Unexpected formation of fluorine-containing multiply substituted dispirocyclohexanes from the reaction of ethyl-4,4,4-trifluoro-1,3- dioxobutanoate and 2-arylideneindane-1,3-diones

Article abstract of DOI:10.1055/s-0029-1217361

In the presence of a catalytic amount of piperidine (10 mol%), reaction of ethyl 4,4,4-trifluoro-3-oxobutanoate 3 and 2-arylidene-indane-1,3-diones 4 gave the unexpected fluorine-containing multiply substituted dispirocyclohexanes 5 in good yields. The st

Full text of DOI:10.1055/s-0029-1217361

1842
LETTER
Unexpected Formation of Fluorine-Containing Multiply Substituted
Dispirocyclohexanes from the Reaction of Ethyl-4,4,4-trifluoro-1,3-
dioxobutanoate and 2-Arylideneindane-1,3-diones
Unexpected
F
orm
a
ation of Fl
i
uorine
-
f
Containi
a
ng Multiply
n
Substituted Dispi
D
rocyclohexanes ai,a Liping Song,*a,b Pengyuan Wang,a Hai Yi,a Weiguo Cao,a Guifang Jin,b Shizheng Zhu,*b Min Shaoc
a
b
c
Department of Chemistry, School of Science, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. of China
Fax +86(21)66132797; E-mail: lpsong@shu.edu.cn
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. of China
Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, P. R. of China
Received 16 February 2009
volving 2-arylidene-indane-1,3-diones or 1,3-indanedi-
one as reaction substrates are studied extensively.12
Abstract: In the presence of a catalytic amount of piperidine
(10 mol%), reaction of ethyl 4,4,4-trifluoro-3-oxobutanoate 3 and
2-arylidene-indane-1,3-diones 4 gave the unexpected fluorine-
containing multiply substituted dispirocyclohexanes 5 in good
yields. The structures of compounds 5 were fully confirmed by
spectroscopic methods and elemental analysis. A representative
compound 5a was further confirmed by XRD analysis. A plausible
reaction mechanism for the formation of compounds 5 was present-
ed.
In order to continue our ongoing research on the synthesis
of fluorine-containing compounds based on trifluoro-
methyl-1,3-dicarbonyl compound, a versatile fluorine-
containing building block,13 herein, we wish to report the
unexpected formation of fluorine-containing multiply
substituted dispirocyclohexanes from the reaction of
ethyl-4,4,4-trifluoro-1,3-dioxobutanoate and 2-arylidene-
indane-1,3-diones.
Key words: fluorine-containing, spiro compound, polysubstitu-
tion, 2-arylidene-indan-1,3-dione, ethyl 4,4,4-trifluoro-3-oxobu-
tanoate
In an initial endeavor, we carried out the reaction of ethyl-
4,4,4-trifluoro-1,3-dioxobutanoate and 2-benzylidene-
indane-1,3-diones in the molar ratio of 1:1 in the presence
of a catalytic amount of triethylamine (20%) in ethanol at
room temperature. However, no reaction occurred. Subse-
quently, the catalyst was changed to a catalytic amount of
piperidine (20%). TLC analysis showed that a new com-
pound was formed, however, ethyl-4,4,4-trifluoro-1,3-di-
oxobutanoate did not react completely. Surprisingly,
It is now well established that introduction of fluorine
atoms or fluoroalkyl moieties into organic substrates
gives rise to important physicochemical modifications of
the concerned molecules.1 Such specific properties have
found applications in various fields.2 For example, the in-
troduction of fluorine atoms or fluoroalkyl groups into
molecules constitutes a classical and systematic modifica-
tion of biological properties used in medicinal chemistry
for the design of new drugs.3 More specifically, fluoro-
alkyl groups (particularly the CF3 group) cause a great in-
terest since they generally increase the lipophilicity of the
compounds and, usually, enhance their bioactive ability.
Consequently, more fluoroalkylated molecules find appli-
cation in the pharmaceutical fields.4 On the other hand,
spiro compounds represent an important class of naturally
occurring substances characterized by highly pronounced
biological properties.5 Due to these observations, fluoro-
alkylated spirocyclic molecules should be valuable build-
ing blocks to construct medicinally relevant complex
structures.
1
according to the H NMR spectrum of newly formed
product, it was clear that two molecules of 2-arylidene-
indane-1,3-diones, derived from the Knoevenagel con-
densation of aromatic aldehyde and 1,3-indanedione un-
der solvent-free conditions,14 were involved in the
reaction. Thus, the molar ratio of ethyl-4,4,4-trifluoro-
1,3-dioxobutanoate to 2-benzylidene-indane-1,3-diones
was modified to 1:2, and the reaction was carried out un-
der the same reaction conditions. After stirring 12 hours at
room temperature, TLC showed that the reaction proceed-
ed smoothly and general workup afforded the product 5a
in 47% yield (Scheme 1).
Based on the results above, the reaction conditions were
optimized to improve the yield by changing the base and
solvent used. The effect of organic bases on the reaction
efficiency and yield was firstly screened (Table 1). The
reactions did not occur either in the absence of base cata-
lyst or in the presence of a catalytic amount of other or-
ganic bases such as pyridine, Et3N, and DBU even with a
prolonged reaction time (24 h; entries 1–4, Table 1). The
reactions gave the product 5a in 59% and 53% yields un-
der the catalysis of DMAP and DABCO, respectively. It
was obvious that piperidine (entries 7–10, Table 1) dem-
onstrated superior catalytic activity and was the best cata-
lyst among those examined. Use of 10 mol% of piperidine
2-Arylidene-indane-1,3-diones are highly reactive 1,1-di-
activated alkenes that have been used extensively as ac-
ceptors in 1,4-addition of a variety nucleophiles6 or in 1,3-
dipolar cycloaddition,7 as dienophile8 and diene9 in Diels–
Alder reactions, respectively, and as versatile synthons in
other reactions,10 especially in the fields of medical and
materials chemistry.11 More recently, the reactions in-
SYNLETT 2009, No. 11, pp 1842–1846
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217361; Art ID: W02209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Unexpected Formation of Fluorine-Containing Multiply Substituted Dispirocyclohexanes
1843
O
1
O
ArCHO solvent-free
2a–g
grind
CO2Et
F3C
HO
Ar
O
O
O
O
O
piperidine (10 mol%)
MeCN
+
F3C
OEt
Ar
Ar
O
O
O
3
4a–g
5a–g
Scheme 1 Reaction of ethyl-4,4,4-trifluoro-1,3-dioxobutanoate 3 with 2-benzylidene-indane-1,3-diones 4
was sufficient to push the reaction forward but 5 mol% of employed as the reaction substrates, the reaction did not
piperidine was not enough (entries 7 and 8, Table 1). afford the corresponding products (entry 8 and 9,
Higher amounts of the catalyst did not further improve the Table 2). Moreover, the effect of steric hindrance on the
yield of product 5a (entries 9 and 10, Table 1).
phenyl ring of 2-arylidene-indane-1,3-dione was also no-
ticeable. Hence, 2-arylidene-indane-1,3-diones bearing
ortho substituents on the phenyl ring did not give the cor-
responding products, even though the reaction was carried
out at higher reaction temperature with a prolonged reac-
tion time (entries 10–12, Table 2). The above results
showed that the reactivity of substrates significantly de-
pended on both the steric and the electronic effects of the
substituents.
The structures of products 5 were fully confirmed by 1H
NMR, 19F NMR, IR spectroscopy, mass spectrometry,
and elemental analysis. For instance, the characteristic
features of 1H NMR in CDCl3 spectra of product 5a were
the appearances of two doublet peaks near d = 4.51 and
5.19 ppm with JH–H = 12.5 Hz for two neighboring pro-
tons on cyclohexane moiety, respectively, indicating the
trans configuration of the vicinal two hydrogen atoms.
The solvent effect was the next considered factor. As
shown in Table 1, the reactions gave the better yield in po-
lar aprotic solvents such as MeCN and CH2Cl2 than that in
protic solvents such as EtOH or MeOH (entries 8, 11–13,
Table 1).
With the optimal results in hand as shown in entry 8
(Table 1), we investigated the scope and limitation of the
reaction with a variety of 2-arylidene-indane-1,3-diones.
The reaction results were summarized in Table 2. It was
clear that the product yield was influenced by both elec-
tronic and steric effects of the substituting groups on the
phenyl ring in the 2-arylidene-indane-1,3-diones. We ob-
served that when 2-arylidene-indane-1,3-diones with
strong electron-donating group on the phenyl ring was
Table 1 Optimization of Reaction Conditions for Product 5a
Table 2 Scope of the Reaction of Ethyl 4,4,4-trifluoro-3-oxobutan-
oate 3 and 2-Arylidene-indane-1,3-diones 415–17
Entry Solvent
Base (equiv)
Time (h) Yield (%)b
a
1
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeOH
EtOH
–
24
24
24
24
10
12
10
8
0
0
Entry
1
Ar
Time (h)
Product Yield (%)a
pyridine (0.1)
Et3N (0.1)
Ph
8
8
5a
5b
5c
5d
5e
5f
5g
–
78
75
83
81
80
86
92
–
3
0
2
4-MeC6H4
4-O2NC6H4
4-ClC6H4
4-FC6H4
4
DBU (0.1)
0
3
8
5
DMAP (0.1)
59
53
72
78
76
78
70
44
47
4
8
6
DABCO (0.1)
piperidine (0.05)
piperidine (0.1)
piperidine (0.3)
piperidine (0.5)
piperidine (0.1)
piperidine (0.1)
piperidine (0.1)
5
8
7
6
3-ClC6H4
3-BrC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-O2NC6H4
2-ClC6H4
2,4-Cl2C6H3
8
8
7
8
9
8
8
24
24
24
24
24
10
11
12
13
8
9
–
–
12
12
12
10
11
12
–
–
–
–
–
–
a Without base.
b Isolated yields.
a Isolated yields.
Synlett 2009, No. 11, 1842–1846 © Thieme Stuttgart · New York

1844
B. Dai et al.
LETTER
The chemical shift of the CF3 group in 19F NMR was a sin-
glet peak at d = –71.65 ppm (s, 3 F), which indicated that
the CF3 group was bonded to a quaternary carbon atom.
Furthermore, the structure of product 5a was confirmed
by XRD analysis (Figure 1).18 The structure revealed that
the proton H3 attached to oxygen O3 of hydroxy group
formed an intramolecular H bond with the oxygen O1 of
carbonyl group of the indan-1,3-dione moiety [distance
O1···H3 = 2.233 Å; angle O3–H3···O1 = 132.36°).
CO2Et
O
O
F3C
piperidine
Ar
O
O
O
O
+
F3C
OEt
Ar
O
A
O
piperidine
Ar
O
CO2Et
CO2Et
F3C
HO
O
F3C
O
Ar
Ar
O
O
O
cyclization
Ar
O
Ar
O
O
O
B
5a–g
Scheme 2 A plausible mechanism for formation of compounds 5
and the Innovation Fund of Shanghai University for financial sup-
port.
References and Notes
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Figure 1 Crystal structure of compound 5a, showing the intramole-
cular H bond
A plausible mechanism for this reaction was shown in
Scheme 2. Ethyl-4,4,4-trifluoro-1,3-dioxobutanoate reac-
ted with 2-arylidene-indane-1,3-diones to generate the in-
termediate A catalyzed by piperidine via a Michael
addition. The intermediate A reacted with the second 2-
arylidene-indane-1,3-dione to give intermediate B, which
then underwent an intramolecular cyclization reaction to
afford the unexpected highly puckered dispirocyclohex-
ane products 5a–g. This explanation was consistent with
the observed results that the reaction for substrates with
ortho substitution on the phenyl ring was inhibited be-
cause of steric hindrance.
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In conclusion, we have developed a facile reaction to ob-
tain a series of novel unexpected fluorine-containing mul-
tiply substituted dispirocyclohexanes in good yields. This
procedure offers several advantages including mild reac-
tion conditions, high yields of products, as well as readily
available starting materials, which makes it a useful and
attractive process for the construction of fluorinated mul-
tiply substituted dispirocyclohexane derivatives.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors thank the National Natural Science Foundation of
China (NNSFC) (Nos. 20672072, 20772080), the Foundation of
Education Commission of Shanghai Municipality (No. J50102),
Synlett 2009, No. 11, 1842–1846 © Thieme Stuttgart · New York

LETTER
Unexpected Formation of Fluorine-Containing Multiply Substituted Dispirocyclohexanes
1845
E. B.; Grishin, Y. K.; Kuznetsova, T. S.; Zefirov, N. S.
column chromatography on silica gel using PE–EtOAc [6:1
(v/v)] as eluent to afford 5a as a colorless solid in 78% yield.
(16) Spectroscopic Data for Products 5
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Compound 5a: colorless solid (509.0 mg), mp 211–214 °C.
1H NMR (500 MHz, CDCl3): d = 0.89 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 3.84 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2 H,
OCH2CH3), 4.51 (d, J = 12.5 Hz, 1 H, CH), 4.56 (s, 1 H,
CH), 5.19 (d, J = 12.5 Hz 1 H, CH), 5.65 (s, 1 H, OH), 6.37
(br, 1 H, ArH), 6.59–7.06 (m, 8 H, ArH), 7.32–7.42 (m, 4 H,
ArH), 7.54–7.56 (m, 3 H ArH), 7.66–7.69 (m, 1 H, ArH),
7.93–7.95 (m, 1 H, ArH). 19F NMR (470 MHz, CDCl3):
d = –71.63 (s, 3 F, CF3). IR (KBr): 3402, 3062, 2981, 2932,
1745, 1711, 1594, 1247, 1184 cm–1. ESI-MS: m/z = 653 [M
+ H]+, 670 [M + NH4]+. Anal. Calcd for C38H27F3O7: C,
69.94; H, 4.17. Found: C, 70.06; H, 4.06.
Compound 5b: colorless solid (510.0 mg), mp 227–229 °C.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.78 (s, 3 H, ArCH3), 2.04 (s, 3 H, ArCH3), 3.84
(qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2 H, OCH2CH3), 4.47 (d,
J = 12.5 Hz, 1 H, CH), 4.51 (s, 1 H, CH), 5.15 (d, J = 12.5
Hz, 1 H, CH), 5.63 (s, 1 H, OH), 6.15 (br, 1 H, ArH), 6.50–
6.70 (m, 4 H, ArH), 6.82–6.86 (m, 2 H, ArH), 7.24–7.36 (m,
2 H, ArH), 7.39–7.43 (m, 2 H, ArH), 7.66–7.69 (m, 4 H,
ArH), 7.92–7.93 (m, 1 H, ArH). 19F NMR (470 MHz,
CDCl3): d = –71.65 (s, 3 F, CF3). IR (KBr): 3408, 3029,
2986, 1741, 1712, 1247 cm–1. ESI-MS: m/z = 681 [M + H]+,
698 [M + NH4]+. Anal. Calcd for C40H31F3O7: C, 70.58; H,
4.59. Found: C, 70.33; H, 4.77.
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Compound 5c: colorless solid (617.0 mg), mp 246–247 °C.
1H NMR (500 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 3.89 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2 H,
OCH2CH3), 4.69 (d, J = 12.5 Hz, 1 H, CH), 4.71 (s, 1 H,
CH), 5.20 (d, J = 12.5 Hz, 1 H, CH), 5.45 (s, 1 H, OH), 6.84–
7.28 (m, 4 H, ArH), 7.43–7.53 (m, 3 H, ArH), 7.58–7.71 (m,
5 H, ArH), 7.76–7.80 (m, 2 H, ArH), 7.97–8.00 (m, 2 H,
ArH). 19F NMR (470 MHz, CDCl3): d = –71.67 (s, 3 F, CF3).
IR (KBr): 3420, 3058, 2979, 2934, 1746, 1710, 1595, 1248,
1188 cm–1. ESI-MS: 743 [M + H]+, 760 [M + NH4]+. HRMS
(MALDI/DHB): m/z calcd for [C38H25F3N2O11 + H]+:
743.1483; found: 743.1501; m/z calcd for [C38H25F3N2O11
+
Na]+: 765.1303; found:765.1309.
Compound 5d: colorless solid (584.0 mg), mp 243–244 °C.
1H NMR (500 MHz, CDCl3): d = 0.95 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 3.87 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2 H,
OCH2CH3), 4.49 (d, J = 12.5 Hz, 1 H, CH), 4.53 (s, 1 H,
CH), 5.11 (d, J = 12.5 Hz, 1 H, CH), 5.52 (s, 1 H, OH), 6.36–
7.07 (m, 7 H, ArH), 7.33–7.51 (m, 4 H, ArH), 7.60–7.72 (m,
3 H, ArH), 7.72–7.75 (m, 1 H, ArH), 7.94–7.96 (m, 1 H,
ArH). 19F NMR (470 MHz, CDCl3): d = –71.70 (s, 3 F, CF3).
IR (KBr): 3408, 3071, 2986, 2937, 1739, 1713, 1593, 1243,
1196 cm–1. ESI-MS: m/z = 721, 723, 725 [M + H]+, 738, 740,
742 [M + NH4]+. Anal. Calcd for C38H25Cl2F3O7: C, 63.26;
H, 3.49. Found: C, 62.87; H, 3.58.
Compound 5e: colorless solid (551.0 mg), mp 222–223 °C.
1H NMR (500 MHz, CDCl3): d = 0.92 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 3.86 (qd, J1 = 7.0 Hz, J2 = 3.5 Hz, 2 H,
OCH2CH3), 4.49 (d, J = 12.5 Hz, 1 H, CH), 4.54 (s, 1 H,
CH), 5.11 (d, J = 12.5 Hz, 1 H, CH ), 5.55 (s, 1 H, OH), 6.09
(br, 1 H, ArH) 6.49–6.93 (m, 6 H, ArH), 7.37–7.49 (m, 4 H,
ArH), 7.56–7.60 (m, 3 H, ArH), 7.70–7.73 (m, 1 H, ArH),
7.93–7.95 (m, 1 H, ArH). 19F NMR (470 MHz, CDCl3):
d = –71.71 (s, 3 F, CF3), –112.61 (m, 1 F, ArF), –114.13 (m,
1 F, ArF). IR (KBr): 3397, 3087, 2983, 2938, 1743, 1711,
1511, 1247, 1190 cm–1. ESI-MS: m/z = 689 [M + H]+. Anal.
Calcd for C38H25F5O7: C, 66.28; H, 3.66. Found: C, 66.04; H,
3.49.
(14) Wu, D. Y.; Ren, Z. J.; Cao, W. G.; Tong, W. Q. Synth.
Commun. 2005, 35, 3157.
(15) A Typical Experimental Procedure for the Preparation
of 5a
To a mixture of ethyl 4,4,4-trifluoro-3-oxobutanoate (184.0
mg, 1.0 mmol) and 2-benzylidene-indane-1,3-dione (468.0
mg, 2.0 mmol) in MeCN (3.0 mL) was added a catalytic
amount of pipreridine (8.5 mg, 0.1 mmol). The resulting
mixture was stirred at r.t. until the reaction was completed
(8 h, monitored by TLC). The solvent was removed under
reduced pressure. And then the residue was purified by
Synlett 2009, No. 11, 1842–1846 © Thieme Stuttgart · New York

1846
B. Dai et al.
LETTER
Compound 5f: colorless solid (620.0 mg), mp 241–243 °C.
1H NMR (500 MHz, CDCl3): d = 0.94 (br, 3 H, OCH2CH3),
3.87 (br, 2 H, OCH2CH3), 4.51 (br, 2 H, CH), 5.13 (br, 1 H,
CH), 5.58 (s, 1 H, OH), 6.34–7.01 (m, 7 H, ArH), 7.43–8.00
(m, 9 H, ArH). 19F NMR (470 MHz, CDCl3): d = –71.63 (s,
3 F, CF3). IR (KBr): 3440, 3055, 2984, 1744, 1710, 1593,
1249, 1235, 1176 cm–1. ESI-MS: m/z = 721, 723, 725 [M +
H]+, 738, 740, 742 [M + NH4]+. Anal. Calcd for
C38H25Cl2F3O7: C, 63.26; H, 3.49. Found: C, 62.91; H, 3.37.
Compound 5g: colorless solid (743 mg), mp 265–266 °C. 1H
NMR (500 MHz, CDCl3): d = 0.95 (br, 3 H, OCH2CH3), 3.88
(br, 2 H, OCH2CH3), 4.48 (br, 2 H, CH), 5.13 (br, 1 H, CH),
5.58 (s, 1 H, OH), 6.61–7.13 (m, 7 H, ArH), 7.35–7.76 (m, 8
H, ArH), 7.95–8.02 (m, 1 H, ArH). 19F NMR (470 MHz,
CDCl3): d = –71.61 (s, 3 F, CF3). IR (KBr): 3441, 3072,
2983, 1744, 1711, 1592, 1250, 1178 cm–1. ESI-MS: m/z =
809, 811, 813 [M + H]+, 826, 828, 830 [M + NH4]+. HRMS
(MALDI/DHB): m/z calcd for [C38H25Br2F3O7 + Na]+:
830.9811; found: 830.9817.
(17) In particular, in the cases of compounds 5f and 5g, the 1H
NMR spectrum showed broad signals due to decreased
rotational flexibility of the highly puckered structures.
(18) CCDC 720376 contains the supplementary crystallographic
data for this paper. These data 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.
Synlett 2009, No. 11, 1842–1846 © Thieme Stuttgart · New York