydes was noticeable. The substit-
uents located at the para or meta positions of aromatic aldehydes
have not shown much effect on the formation of products (entries
3 and 8, Table 2). But ortho-substituted aromatic aldehydes such as
2-chloro-benzaldehyde gave no expected product. TLC analysis
showed that the starting material remained unreacted. Similarly,
steric hindered aromatic aldehydes such as 2,4-dichloro-benzalde-
hyde, gave no expected product either. The above results showed
that the reactivity of substrates significantly depended on both
the electronic and the steric effects of the substituents.
Based on the above results, a possible mechanism for the for-
mation of 4(a–k) was illustrated in Scheme 1. First, an intermedi-
ate A or B was formed via initial Knoevenagel condensation
reaction followed by Michael addition reaction catalyzed by
NH4OAc, which then underwent intramolecular cyclization reac-
tion to afford the compounds 4(a–k) exclusively.
Finally, we studied the dehydration of compounds 4. It should
be indicated that the hemi-ketal moiety in compounds 4 is stable.
Due to the strong electron-withdrawing effect of trifluoromethyl
group on the six-membered ring, compounds 4 resist dehydration
under the present reaction conditions. It was found that water was
smoothly eliminated from compounds 4 and the corresponding
dehydrated derivatives 5 were obtained in good yields by the treat-
ment of an excess of p-TsOH in refluxing toluene. The reaction re-
sults were listed in Table 3. The structure identity of compounds 5
was fully supported by spectral and microanalysis data.
The structures of compounds 4(a–k) were fully confirmed by 1H
NMR, 19F NMR, MS, IR spectroscopies, and elemental analysis. For
instance, the characteristic features of the 1H NMR in CDCl3 spectra
of 4a were the appearance of doublets at d 3.92 and 2.94 ppm with
JH–H = 11.5 Hz for 3-H and 4-H protons, respectively, indicating a
trans configuration of the vicinal two hydrogen atoms. The stereo-
chemistry of 4 was attributed to that the intra-molecular cycliza-
tion would be an energetically favorable process, affording more
stable ‘trans’ configuration of 4. The chemical shift of CF3 group
in 19F NMR was a singlet peak at d À83.65 ppm (s, 3F), which indi-
cated that the CF3 group was bonded to a quaternary carbon atom.
The structure of compound 4f was further confirmed by single
In summary, we have shown that the one-pot three-component
reaction provides a facile and convenient approach to synthesize
the ethyl 4-aryl-2-hydroxy-5-oxo-2-(trifluoromethyl)-2,3,4,5,6,7-
hexahydrocyclopenta[b]pyran-3-carboxylate derivatives from
readily available starting materials. The soft brønsted acid, NH4OAc,
plays a unique role in this one-pot, three-component reaction.
Meanwhile, the dehydration of hemi-ketal moiety to ethyl 4-aryl-
5-oxo-2-(trifluoromethyl)-4,5,6,7-tetrahydrocyclopenta[b]pyran-
3-carboxylate derivatives were also achieved. These new
compounds may be considered as useful CF3-containing substrates
for the synthesis of a variety of heterocyclic compounds with
potential biological activity.
O
O
O
Ar
O
O
O
O
O
Ar
Ar
Ar
NH4OAc
EtO
F3C
EtO
F3C
OEt
NH4OAc
2
3
CF3
OH
O
O
HO
B
A
-
H
2
O
OAc
OAc
4
4
NH
NH
Ar
O
O
CO2Et
O
O
ArCHO
+
OH
CF3
ArCHO
+
F3C
OEt
O
O
2
4(a-k)
3
1(a-k)
1(a-k)
Scheme 1. Plausible mechanism for formation of 4(a–k).

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J. Liu et al. / Tetrahedron Letters 53 (2012) 2469–2472
X. F.; Xing, C. H.; Li, D. M.; Zhu, S. Z.; Deng, H. M.; Shao, M. Synlett 2010, 830–
Acknowledgments
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Synlett 2009, 1842–1846; (e) Song, S. D.; Song, L. P.; Dai, B. F.; Yi, H.; Jin, G. F.;
Zhu, S. Z.; Shao, M. Tetrahedron 2008, 64, 5728–5735; (f) Li, D. M.; Song, L. P.; Li,
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2255–2263.
The authors thank the National Natural Science Foundation of
China (NNSFC) (Nos. 21072128, 20772080), Leading Academic Dis-
cipline Project of Shanghai Municipal Education Commission (No.
J50102), the Key Laboratory of Organofluorine Chemistry, and
Shanghai Institute of Organic Chemistry for financial support.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.
023.
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17. Typical experimental procedure for synthesis of 4a: To a mixture of benzaldehyde
1a (159.0 mg, 1.5 mmol), 1,3-cyclopentanedione 2 (147.0 mg, 1.5 mmol), and
ethyl 4,4,4-trifluoro-3-oxobutanoate 3 (276.0 mg, 1.5 mmol) in 15 mL EtOH
was added 1.0 mmol of NH4OAc as catalyst. The resultant mixture was stirred
at room temperature for 8 h. The progress of the reaction was monitored by
TLC. After completion of the reaction, the solvent was evaporated and the
residue was purified by column chromatography on
a silica gel using
petroleum ether/ethyl acetate (1:1, v/v) as eluent to afford the pure product
4a 371.1 mg, 67% yield.
18. Spectroscopic data for products 4: compound 4a: White solid; mp: 192.6–
193.1 °C; 1H NMR (CDCl3, 500 MHz): d = 0.98 (t, J = 7.0 Hz, 3H), 2.52 (t,
J = 5.0 Hz, 2H), 2.71–2.85 (m, 2H), 2.94 (d, J = 11.5 Hz, 1H), 3.92 (dt,
J1 = 11.5 Hz, J2 = 2.5 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 5.85 (s, 1H), 7.10–7.12
(m, 2H), 7.28–7.35 (m, 3H). 19F NMR (470 MHz, CDCl3): d = À83.85 (s, 3F, CF3);
IR (KBr) mmax: 3426, 3070, 2987, 2939, 2768, 2578, 1741, 1620, 1371, 1351,
1236, 1194, 1166, 1110, 1002, 964, 746, 703 cmÀ1; MS (ESI) m/z: 371 [M+H]+,
393 [M+Na]+; Anal. Calcd for C18H17F3O5: C, 58.38; H, 4.63. Found: C, 58.51; H,
4.75.
19. CCDC 860234 contains the Supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic
Centre via www.ccdc.ac.uk/data_request/cif.
20. Typical experimental procedure for synthesis of 5c: A mixture of 4c (404.5 mg,
1.0 mmol) and p-TsOH (4.0 mmol) in 15 mL toluene was refluxed for 12 h until
completion of the reaction (monitored by TLC). The mixture was cooled to
room temperature. And then it was poured into water and extracted with ethyl
acetate. The organic layer was dried over MgSO4 and filtered. The solvent was
evaporated and the residue was purified by column chromatography on a silica
gel using petroleum ether/ethyl acetate (4:1, v/v) as eluent to afford the pure
product 5c 274.5 mg, 71% yield.
21. Spectroscopic data for products 5: Compound 5c: White solid; mp: 77.3–78.3 °C;
1H NMR (CDCl3, 500 MHz): d = 1.07 (t, J = 7.0 Hz, 3H), 2.50–2.53 (m, 2H), 2.74–
2.86 (m, 2H), 4.02–4.12 (m, 2H), 4.67 (s, 1H), 7.13–7.27 (m, 4H), 19F NMR
(470 MHz, CDCl3): d = À66.98 (s, 3F,); IR (KBr)
mmax: 3061, 2989, 2941, 1732,
1691, 1643, 1375, 1218, 1151, 1067, 1037, 947, 742, 698 cmÀ1; MS (ESI) m/z:
387/389 [M+H]+, 409/411 [M+Na]+; Anal. Calcd for C18H14ClF3O4: C, 55.90; H,
3.65. Found: C, 55.97; H, 3.70.