Iodine catalyzed one-pot multi-component reaction to CF3- containing spiro[indene-2,3′-piperidine] derivatives

Article abstract of DOI:10.1016/j.jfluchem.2011.09.006

In the presence of a catalytic amount of molecular iodine (0.1 equiv.), the one-pot multi-component reaction of ethyl trifluoroacetoacetate 1, indan-1,3-dione 2, ammonium acetate 3 and aromatic aldehyde 4 mainly gave the ethyl-6′-hydroxy-1,3-dioxo-2′,4′-d

Full text of DOI:10.1016/j.jfluchem.2011.09.006

Journal of Fluorine Chemistry 133 (2012) 127–133
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Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Iodine catalyzed one-pot multi-component reaction to CF3-containing
spiro[indene-2,30-piperidine] derivatives
a
a
b
Baifan Dai a, Yijun Duan a, Xiaoqing Liu a, Liping Song a,b, , Min Zhang , Weiguo Cao , Shizheng Zhu ,
*
Hongmei Deng c, Min Shao c
a Department of Chemistry, College of Science, Shanghai University, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 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:
In the presence of a catalytic amount of molecular iodine (0.1 equiv.), the one-pot multi-component
reaction of ethyl trifluoroacetoacetate 1, indan-1,3-dione 2, ammonium acetate 3 and aromatic aldehyde
4 mainly gave the ethyl-60-hydroxy-1,3-dioxo-20,40-diaryl-60-(trifluoromethyl)-1,3-dihydrospiro[in-
dene-2,30-piperidine]-50-carboxylate derivatives 5, along with the minor product 2-trifluoromethyl-
2,3,4,5-tetrahydro-1H-indeno[1,2-b]pyridine derivatives 6. A plausible reaction mechanism for the
Received 29 June 2011
Received in revised form 9 September 2011
Accepted 16 September 2011
Available online 21 September 2011
formation of 5, 6 was presented. The structures of compounds 5, 6 were fully confirmed by 1H NMR, 19
F
Keywords:
NMR, MS, IR spectroscopies and elemental analysis or high resolution mass spectra (HRMS). Meanwhile,
the representative 5a and 6h were further confirmed by XRD analysis.
ß 2011 Elsevier B.V. All rights reserved.
Iodine catalysis
Spiropiperidine
Ethyl trifluoroacetoacetate
Pyridine derivatives
One-pot multi-component
reactionDedicated to Professor Wei-Yuan
Huang on the occasion of his 90th birthday.
1. Introduction
The spiropiperidine and its derivatives are important biologi-
cally active compounds [4], which have profound medical
In recent times, the use of molecular iodine has received
considerable attention as an inexpensive, nontoxic, readily
available catalyst for various organic transformations to afford
the corresponding products in excellent yields with high
selectivity [1]. The mild Lewis acidity associated with iodine
enhanced its usage in organic synthesis to realize several organic
transformations using stoichiometric levels to catalytic amounts.
Owing to numerous advantages associated with this eco-friendly
element, iodine has been explored as a powerful catalyst for
various organic transformations [2]. So the development of a
reaction that uses catalytic amounts of mild toxic and readily
available iodine should greatly contribute to the creation of
environmentally benign processes. Interestingly, to some extent,
the reactions promoted by iodine usually afford the unexpected
results [3].
applications. In addition, spiropiperidinyl ring systems have been
isolated from various plant alkaloids and animal toxins [5]. For
example, some neurotoxic spirofused piperidines were isolated
from the neotropical poisonous frog Dendrobates histrionicus and
their spirofused analogues, the alkaloids sibirine, nitramine,
isonitramine and nitrabirine, were isolated from plants of the
genus Nitraria [6].
Fluorine-containing compounds have attracted much interest
because of their unique chemical, physical, and biological activities
[7]. In particular, fluorine-containing heterocycles are now widely
recognized as important organic molecules showing interesting
biological activities with potential for applications in the medicinal
and agricultural fields [8]. With the aim to develop more efficient
synthetic processes, environmental friendly, shorten the synthetic
route, and in the continuation of our recent interest in the
construction of fluorine-containing heterocycles scaffolds [9], we
develop a facile, multi-component reaction involving condensa-
tion of ethyl trifluoroacetoacetate (1), 1,3-indanedione (2),
ammonium acetate (3), and aromatic aldehyde (4) in the presence
of catalytic amount of molecular iodine under mild reaction
conditions to afford a series of novel trifluoromethyl-containing
* Corresponding author at: Department of Chemistry, College of Science,
Shanghai University, Shanghai 200444, China.
E-mail address: lpsong@shu.edu.cn (L. Song).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.09.006

128
B. Dai et al. / Journal of Fluorine Chemistry 133 (2012) 127–133
spiro[indene-2,30-priperindine] scaffolds 5 in moderate yields,
along with the minor product 6, respectively.
Table 1
The effect of a variety of the amounts of iodine and solvents on this one-pot
reaction.a
Entry
Solvent
Iodine
(mol%)
Time (h)
Yieldsb (%)
2. Results and discussion
Products 5 and 6
In an initial endeavour, we carried out the one-pot, four-
component reaction of equivmolar amounts of ethyl trifluoroace-
toacetate (1), 1,3-indanedione (2), ammonium acetate (3), and
benzaldehyde (4) in ethanol as solvent. The reaction mixture was
stirred for 12 h at room temperature, however, TLC showed that
there was no reaction occurred, even though the reaction mixture
was heated to reflux with prolonged reaction time. Subsequently, a
catalytic amount of molecular iodine (0.2 equivmolar) was
introduced into the reaction mixture, after stirring for 4 h at room
temperature, TLC analysis showed that two new compounds were
formed, however the starting materials did not disappeared
completely. After simple workup, one major product was isolated
in 42% yield, and the amount of the other minor product was
insufficient to be identified. The 1H NMR spectra of the major
product was not consistent with the one molecular aryl group,
Further analysis of the NMR spectra revealed that this compound
might contain two molecular aryl groups framework. Finally, the
structure of major product 5a was unequivocally established by
the X-ray diffraction analysis of its single crystal (Fig. 1). The
formation of a trifluoromethyl-containing spiro[indene-2,30-piper-
idine] structure is very unusual and may find its application in
related transformation leading to useful products. Encouraged by
this unexpected result, we initially optimized the reaction
conditions by varying the molecular ratio of the starting materials.
So the molecular ratio of the starting materials was modified to
equivmolar amount of ethyl trifluoroacetoacetate (1), 1,3-indane-
dione (2), ammonium acetate (3), and 2.0 equivmolar of
benzaldehyde (4), and the reaction was performed under the
same reaction conditions. After stirring for 4 h at room tempera-
ture, TLC analysis showed the reaction was completed. General
workup afforded the major product 5a in 70% yield, along with the
minor product 6a in 9% yield, respectively.
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
CH2Cl2
CH3CN
DME
0
5
12
6
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
–
52
70
71
70
69
71
70
40
40
45
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
–
7
3
10
10
20
40
10
10
10
10
10
4
9
4c
5
3.5
4
9
9
6
4
9
7d
8
4
9
4.5
6
8
9
Trace
Trace
Trace
10
11
6
8
a
Reaction conditions: ethyl 4,4,4-trifluoro-3-oxobutanoate 1 (1.0 mmol), 1,3-
indanedione 2 (1.0 mmol), ammonium acetate 3 (1.0 mmol), and benzaldehyde 4
(2.0 mmol), solvent: 10 mL.
b
Isolated yield.
c
The reaction was carried out in freshly distilled absolute EtOH under nitrogen.
d
The reaction was carried out in refluxing in EtOH as solvent.
molecular iodine, the reaction did not occur even after reflux for
12 h in ethanol (entry 1, Table 1). The 0.05 equivmolar amount of
molecular iodine was insufficient to push the reaction forward,
resulting in the decrease of the yields of products 5a and 6a, even
though the reaction was carried out with prolonged the reaction
time to 6 h (entry 2, Table 1). Higher catalyst loading (from 0.2 to
0.4 equivmolar amount of molecular iodine) neither shortened the
reaction time, nor increased the products yields obviously (entries
5–6, Table 1). Thus, we choosed 0.1 equivmolar amount of
molecular iodine as the catalyst loading for this one-pot, four-
component reaction. Meanwhile, we also investigated the reaction
temperature affecting the reaction efficiency and the products
yields. It was found that the reaction time might be shortened to
3.5 h in refluxing temperature, however, the products yields were
not increased significantly (entry 4, Table 1).
Solvent effect was the next considered factor. As shown in Table
1, generally, the reactions gave the better yield in polar protic
solvents such as EtOH and MeOH than those in aprotic solvents
(entries 2–8 and 9–11, Table 1). Moreover, the reaction in absolute
ethanol under the nitrogen atmosphere gave almost the same
product yields as that in the commercially available ethanol,
indicating that the trace of water in ethanol did not accelerate the
reaction obviously (entry 7, Table 1).
Based on the results above, the reaction conditions were further
optimized to improve the yield by changing the catalytic amounts
of molecular iodine and solvent. We first investigated the relation
of the reaction outcome with the catalytic amounts of molecular
iodine. As shown in Table 1, in the absence of a catalytic amount of
With the optimal results in hand as shown in entry 3, Table 1,
we investigated the scope and limitation of this one-pot, four-
component reaction with a variety of aromatic aldehydes, and the
Table 2
Results of the one-pot, four-component reaction.a
Entry
Ar=
Time (h)
Yieldsb (%)
Product 5 and 6
1
2
3
4
5
6
7
8
9
4a C6H5
4
6
5a
5b
5c
5d
5e
5f
70
55
68
71
70
72
53
75
6a
6b
6c
6d
6e
6f
9
8
4b p-NO2C6H4
4c p-ClC6H4
4
9
4d p-CH3OC6H4
4e p-CH3C6H4
4f o-CH3OC6H4
4g o-NO2C6H4
4h m-phOC6H4
4g 3,4-(MeO)2C6H3
4
11
10
10
9
4
4
6
5g
5h
6g
6h
4
10
c
c
10
–
–
a
Reaction conditions: ethyl 4,4,4-trifluoro-3-oxobutanoate 1 (1.0 mmol), 1,3-
indanedione 2 (1.0 mmol), ammonium acetate 3 (1.0 mmol), and aromatic aldehyde
4 (2.0 mmol), ethanol (10 mL, AR), room temperature.
b
Isolated yields.
c
Fig. 1. X-ray crystal structure of 5a.
Not isolated.

B. Dai et al. / Journal of Fluorine Chemistry 133 (2012) 127–133
129
O
O
Ar
O
O
Ar
O
O
O
I2 (cat.)
EtOH
OEt
ArCHO
+ NH4OAc +
+
OEt
+
F3C
OEt
OH
CF3
OH
CF3
O
N
H
N
H
O
Ar
2
3
1
4(a-h)
5(a-h)
major
6(a-h)
minor
Ar= C6H5,
p-NO2C6H4,
p-ClC6H4,
a
p-CH3C6H4,
e
f
g
h
b
c
o-CH3OC6H4,
o-NO2C6H4,
m-PhOC6H4,
p-CH3OC6H4, d
Scheme 1. Reaction of ethyl trifluoroacetoacetate (1) with 1,3-indanedione (2), ammonium acetate (3), and aromatic aldehyde (4).
above results have shown that the reactivity of the aromatic
aldehyde differs significantly depending on the nature of electronic
effect, other than of the steric effect of the substituents (Scheme 1).
The structures of compounds 5 and 6 were fully confirmed by
1H NMR, 19F NMR, MS, IR spectroscopies and elemental analysis.
For instance, the characteristic features of 1H NMR in CDCl3 spectra
of 5a were the appearances of doublets at d 4.54 and 4.12 ppm with
JH–H = 12.5 Hz for 3-H and 4-H protons, respectively, indicating
that a trans configuration of the vicinal two hydrogen atoms. The
chemical shift of CF3 group in 19F NMR was a singlet peak at
d
ꢀ84.01 ppm (s, 3F), which indicated that the CF3 group was bonded
to a quaternary carbon atom. The similar pattern of characteristic
doublet peaks in 1H NMR spectra and the singlet peak in 19F NMR
spectra were also observed in compounds 6. Furthermore, the
structure of compound 6h was further confirmed by XRD analysis,
and crystal structure of compound 6h was shown in Fig. 2.
Singh and his co-workers reported the comparable one-pot
multicomponent reaction to functionalized unsymmetrical dihy-
dro-1H-indeno[1,2-b]pyridines by grinding under the solvent- and
catalyst-free conditions [10]. Dihydro-1H-indeno[1,2-b]pyridine
derivative was also obtained in four-component reaction catalyzed
by Yb(OTf)3 [11]. By comparison, we also investigated that the one-
pot, multicomponent reaction involving condensation of non-
fluorinated substrate instead of ethyl trifluoroacetoacetate cata-
lyzed by molecular iodine under the present reaction conditions.
To our surprise, the reaction results were consistent with the
previous results using the fluorinated substrates. It gave the
corresponding spiro[indene-2,30-piperidine] 7 as a major product
in 69% yield, along with the a minor product 8 in 9% yield [10]. The
slight difference between the fluorinated and non-fluorinated
substrates was that the reaction directly gave the corresponding
dehydrated products 7 and 8 (Scheme 2). This difference was
attributed to unique catalytic activity of molecular iodine.
Fig. 2. X-ray crystal structure of 6h.
corresponding expected products were obtained, in which the
compounds 5(a–h) were the major products, along with the minor
products 6(a–h). The reaction results are summarized in Table 2.
Various aromatic aldehydes bearing either electron-donating or
electron-withdrawing group have not shown the obvious effort on
the formation of the products. On the other hand, the substituents
located at para, meta or ortho positions of aryldehydes have not
shown the much effort on the formation of products, either (entries
2–8). Surprisingly, the reactions of electron-rich aromatic alde-
hyde were not successful. That is, the corresponding products were
not formed. For example, in the case of 3,4-dimethoxy-benzalde-
hyde, there was no corresponding products were formed. The
Based on the above results, A plausible mechanism for the
formation of 5 and 6 was illustrated in Scheme 3, it is conceivable
that the initial event is the formation of intermediate ‘‘A’’ form
ethyl trifluoroacetoacetate (1) with 1,3-indanedione (2), and
aromatic aldehyde (4) via Knoevenagel condensation reaction,
followed by Michael addition reaction. The second key intermedi-
ate is aldehyde imine, produced by the condensation of aromatic
aldehyde with ammonia. And then there were two pathways to
O
O
O
O
O
CHO
O
O
I
2 (10%)
OEt
OEt
+
+ NH4OAc
+
+
O
H3C
OEt
EtOH
N
H
CH3
CH3
N
H
O
2
1'
3
4
7
8
69%, major
9%, minor
Scheme 2. Reaction result of non-fluorinated substrate.

130
B. Dai et al. / Journal of Fluorine Chemistry 133 (2012) 127–133
F3C
O
O
OH
Ar
F3C
O
F3C
O
HN
OEt
H2N
O
NH4OAc
OEt
OEt
O
Ar
Ar
O
O
O
F
E
6
path B
O
F3C
O-
O
O
O
O
O
ArCHO
OEt
F3C
O
I2
Ar
O
A
NH
path A
ArCHO
NH4OAc
Ar
B
F3C
NH2
F3C
NH
Ar
O
Ar
O-
Ar
O
O
O
O
O
NH
OH
+H+
CF3
O
O
OEt
OEt
Ar
Ar
OEt
Ar
O
O
5
D
C
Scheme 3. A plausible mechanism of one-pot, four-component reaction.
proceed. Condensation of intermediate ‘‘A’’ with intermediate ‘‘B’’
give the acyclic intermediate ‘‘D’’, which undergoes intramolecular
cyclization to form the major product spiro[indene-2,30-piperi-
dine] derivatives 5 (Path A). Alternatively, intermediate ‘‘A’’ reacts
with ammonia to afford the intermediate ‘‘F’’, which undergoes
intramolecular cyclization with participation of amino function
and carbonyl group to form the minor product tetrahydroin-
deno[1,2-b]pyridine derivatives 6 (Path B).
recorded in CDCl3 on Bruker AM-500 instruments with Me4Si and
CFCl3 (with upfield negative) as the internal and external standards,
respectively. IR spectra were obtained with a Nicolet AV-360
spectrophotometer. Lower resolution mass spectra were deter-
minedwithAgilent 1100LC/MSD SLinstrument usingESI technique.
High resolution mass spectra were run on Ionspec 4.7 T FTMS using
MALDI/DHB. Elemental analyses were performed using a Vario EL III
Analyzer. X-ray crystal structure data were collected on a Bruck
SMART Apex2 CCD area-detector diffractometer using graphite
˚
monochromatized Mo Ka radiation (l = 0.71073 A) at 296(2) K.
3. Conclusion
In conclusion, we have developed a convenient one-pot, four-
component reaction to trifluoromethyl-containing spiro[indene-
2,30-piperidine] derivatives and tetrahydroindeno[1,2-b]pyridine
derivatives from ethyl trifluoroacetoacetate (1), 1,3-indanedione
(2), ammonium acetate (3), and benzaldehyde (4) in the presence
of catalytic amount of molecular iodine (10%) under the mild
reaction conditions. These molecular iodine catalyzed one-pot,
multi-component reactions provide a rapid and efficient route to
the preparation of a variety of unusual fluorinated heterocycles.
4.2. Typical experimental procedure for the synthesis of compounds
5a–h and 6a–h
To a 10 mL ethanol solution containing ethyl trifluoroacetoa-
cetate (1.0 mmol), 1,3-indanedione (1.0 mmol), ammonium ace-
tate (1.0 mmol) and benzaldehyde (2.0 mmol) was added a
catalytic amount of molecular iodine (0.1 mmol). The reaction
mixture was stirred at room temperature for 4 h. After the reaction
was completed (Monitored by TLC), the solution was concentrated
under reduced pressure and the residue was re-dissolved in 30 mL
of ethyl acetate. The solution was washed with aq. Na2S2O3
solution to remove iodine, followed by H2O (20 mL ꢁ 2). The
organic layer was dried over anhydrous Na2SO4 and evaporated to
dryness. The residue was purified by column chromatography on
silica gel using petroleum/ethyl acetate = 6:1 (v/v) as eluent to
afford 5a as a white solid in 70% yield and 6a as a red solid in 9%
yield.
4. Experimental
4.1. General
Melting points were measured with digital melting point
apparatus (WRS-1B, Shanghai precision & scientific instrument
CO., LTD.) and were uncorrected. 1H and 19F NMR spectra were

B. Dai et al. / Journal of Fluorine Chemistry 133 (2012) 127–133
131
4.2.1. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-diphenyl-
4.2.6. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(2-
60(trifluoromethyl)-spiro [indene-2,30-piperidine]-50-carboxylate (5a)
White solid, mp: 171–173 8C. IR (KBr, cmꢀ1): 3400, 2922, 2852,
1787, 1742, 1711, 1510, 1247, 1190, 1163, 836, 754. 1H NMR
methoxyphenyl)-60(trifluoromethyl)-spiro[indene-2,30-piperidine]-
50-carboxylate (5f)
White solid, mp: 168–170 8C. IR (KBr, cmꢀ1): 3367, 3305, 3003,
2965, 2919, 1742, 1707, 1599, 1495, 1250, 1171, 1028, 759. 1H
(CDCl3, 500 MHz):
d 0.77 (t, J = 7.0 Hz, 3H, OCHACHB); 2.63 (s, 1H,
NH); 3.85 (qd, J1 = 7.0 Hz, J2 = 2.0 Hz, 2H, OCHACHB); 4.12 (d,
J = 12.5 Hz, 1H, CH); 4.54 (d, J = 12.5 Hz, 1H, CH); 5.04 (s, 1H, OH);
5.58 (s, 1H, CH); 6.95–7.02 (m, 8H, ArH); 7.10–7.17 (m, 2H, ArH);
7.38–7.45 (m, 3H, ArH); 7.56–7.54 (m, 1H, ArH). 19F NMR (CDCl3,
NMR (CDCl3, 500 MHz): d 0.73 (t, J = 7.0 Hz, 3H, OCHACHB); 2.73
(br, 1H, NH); 3.63 (s, 3H, OCH3); 3.79 (q, J = 7.0 Hz, 2H, OCHACHB);
3.85 (s, 3H, OCH3); 4.42 (d, J = 13.0 Hz, 1H, CH); 5.05 (d, J = 13.0 Hz,
1H, CH); 5.51 (s, 1H, OH); 5.72 (s, 1 H, CH); 6.38–6.41 (m, 1H, ArH),
6.57–6.69 (m, 3H, ArH); 6.88–7.02 (m, 3H, ArH); 7.19–7.21 (m, 1H,
ArH); 7.32–7.33 (m, 1H, ArH); 7.40–7.45 (m, 2H, ArH); 7.58–7.59
470 MHz):
d
ꢀ84.02 (s, 3F, CF3). MS (ESI) m/z: 524 [M+H] +. Anal.
Calcd for: C29H24F3NO5 (%): C, 66.53; H, 4.62; N, 2.68. Found: C,
66.23; H, 4.94; N, 2.54.
(m, 1H, ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ83.97 (s, 3F, CF3). MS
(ESI) m/z: 584 [M+H] +. Anal. Calcd for: C31H28F3NO7 (%): C, 63.80;
4.2.2. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(4-
nitrophenyl)-60(trifluoromethyl)-spiro[indene-2,30-piperidine]-50-
carboxylate (5b)
H, 4.84; N, 2.40. Found: C, 63.44, H 4.87, N: 2.29.
4.2.7. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(2-
nitrophenyl)-60(trifluoromethyl)-spiro[indene-2,30-piperidine]-50-
carboxylate (5g)
White solid, mp: 173–175 8C. IR (KBr, cmꢀ1): 3415, 3311, 2988,
1736, 1704, 1535, 1353, 1248, 1189, 789, 768, 719. 1H NMR (CDCl3,
White solid, mp: 174–175 8C. IR (KBr, cmꢀ1): 3416, 3301, 3019,
2975, 1942, 1737, 1701, 1527, 1348, 1242, 1185, 1086, 861, 695. 1H
NMR (CDCl3, 500 MHz):
d
0.86 (t, J = 7.5 Hz, 3H, OCHACHB); 2.67 (s,
1H, NH), 3.89 (q, J = 7.5 Hz, 2H, OCHACHB), 4.27 (d, J = 13.0 Hz, 1H,
CH), 4.57 (d, J = 13.0 Hz, 1H, CH), 5.17 (s, 1H, OH), 5.46 (s, 1H, CH),
7.30–7.39 (m, 4H, ArH), 7.48–7.58 (m, 4H, ArH), 7.94–7.87 (m, 4H,
500 MHz): d 0.84 (t, J = 7.5 Hz, 3H, OCHACHB); 2.69 (s, 1H, NH); 3.97
(qd, J1 = 7.5 Hz, J2 = 2.5 Hz, 2H, OCHACHB); 4.68 (d, J = 12.5 Hz, 1H,
CH); 5.19 (d, J = 12.5 Hz, 1H, CH); 5.81 (s, 1H, OH); 5.86 (s, 1H, CH);
7.10–7.17 (m, 2H, ArH); 7.19–7.25 (m, 2H, ArH); 7.36–7.38 (m, 1H,
ArH); 7.49–7.61 (m, 6H, ArH); 7.73–7.74 (m, 1H, ArH). 19F NMR
ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ83.91 (s, 3F, CF3); MS (ESI) m/
z: 614 [M+H]+, 615 [M+2H]+. HRMS for [C29H22F3N3O9+H]+ Calcd:
614.1386; Found: 614.1381.
(CDCl3, 470 MHz):
d
ꢀ83.70 (s, 3F, CF3). MS (ESI) m/z: 614 [M+H]+;
4.2.3. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(4-
chloroophenyl)-60(trifluoromethyl)-spiro[indene-2,30-piperidine]-50-
carboxylate (5c)
HRMS for [C29H22F3N3O9+H]+ Calcd: 614.1386. Found: 614.1381.
4.2.8. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(3-
phenoxyphenyl)-60(trifluoromethyl)-spiro[indene-2,30-piperidine]-50-
carboxylate (5h)
White solid, mp: 172–175 8C. IR (KBr, cmꢀ1): 3437, 3339, 2983,
1725, 1705, 1595, 1492, 1741, 1373, 1339, 1254, 1203, 1015, 986,
832, 759. 1H NMR (CDCl3, 500 MHz):
d
0.85 (t, J = 7.5 Hz, 3H,
White solid, mp: 187–190 8C. IR (KBr, cmꢀ1): 3432, 3307, 3065,
2982, 1740, 1705, 1586, 1487, 1240, 1187, 1091, 1019, 777, 750,
OCHACHB); 2.56 (s, 1H, NH); 3.88 (q, J = 7 .5 Hz, 2H, OCHACHB); 4.08
(d, J = 12.5 Hz, 1H, CH); 4.48 (d, J = 12.5 Hz, 1H, CH); 5.00 (s, 1H, OH);
5.51 (s, 1H, CH); 6.96–7.12 (m, 8H, ArH); 7.48–7.53 (m, 3H, ArH);
692. 1H NMR (CDCl3, 500 MHz):
d: 0.88 (t, J = 7.0 Hz, 3H, OCHACHB);
2.61 (s, 1H, NH); 3.92 (qd, J1 = 7.0 Hz, J2 = 2.0 Hz, 2H, OCHACHB);
4.09 (d, 1H, J = 12.5 Hz, CH); 4.48 (d, J = 12.5 Hz, 1H, CH); 4.99 (s,
1H, OH); 5.50 (s, 1 H, CH); 6.59–6.66 (m, 5H, ArH); 6.77–6.86 (m,
3H, ArH); 6.93–7.01 (m, 3H, ArH); 7.06–7.09 (m, 2H, ArH); 7.23–
7.28 (m, 5H, ArH); 7.55–7.62 (m, 4H, ArH). 19F NMR (CDCl3,
7.57–7.59 (m, 1H, ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ84.01 (s, 3F,
CF3). MS (ESI) m/z: 592 [M+H]+. Anal. Calcd for: C29H22Cl2F3NO5 (%):
C, 58.80; H, 3.74; N, 2.36. Found: C, 58.86; H, 3.68; N, 2.30.
4.2.4. Ethyl 1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(4-
methoxyophenyl)-60(trifluoromethyl)-spiro[indene-2,30-piperidine]-
50-carboxylate (5d)
470 MHz):
d
ꢀ83.95 (s, 3F, CF3). MS (ESI) m/z: 708 [M+H] +, Anal.
Calcd for C41H32F3NO7 (%): C, 69.58; H, 4.56; N, 1.98. Found: C,
69.57; H, 4.75, N, 1.86.
White solid, mp: 178–180 8C. IR (KBr, cmꢀ1): 3420, 3353, 3030,
2982, 2926, 1919, 1742, 1706, 1464, 1342, 1255, 1183, 1156, 1080,
4.2.9. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-phenyl-2-
(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-carboxylate (6a)
Red solid, mp: 197–200 8C. IR (KBr, cmꢀ1): 3394, 3237, 3060,
2997, 1702, 1666, 1574, 1543, 1381, 1233, 1177, 768, 717, 702. 1H
809, 567. 1H NMR (CDCl3, 500 MHz):
d 0.82 (t, 3H, J = 7.0 Hz,
OCHACHB); 2.54 (s, 1H, NH); 3.57 (s, 3H, OCH3); 3.58 (s, 3H, OCH3);
3.85 (q, J = 7.0 Hz, 2H, OCHACHB); 4.04 (d, J = 12.5 Hz, 1H, CH); 4.48
(d, J = 12.5 Hz, 1H, CH); 4.96 (s, 1H, OH); 5.53 (s, 1H, CH); 6.48–6.54
(m, 4H, ArH); 7.00–7.08 (m, 4H, ArH); 7.40–7.47 (m, 3H, ArH);
NMR (CDCl3, 500 MHz): d 0.91 (t, J = 7.0 Hz, 3H, OCHACHB); 3.07 (d,
J = 11.5 Hz, 1H, CH); 3.98 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2H, OCHACHB);
4.10 (d, J = 11.5 Hz, 1H, CH); 5.71 (s, 1H, NH); 5.95 (s, 1H, OH);
7.13–7.14 (m, 1H, ArH); 7.22–7.24 (m, 2H, ArH); 7.31–7.38 (m, 6H,
7.56–7.58 (m, 1H, ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ84.02 (s, 3F,
CF3). MS (ESI) m/z: 584 [M+H] +; Anal. Calcd for: C31H28F3NO7 (%):
C, 63.80; H, 4.84; N: 2.40. Found: C, 63.94; H, 4.71; N, 2.45.
ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ82.69 (s, 3F, CF3). MS (ESI) m/
z: 418 [M+H]+. Anal. Calcd for: C22H18F3NO4 (%): C, 63.31; H, 4.35;
4.2.5. Ethyl spiro-1,3-dihydro-60-hydroxy-1,3-dioxo-20,40-di(p-tolyl)-
60(trifluoromethyl)-[indene-2,30-piperidine]-50-carboxylate (5e)
White solid, mp: 170–172 8C. IR (KBr, cmꢀ1): 3421, 3354, 3030,
2982, 1919, 1742, 1707, 1515, 1461, 1254, 1183, 1081, 809, 569. 1H
N, 3.36. Found: C, 63.13; H, 4.36; N, 3.20.
4.2.10. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(4-nitrophenyl)-
2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-carboxylate (6b)
Red solid, mp: 183–184 8C. IR (KBr, cmꢀ1): 3421, 3334, 2987,
2941, 1943, 1723, 1668, 1573, 1524, 1347, 1199, 1083, 1019, 716,
NMR (CDCl3, 500 MHz): d 0.78 (t, 3H, J = 7.0 Hz, OCHACHB); 2.04 (s,
3H, ArCH3); 2.06 (s, 3H, ArCH3); 2.57 (s, 1H, NH); 3.84 (q, J = 7.0 Hz,
2H, OCHACHB); 4.07 (d, 1H, J = 12.5 Hz, CH); 4.50 (d, J = 12.5 Hz, 1H,
CH); 4.98 (s, 1H, OH); 5.55 (s, 1H, CH); 6.76–6.80 (m, 3H, ArH);
6.82–6.85 (m, 3H, ArH); 6.88–7.04 (m, 2H, ArH); 7.38–7.40 (m, 1H,
ArH); 7.42–7.48 (m, 2H, ArH); 7.53–7.57 (m, 1H, ArH). 19F NMR
699. 1H NMR (CDCl3, 500 MHz):
d 0.94 (t, J = 7.0 Hz, 3H, OCHACHB);
3.05 (d, J = 11.5 Hz, 1H, CH); 3.99 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2H,
OCHACHB); 4.01 (d, J = 11.5 Hz, 1H, CH); 5.55 (s, 1H, NH); 5.97 (s,
1H, OH); 7.16–7.17 (m, 1H, ArH); 7.35–7.42 (m, 5H, ArH); 8.19–
(CDCl3, 470 MHz):
Anal. Calcd for: C31H28F3NO5 (%): C, 67.51; H, 5.12; N, 2.54. Found:
C, 67.48; H, 5.22; N, 2.47.
d
ꢀ84.02 (s, 3F, CF3). MS (ESI) m/z: 552 [M+H] +;
8.20 (m, 1H, ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ82.55 (s, 3F, CF3).
MS (ESI) m/z: 463 [M+H]+; HRMS for [C22H17F3N2O6 + H]+ Calcd:
463.1117. Found: 463.1112.

132
B. Dai et al. / Journal of Fluorine Chemistry 133 (2012) 127–133
4.2.11. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(4-
chlorophenyl)-2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-
carboxylate (6c)
4.2.16. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(3-
phenoxyphenyl)-2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-
carboxylate (6h)
Red solid, mp: 179–180 8C. IR (KBr, cmꢀ1): 3426, 3336,
2989,1895, 1729, 1669, 1574, 1529, 1227, 1197, 1086, 716. 1H
Red solid, mp: 184–186 8C. IR (KBr, cmꢀ1): 3388, 3221, 3056,
2919, 1932, 1702, 1666, 1576, 1543, 1489, 1300, 1243, 1199, 1179,
NMR(CDCl3, 500 MHz):
d
0.94 (t, J = 7.5 Hz, 3H, OCHACHB); 2.97 (d,
1085, 751, 718, 701. 1H NMR(CDCl3, 500 MHz):
d 1.03 (t, 3H,
J = 11.5 Hz, 1H, CH); 3.98 (qd, J1 = 7.5 Hz, J2 = 3.5 Hz, 2H, OCHACHB);
4.04 (d, J = 11.5 Hz, 1H, CH); 5.58 (s, 1H, NH); 5.96 (s, 1H, OH);
7.08–7.17 (m, 3H, ArH); 7.26–7.28 (m, 2H, ArH); 7.28–7.34 (m, 3H,
J = 7.0 Hz, OCHACHB); 3.05 (d, 1H, J = 11.5 Hz, CH); 4.05 (q,
J = 7.0 Hz, 2H, OCHACHB); 4.09 (d, J = 11.5 Hz, 1H, CH); 5.67 (s,
1H, OH); 5.89 (s, 1H, NH); 6.94–6.95 (m, 2H, ArH); 6.99–6.71 (m,
3H, ArH); 7.07–7.13 (m, 2H, ArH); 7.29–7.39 (m, 6H, ArH). 19F NMR
ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ82.62 (s, 3F, CF3). MS (EI) (m/z,
%): 451 ([M]+, 3.39). 362/360 ([MꢀH2OꢀCO2C2H5]+, 39/100). Anal.
Calcd for: C22H17ClF3NO4 (%): C, 58.48; H, 3.79; N, 3.10. Found: C,
58.82; H, 4.14; N 2.96.
(CDCl3, 470 MHz):
d
ꢀ82.68 (s, 3F, CF3). MS (ESI) m/z: 510 [M+H]+.
Anal. Calcd for: C28H22F3NO5 (%): C, 66.01; H, 4.35; N, 2.75. Found:
C, 65.87; H, 4.56; N, 2.31.
4.2.12. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(4-
methoxyphenyl)-2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-
carboxylate (6d)
Red solid, mp: 201–202 8C. IR (KBr, cmꢀ1): 3421, 3273, 2986,
2930, 1721, 1671, 1576, 1535, 1207, 1185, 1081, 715. 1H NMR
4.2.17. Ethyl 1,3-dihydro-20,30dihydro-60-methyl-1,3-dioxo-20,40-
diphenyl-spiro[indene-2,30-40H-pyridine]-50-carboxylate (7)
Yellow solid, mp: 169–171 8C. IR (KBr, cmꢀ1): 3422, 3070, 3028,
2973, 2899, 2872, 1989, 1736, 1701, 1613, 1491, 1253, 763, 705. 1H
NMR (CDCl3, 500 MHz): d 0.58 (t, J = 7.0 Hz, 3H, OCHACHB); 2.48 (s,
(CDCl3, 500 MHz):
d
0.94 (t, J = 7.0 Hz, 3H, OCHACHB); 3.01
3H, CH3); 3.69 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2H, OCHACHB); 4.52 (s,
1H, NH); 4.70 (s, 1H, CH); 4.86 (s, 1H, CH); 6.80–6.97 (m, 4H, ArH);
7.01–7.07 (m, 4H, ArH); 7.13–7.15 (m, 2H, ArH); 7.35–7.41 (m, 3H,
ArH); 7.46–7.48 (m, 1H, ArH). MS (ESI) m/z: 452 [M+H]+. Anal.
Calcd for: C29H25NO4 (%): C, 77.14; H, 5.58; N, 3.10. Found: C, 77.09;
H, 5.62; N, 3.14.
(d, J = 11.5 Hz, 1H, CH); 3.77 (s, 3H, OCH3); 3.98 (qd, 2H,
J1 = 7.0 Hz, J2 = 3.5 Hz, OCHACHB); 4.04 (d, J = 11.5 Hz, 1H, CH);
5.66 (s, 1H, NH); 6.04 (s, 1H, OH); 6.81–6.84 (m, 2H, ArH); 7.09–
7.13 (m, 3H, ArH); 7.27–7.38 (m, 3H, ArH). 19F NMR (CDCl3,
470 MHz):
d
ꢀ82.63 (s, 3F, CF3); MS (EI) (m/z, %): 447 ([M]+,
5.83); 356 ([MꢀH2OꢀCO2C2H5]+, 100). Anal. Calcd for:
C
23H20F3NO5 (%): C, 61.74; H, 4.51; N, 3.13. Found: C: 61.33,
4.2.18. Ethyl 4,5-dihydro-2-methyl-5-oxo-4-phenyl-1H-indeno[1,2-
b]pyridine-3-carboxylate (8)
Orange solid, mp: 153–155 8C. IR (KBr, cmꢀ1): 3443, 3272, 2976,
2924, 1704, 1637, 1511, 1180, 1088, 705. 1H NMR (CDCl3,
H, 4.77; N, 3.28.
4.2.13. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(4-
methyphenyl)-2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-
carboxylate (6e)
Red solid, mp: 196–198 8C. IR (KBr, cmꢀ1): 3421, 3273, 3051,
2986, 1721, 1671, 1575, 1536, 1206, 1185, 715, 536. 1H NMR
500 MHz):
d 1.15 (t, J = 7.0 Hz, 3H, OCHACHB); 2.53 (s, 3H, CH3);
4.06 (d, J = 7.0 Hz, 2H, OCHACHB); 5.04 (s, 1H, CH); 6.83 (s, 1H, NH);
7.09–7.11 (m, 2H, ArH); 7.15–7.31 (m, 4H, ArH); 7.35–7.39 (m, 3H,
ArH). MS (EI) (m/z, %): 345 ([M]+, 16.78), 272 ([MꢀCO2C2H5]+, 4.58),
268 ([MꢀC7H6]+, 100). Anal. Calcd for: C22H19NO3 (%): C, 76.50; H,
5.54; N, 4.06. Found: C, 76.31; H, 5.36; N, 4.12.
(CDCl3, 500 MHz):
d 0.92 (t, J = 7.0 Hz, 3H, OCHACHB); 2.31 (s, 3H,
ArCH3); 3.02 (d, J = 11.5 Hz, 1H, CH); 3.97 (qt, J1 = 7.0 Hz,
J2 = 3.5 Hz, 2H, OCHACHB); 4.04 (d, J = 11.5 Hz, 1H, CH); 5.67 (s,
1H, NH); 5.94 (s, 1H, OH); 7.07–7.11 (m, 5H, ArH); 7.28–7.34 (m,
4.3. X-ray crystal structure data of compounds 5a and 6h
3H, ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ82.69 (s, 3F, CF3). MS (ESI)
m/z: 432 [M+H]+. Anal. Calcd for: C23H20F3NO4 (%): C, 64,03; H,
CCDC 723103, 723104 contain the supplementary crystallo-
graphic data for this paper. These results can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033.
4.67; N, 3.25, Found: C, 64.35; H, 4.50; N, 3.19.
4.2.14. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(2-
methoxyphenyl)-2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-
carboxylate (6f)
Red solid, mp: 203–205 8C; IR (KBr, cmꢀ1): 3547, 3411, 3227,
3172, 3060, 2982, 1701, 1631, 1590, 1558, 1208, 1187, 1089, 752,
Acknowledgements
718. 1H NMR (CDCl3, 500 MHz):
d 0.83 (br, 3H, OCHACHB); 3.05 (d,
J = 11.5 Hz, 1H, CH); 3.73 (br, 2H, OCHACHB); 3.91 (br, 3H, OCH3);
4.80 (d, J = 11.5 Hz, 1H, CH); 5.84 (br, 1H, NH); 6.12 (s, 1H, OH);
6.86–6.90 (m, 2H, ArH); 7.08–7.14 (m, 2H, ArH); 7.26–7.31 (m, 4H,
This work was supported by the National Natural Science
Foundation of China (NNSFC) (Nos. 21072128, 20772080),
Leading Academic Discipline Project of Shanghai Municipal
Education Commission (No. J50102), the Foundation of Education
Commission of Shanghai Municipality (08zz44) and the Key
Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry.
ArH). 19F NMR (CDCl3, 470 MHz):
d
ꢀ82.85 (s, 3F, CF3). MS(EI): (m/z,
%): 447 ([M]+, 5.27); 356 ([M-CO2C2H5-H2O]+, 100). HRMS for
[C23H20F3NO5]+ Calcd: 447.1294. Found: 447.1292.
4.2.15. Ethyl 2,3,4,5-tetrahydro-2-hydroxy-5-oxo-4-(4-nitrophenyl)-
2-(trifluoromethyl)-1H-indeno[1,2-b]pyridine-3-carboxylate (6g)
Red solid, mp: 195–197 8C. IR (KBr, cmꢀ1): 3423, 3309, 3919,
2851, 1736, 1699, 1533, 1353, 1201, 788, 793. 1H NMR (CDCl3,
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