Perfluoroalkylated-pyridine catalyzed Aldol condensations of aldehydes and ketones in a fluorous biphasic system without fluorous solvent

Article abstract of DOI:10.1016/j.jfluchem.2009.02.013

Aldol condensation of different ketones with various aromatic aldehydes proceeds efficiently in the presence of catalytic amount of perfluoroalkylated-pyridine in a fluorous biphasic system without fluorous solvent, which has prompted various concerns involving cost, solvent leaching, and environmental persistence. The catalyst can be recovered by simple cooling and precipitation and used again.

Full text of DOI:10.1016/j.jfluchem.2009.02.013

Journal of Fluorine Chemistry 130 (2009) 484–487
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Perfluoroalkylated-pyridine catalyzed Aldol condensations of aldehydes and
ketones in a fluorous biphasic system without fluorous solvent
*
Wen-Bin Yi , Chun Cai
Chemical Engineering College, Nanjing University of Science and Technology, 200 Xlaolingwei, Nanjing 210094, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Aldol condensation of different ketones with various aromatic aldehydes proceeds efficiently in the
presence of catalytic amount of perfluoroalkylated-pyridine in a fluorous biphasic system without
fluorous solvent, which has prompted various concerns involving cost, solvent leaching, and
environmental persistence. The catalyst can be recovered by simple cooling and precipitation and
used again.
Received 23 December 2008
Received in revised form 1 February 2009
Accepted 20 February 2009
Available online 5 March 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Perfluoroalkylated-pyridine
Aldol condensation
Fluorous biphasic catalysis
Fluorous-solvent-free
1. Introduction
In the course of our extensive synthetic and physical
investigations involving perfluoroalkylated-pyridines 1–3 (Fig. 3)
Recently, reactions carried out in a fluorous biphasic system
(FBS, Fig. 1) have become one of the most important methods for
facile catalyst separation from the reaction mixture and recycling
[7–10], we noticed that 1 is very thermomorphic in less polar
hydrocarbon solvents. On the other hand, the Aldol condensation is
one of the most fundamental and important carbon–carbon bond-
forming reactions. The reactions are usually catalyzed by strong
acids or bases, and various Lewis acids [11]. Inspired by recent
reports on the N-methylimidazole as a Lewis base catalyst for the
Aldol condensation of trimethylsilyl enolate with aldehyde [12,13],
we have applied the perfluoroalkylated-pyridines 1 catalyst to the
Aldol condensation of ketones with aldehydes under FBS without
fluorous solvent. It was exciting to find that rather high yields of
´
´
of the catalyst since FBS was introduced by Horvath and Rabai [1].
No catalyst recovery method is without potential drawbacks [2,3].
Accordingly, the fluorous solvent requirement in Fig. 1 has
prompted various concerns involving cost, solvent leaching, and
environmental persistence [4]. Small amounts of fluorous solvents
are similarly found in the organic layers of fluorous/organic liquid/
liquid biphase systems. This makes losses unavoidable upon phase
separation. Therefore, the development of the strategy to eliminate
the fluorous solvent requirement for fluorous catalysis is a topic of
enormous importance.
the corresponding
a,b-unsaturated ketones were obtained, and
the fluorous catalyst is easily separated under fluorous-solvent-
free conditions and can be reused several times without a
significant loss of catalytic activity. We would like to report
herein the work on this new application of the catalytic system.
Fluorous catalysis without fluorous solvent suggested that
fluorous catalyst might be utilized under one-liquid-phase
conditions involving ordinary organic solvents as shown in
Fig.
2 [4]. The system would first be warmed to achieve
2. Experimental
monophasic reaction conditions. Subsequent cooling would
precipitate the catalyst, and recovery would involve a simple
liquid/solid phase separation [5]. The first example of the
applicability of this concept to fluorous catalysis was introduced
by Gladysz’s group [4,6].
2.1. General remarks
Melting points were obtained with Shimadzu DSC-50 thermal
analyzer. 1H NMR and 19F NMR spectra were characterized with a
Bruker Advance RX300 spectrometer. IR spectra were recorded on
a Bomen MB154S infrared analyzer. Mass spectra were recorded on
a Saturn 2000GC/MS instrument. All fluorous solvents were
purchased from Aldrich Co. Commercially available reagents were
used without further purification.
* Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
E-mail address: yiwenbin@mail.njust.edu.cn (W.-B. Yi).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.02.013

W.-B. Yi, C. Cai / Journal of Fluorine Chemistry 130 (2009) 484–487
485
1H), 7.11 (d, J = 16.0 Hz, 1H), 6.24 (d, 2H), 7.10–7.34 (m, 4H), 7.36–
8.02 (m, 5H). MS (EI) m/z 244 (M++2), 242 (M+).
4-Methylchalcone: A yellowish solid; m.p. 98 8C (lit. [14] 97–
98 8C). IR (KBr)
y
3210, 2915, 1760, 1696, 1652, 1086, 942, 843,
2.32 (s, 3H), 6.01 (d,
722 cmꢁ1 1H NMR (300 MHz, TMS, CDCl3)
.
d
J = 16.4 Hz, 1H), 7.04 (d, J = 16.4 Hz, 1H), 7.06–7.36 (m, 4H), 7.38–
7.83 (m, 5H). MS (EI) m/z 221 (M+).
Fig. 1. Fluorous biphasic catalysis with fluorous solvent (the liquid/liquid FBS).
4-Methoxychalcone: A russety solid; m.p. 75–76 8C (lit. [14] 75–
77 8C). IR (KBr)
y
3303, 2979, 1830, 1722, 1660, 1185, 929,
3.72 (s, 3H), 5.96 (d,
815 cmꢁ1 1H NMR (300 MHz, TMS, CDCl3)
.
d
J = 16.0 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H), 6.92–7.21 (m, 4H), 7.32–
7.99 (m, 5H). MS (EI) m/z 238 (M+).
4-Nitrochalcone: A brown solid; m.p. 158–159 8C (lit. [14] 158–
160 8C). IR (KBr)
y
3235, 2908, 1872, 1673, 1660, 1476, 923,
6.35 (d, J = 16.1 Hz,
Fig. 2. Fluorous biphasic catalysis without fluorous solvent (the liquid/solid FBS).
834 cmꢁ1 1H NMR (300 MHz, TMS, CDCl3)
.
d
1H), 7.40 (d, J = 16.1 Hz, 1H), 7.36–7.68 (m, 3H), 7.70–8.32 (m, 4H).
MS (EI) m/z 252 (M+).
2,6-Dibenzylidenecyclohexanone: A yellow solid; m.p. 116 8C (lit.
[15] 116–117 8C). IR (KBr)
y
3020, 2922, 1664, 1612, 1570, 1269,
1.75–1.86
1138, 768, 689 cmꢁ1. 1H NMR (300 MHz, TMS, CDCl3)
d
(m, 2H), 2.94 (t, J = 6.4 Hz, 4H), 7.28–7.46 (m, 10H), 7.80 (s, 2H). MS
(EI) m/z 273 (M+).
Fig. 3. Perfluoroalkylated-pyridines.
2,6-Di(p-methoxybenzylidene)cyclohexanone:
m.p. 202–204 8C (lit. [15] 203–204 8C). IR (KBr)
1658, 1606, 1568, 1265, 1140, 780, 687 cmꢁ1 1H NMR (300 MHz,
A
yellow solid;
y
3022, 2920,
2.2. Typical procedure for Aldol condensation in a liquid/liquid FBS
.
TMS, CDCl3) d 1.80–1.84 (m, 2H), 2.96 (t, J = 6.0 Hz, 4H), 3.85 (s, 6H),
The benzaldehyde (4 mmol) was slowly added into a mixture of
6.92–7.38 (m, 8H), 7.79 (s, 2H). MS (EI) m/z 333 (M+).
1
(227 mg, 0.4 mmol), n-octane (3 mL) and perfluorodecalin
2,6-Di(p-nitrobenzylidene)cyclohexanone: A russety solid; m.p.
(C10F18, cis- and trans-mixture, 3 mL) containing the acetophenone
(5 mmol). The mixture was stirred at 80 8C for 16 h. The bottom
fluorous layer was then separated (to be reused). The upper organic
phase was washed with water (10 mL), 10% NaHCO3 solution
(10 mL) and water (10 mL ꢀ2), and dried over Na2SO4. The solvent
was removed under reduced pressure and the residue was purified
by a silica gel column chromatography (20% EtOAc in petroleum
ether) to give the Aldol product.
158 8C (lit. [15] 159 8C). IR (KBr)
y
3086, 2933, 1670, 1612, 1581,
1.86–1.92
1525, 1340, 805 cmꢁ1. 1H NMR (300 MHz, TMS, CDCl3)
d
(m, 2H), 2.99 (t, J = 5.6 Hz, 4H), 7.60–8.24 (m, 8H), 8.32 (s, 2H). MS
(EI) m/z 363 (M+).
2,6-Di(p-methoxybenzylidene)cyclopentanone:
A
green solid;
2965, 2840,
m.p. 211–212 8C (lit. [15] 210–211 8C). IR (KBr)
y
1649, 1592, 1506, 1247, 1025, 830 cmꢁ1. 1H NMR (300 MHz, TMS,
CDCl3)
d 3.11 (t, 4H), 3.86 (s, 6H), 6.96–7.59 (m, 8H), 7.60 (s, 2H).
MS (EI) m/z 319 (M+).
2.3. Typical procedure for Aldol condensation in a liquid/solid FBS
2,6-Di(p-nitrobenzylidene)cyclopentanone: A russety solid; m.p.
230–233 8C (lit. [15] 230–231 8C). IR (KBr)
y
3108, 2850, 1708,
The benzaldehyde (4 mmol) was slowly added into a mixture of
1 (227 mg, 0.4 mmol), n-octane (6 mL) and the acetophenone
(5 mmol). After stirring at 80 8C for 16 h, the reaction mixture was
cooled to 0 8C and the catalyst was separated (to be reused). The
organic phase was washed with water (10 mL), 10% NaHCO3
solution (10 mL) and water (10 mL ꢀ2), and dried over Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by a silica gel column chromatography (20% EtOAc in
petroleum ether) to give the Aldol product.
1600, 1525, 1344, 821 cmꢁ1. 1H NMR (300 MHz, TMS, CDCl3)
d 3.06
(t, 4H), 7.61–8.13 (m, 8H), 8.28 (s, 2H). MS (EI) m/z 349 (M+).
2.4. Typical procedure for catalyst recycling in a liquid/solid FBS
After the reaction as described above, the mixture was allowed
to stand at 0 8C for ca. 1 h without stirring, and the upper organic
phase was separated using a pipette. The solid obtained was
washed with cold n-octane (0–3 8C) and dried at room temperature
for 12 h in vacuum. The resulting catalyst was ready for further
runs: The aldehyde (4 mmol), n-octane (6 mL) and the ketone
(5 mmol) were added to 1 (227 mg, 0.4 mmol) and the mixture was
stirred at 80 8C.
Chalcone: A yellowish solid; m.p. 56–57 8C (lit. [14] 57–58 8C).
IR (KBr)
NMR (300 MHz, TMS, CDCl3)
y .
3230, 2931, 1830, 1730, 1655, 1287, 753, 682 cmꢁ1 1H
d
6.12 (d, J = 16.0 Hz, 1H), 7.25 (d,
J = 16.0 Hz, 1H), 7.09–7.30 (m, 5H), 7.39–7.93 (m, 5H). MS (EI) m/z
207 (M+).
40-Methoxychalcone: A russety solid; m.p. 109–111 8C (lit. [14]
3. Results and discussion
109–110 8C). IR (KBr)
y
3210, 2880, 1833, 1725, 1670, 1210, 856,
3.78 (s, 3H), 6.10 (d,
730 cmꢁ1 1H NMR (300 MHz, TMS, CDCl3)
.
d
Perfluorinated pyridine 1 was prepared according to the
method described by Uemura and co-workers [16]. 1 was soluble
in perfluorodecalin (C10F18, cis- and trans-mixture), perfluoro-
methylcyclohexane (CF3C6F11) and perfluorotoluene (CF3C6F5). It
also showed significant solubility in ether, THF, CHCl3 and CH2Cl2.
However, 1 appeared to be very poorly soluble in n-octane, n-
hexane and toluene at room temperature. Quantitative data on
fluorous phase affinities were sought. The perfluorodecalin/
toluene partition coefficients were determined by GC according
the previously reported method [17,18]. These reflect relative as
opposed to absolute solubilities. In perfluoroalkylated-pyridines 1,
J = 16.0 Hz, 1H), 7.24 (d, J = 16.0 Hz, 1H), 7.08–7.62 (m, 9H). MS (EI)
m/z 238 (M+).
40-Nitrochalcone: A yellow solid; m.p. 151–153 8C (lit. [14] 151–
152 8C). IR (KBr)
y
3010, 2895, 1708, 1680, 1642, 1468, 920,
6.33 (d, J = 16.1 Hz,
837 cmꢁ1 1H NMR (300 MHz, TMS, CDCl3)
.
d
1H), 7.35 (d, J = 16.1 Hz, 1H), 7.14–7.38 (m, 5H), 7.49–8.24 (m, 4H).
MS (EI) m/z 253 (M+).
4-Chlorochalcone: A yellow solid; m.p. 114–115 8C (lit. [14]
114–117 8C). IR (KBr)
y
3080, 2908, 1780, 1712, 1650, 1205, 913,
6.20 (d, J = 16.0 Hz,
748 cmꢁ1 1H NMR (300 MHz, TMS, CDCl3)
.
d

486
W.-B. Yi, C. Cai / Journal of Fluorine Chemistry 130 (2009) 484–487
Table 1
Table 2
The condensation of benzaldehyde with acetophenone in liquid/liquid or liquid/
solid FBSa
Perfluoroalkylated pyridine 1 catalyzed Aldol condensation in liquid/solid FBSa
.
.
Entry
R1
R2
R3
Time (h)
Yield (%)b
Solvent
Yield (%)b
Cycle 1
1
2
4-CH3OPh
4-NO2Ph
Ph
H
H
H
H
H
H
Ph
16
16
16
16
16
16
8
72
95
91
79
68
96
94
93
96
92
97
4c
Ph
Cycle 2
Cycle 3
Cycle 4
Cycle 5
3
4-ClPh
4-CH3Ph
4-CH3OPh
4-NO2Ph
Ph
n-Octane/perfluorodecalin
n-Octane
91
90
90
89
90
87
88
87
85
84
4
Ph
5
Ph
6
Ph
a
The reaction condition: aldehyde, 4 mmol; ketone, 5 mmol; n-octane/per-
fluorodecalin, 3 mL/3 mL; n-octane, 6 mL; 80 8C.
7
(CH2)6
(CH2)6
(CH2)6
(CH2)5
(CH2)5
CH3
8
4-CH3OPh
4-NO2Ph
4-CH3OPh
4-NO2Ph
C3H7
12
16
12
16
24
24
24
b
Isolated yield based on the aldehyde.
9
10
11
12
13
14
Rf8 (Rf8 = C8F17) pony tails give high fluorous phase affinities
(coefficient for 1 was 92.1:7.9), allowing essentially quantitative
recovery. Indeed, 2 was less thermomorphic than 1 and 3. Between
0 and 80 8C, solubility of 1 in n-octane increased ca. 80-fold. The
increase of 3 was 70-fold between 0 and 80 8C. However, 3 was
liquid over the temperature range from ꢁ20 8C to 0 8C. Thus, it is
impossible to recover fluorous catalyst by liquid/solid separation
when using 2 and 3.
H
CH3
CH3
H
C3H7
6c
CH3
C4H9
3c
a
The reaction condition: aldehyde, 4 mmol; ketone, 5 mmol; cycloalkanone
2.5 mmol; n-octane, 6 mL; 80 8C.
b
Isolated yield based on the aldehyde.
c
Yields calculated by GC.
The Aldol condensation of benzaldehyde with acetophenone
was firstly investigated. The control experiment elucidated that no
condensation product could be obtained in the absence of fluorous
catalyst. Then, the condensation employing fluorous catalysis
technology in the protocols of Figs. 1 and 2 was examined with
perfluoroalkylated pyridine 1 catalyst (Table 1). In stage of liquid/
liquid FBS, experiments were conducted in binary system
perfluorodecalin/n-octane (1:1, v/v). Reactions proceeded under
one-phase conditions at 80 8C. After 16 h, condensation product
was obtained in 91% isolated yield. As summarized in Table 1, good
yields were maintained for 3–5 cycles. The stage was set for the
experimental sequence in liquid/solid FBS (Fig. 2). Benzaldehyde
and acetophenone were combined in n-octane at room tempera-
ture. The sample was next warmed to 80 8C and became
homogeneous. After stirring for 16 h, the reaction mixture was
cooled. The catalyst 1 precipitated as a white solid. The solid was
separated, washed with cold n-octane (0–3 8C), dried at vacuum
and then reused for the next reaction. As would be expected, the
fluorous catalyst can be reused several times without a significant
loss of yield.
summarized in Table 2. The condensation products were isolated
and identified as
a,b-unsaturated ketones, and no side-reactions
were observed. Based on 1H NMR and GC–MS data, the reaction
was found to give the E-stereoisomer as the sole product. In
general, reactions between aromatic aldehydes and ketones
gave good results, but not those of aliphatic compounds. The
condensations of p-substituted benzaldehyde with p-substituted
acetophenones yielded the corresponding chalcones and the
product yields were remarkably affected by the substituent groups
of either aldehydes or ketones: reactants having electron-with-
drawing substituents gave high yields and those having electron-
donating ones gave low yields. The cross-condensations of
cyclopentanone and cyclohexanone with different aromatic
aldehydes were finished within 8–16 h and excellent yields (92–
97%) of
a,
a0-bis(substituted) benzylidene cyclopentanones and
cyclohexanones were obtained, regardless of the kind of sub-
stituent group on benzaldehyde. However, the catalyst 1 system
appeared to show no catalytic activity for the condensation of the
aliphatic ketones such as acetone and 2-butanone with the
aliphatic aldehydes, butanal and pentanal under the conditions
described in Table 2.
The problem on leaching in these catalyst recycling systems
was studied. In the liquid/liquid FBS system, ca. 0.8% of ligand 1 and
trace of perfluorodecalin (<1%) was found by GC–MS in organic
layer. In fact, we also investigated the exact amount of ligand 1 in
the recovered fluorous phase by GC, finding that 99.1% of ligand 1
retained in perfluorodecalin. As to the liquid/solid FBS case, the
solubility data of 1 in n-octane predict catalyst leaching of ca. 1%
percycle when liquid/solid phase separations are conducted at 0 8C
4. Conclusion
In conclusion the perfluoroalkylated pyridine 1 was found to be
highly efficient for Aldol condensation under fluorous-solvent-free
conditions. The catalyst can be applied under homogeneous
conditions at elevated temperatures and efficiently recovered by
simple liquid/solid phase separation at lower temperature. The
simple procedures as well as easy recovery and reuse of this novel
catalytic system are expected to contribute to the development of
more benign method for catalyst recovery—‘‘fluorous catalysis
without fluorous solvents’’—that removes many objections to be
organic/fluorous liquid/liquid FBS.
according to the quantities in our previous report [7]. Based on 19
F
NMR and GC–MS data, only trace of the catalyst (<0.6%) was found
in separated organic layer. In addition, there were no significant
differences between the IR spectra of the initial and recovered
perfluoroalkylated pyridine, which may indicate that the fluorous
catalyst is recovered unaltered after the condensation has taken
place. These results suggest the robustness of the catalytic system
for recycled use.
Acknowledgments
From these observations it was revealed that using perfluor-
oalkylated pyridine 1 as fluorous catalyst the technology of liquid/
solid FBS (Fig. 2) can be considered the most attractive alternative
to existing traditional liquid/liquid FBS (Fig. 1). Next, we applied
the strategy in Fig. 2 to other Aldol condensations. The results were
We thank the Nature and Science Foundation of Jiangsu
Province (BK2007592) and the National Defense Committee of
Science and Technology of China (40406020301) for financial
support.

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487
References
[11] R.L. Reeves, in: S. Patai (Ed.), Chemistry of Carbonyl Group, Wiley, New York, 1966,
pp. 580–593.
[12] R. Srivastava, J. Mol. Catal. A: Chem. 264 (2007) 146–152.
[13] H. Hagiwara, H. Inoguchi, M. Fukushima, T. Hoshi, T. Suzuki, Tetrahedron Lett. 47
(2006) 5371–5373.
[1] T.H. Horva´th, J. Ra´bai, Science 266 (1994) 72–76.
[2] J.A. Gladysz, Pure Appl. Chem. 73 (2001) 1319–1324.
[3] J.A. Gladysz, Chem. Rev. 102 (2002) 3215–3216.
[14] K. Watanabe, A. Imazawa, Bull. Chem. Soc. Jpn. 55 (1982) 3208–3211.
[15] M. Zheng, L.C. Wang, J.G. Shao, Q. Zhong, Synth. Commun. 27 (1997) 351–354.
[16] T. Nishimura, Y. Maeda, N. Kakiuchi, S. Uemura, J. Chem. Soc., Perkin Trans. 1
(2000) 4301–4305.
[4] M. Wende, J.A. Gladysz, J. Am. Chem. Soc. 125 (2003) 5861–5872.
[5] V.K. Dioumaev, R.M. Bullock, Nature 424 (2003) 530–532.
[6] M. Wende, R. Meier, J.A. Gladysz, J. Am. Chem. Soc. 123 (2001) 11490–11491.
[7] W.B. Yi, C. Cai, Catal. Commun. 9 (2008) 1291–1296.
[17] C. Rocaboy, F. Hampel, J.A. Gladysz, J. Org. Chem. 67 (2002) 6863–6870.
[18] J. Nishikido, M. Kamishima, H. Matsuzawa, K. Mikami, Tetrahedron 58 (2002)
8345–8349.
[8] W.B. Yi, C. Cai, X. Wang, Eur. J. Org. Chem. (2007) 3445–3448.
[9] W.B. Yi, C. Cai, X. Wang, J. Mol. Catal. A: Chem. 274 (2007) 68–71.
[10] W.B. Yi, C. Cai, X. Wang, J. Fluorine Chem. 128 (2007) 919–924.