Iodine catalyzed synthesis of α,α′-bis(substituted benzylidene)-1-carbethoxy-4-piperidone

Article abstract of DOI:10.1002/jhet.5570450244

(Chemical Equation Presented) A facile and efficient method for the preparation of α,α′-bis(substituted benzylidene)-1-carbethoxy- 4-piperidone is described using iodine as a catalyst in acetonitrile. The reaction proceeds rapidly at room temperature, giv

Full text of DOI:10.1002/jhet.5570450244

Mar-Apr 2008
579
Iodine Catalyzed Synthesis of α,α'-Bis(Substituted Benzylidene)-1-
Carbethoxy-4-Piperidone
Mohamed. A. Ameen* and Essam, Kh. Ahmed
Chemistry Department, Faculty of Science, El-Minia University, El-Minia, Egypt
E-mail: m_ameen10@yahoo.com
Received March 1, 2007
H
O
H
Ar
Ar
N
CO2Et
A facile and efficient method for the preparation of α,α'-bis(substituted benzylidene)-1-carbethoxy-4-
piperidone is described using iodine as a catalyst in acetonitrile. The reaction proceeds rapidly at room
temperature, giving high yields of products.
J. Heterocyclic Chem., 45, 579 (2008).
by using cyclopentanone trimethylsilyl enol ethers as
starting materials. Moreover, the temperature of the
reaction has to be raised to 70–80 °C for the
cyclohexanone analogue [17]. The first example in which
cross-Aldol condensation of ketones with aldehydes was
carried out at room temperature to give enones was
reported by the use of iodotrimethylsilane (TMSI) [18].
In this context, we now developed a mild and more
efficient method for the synthesis of α,α'-bis(substituted
benzylidene)-1-carbethoxy-4-piperidone at room temp-
erature using CH3CN as a solvent. While this work was
progressing another research group [19] published the
successful synthesis of analogues of our target
compounds, containing a cyclopentanone unit, using
iodine at RT.
INTRODUCTION
The α,α'-bis(substituted benzylidene)cycloalkanones
are very important precursors to potentially bioactive
pyrimidine derivatives [1], intermediates of agrochemical,
pharmaceuticals, and perfumes [2], new organic materials
for nonlinear optical applications [3], cytotoxic analogues
[4] and the units of liquid-crystalline polymers [5]. In
addition, these compounds undergo double 1,3-dipolar
cycloaddition reaction [6] with azomethine ylides to give
bis-spiropyrrolidines, which are often the central ring
systems of numerous natural products [7].
Generally benzylidenecycloalkanones are prepared by
cross-Aldol condensation of cycloalkanones with
aldehydes in the presence of strong acids or bases.
However, traditional acid- or base-catalyzed reactions
often suffer from reverse and side reactions and therefore
give low yields of products [8]. Cp2TiPh2 [9] and
anhydrous RuCl3 [10] are reported to give good yields of
enone products, but require longer reaction times and high
temperatures (120 °C) in sealed, ampoules and tubes,
whereas Rh-porphyrin complex-catalyzed reactions
reported to give 30% cross-Aldol product [11].
Microwave assisted syntheses [12] using KF/Al2O3 and
BMPTO and several catalytic procedures [13] using
different complexes of metal ions as catalysts have been
reported. Solvent-free synthesis mediated by magnesium
hydrogen sulfate [14] or Yb(OTf)3 [15], is known for
these compounds. However, this procedure requires
longer reaction times (7 h) and heating temperature up to
60 °C.
RESULTS AND DISCUSSION
To the best of our knowledge, this is one of the few
examples [18,19] in which cross-Aldol condensation of
ketones with aldehydes, is carried out at room temperature
to give enones. We found that CH3CN is more effective
solvent in terms of yields than other solvents tested such
as CHCl3, THF and EtOH. The minimum amount of
iodine required to get maximum yields of the products is
39.5 mmol% with respect to the aldehydes (0.79 mmol of
iodine is necessary for 2 mmol of an aldehyde along with
one mmol of hetero ketone) (Scheme 1).
Firstly, the reaction of benzaldehyde (2a; 10 mmol)
with 1-carbethoxy-4-piperidone (1; 5 mmol) was chosen
as the model reaction to detect whether the use of iodine
was efficient and to investigate the optimized conditions.
The reaction was found to be complete at room
temperature in 6 hours to give the desired product in 81%
yield. In the absence of any catalyst, the product α,α'-
Recently the preparation of products of the type of the
title compounds has been reported [16] using FeCl3·6H2O
as catalyst in an ionic liquid medium at 80 °C. Even
though SmI3 has been used to synthesize α,α'-
bis(substituted benzylidene)cyclopentanones at room
temperature, the required products can only be obtained
dibenzylidene-1-carbethoxy-4-piperidone
(3a)
was
obtained in a very low yield (9%) even after stirring for 2
days.

580
M. A. Ameen and E. Kh. Ahmed
Vol 45
Scheme 1
olefinic proton in all substitutents causes strong
enhancement to the methylene protons, whereas little
effect was noted on the aryl protons.
In conclusion, we have achieved a general and efficient
synthesis of α,α'-bis(substituted benzylidene)-1-carbeth-
oxy-4-piperidone at room temperature using iodine as a
catalyst. The scope and generality of the present method
makes it an attractive addition to the existing
methodologies in the literature.
H
H
O
O
I2
Ar
Ar
ArCHO
+
CH3CN, r.t.
N
N
2
CO2Et
CO2Et
3
1
Based on the results obtained above, we turned our
attentions to apply the methodology to other derivatives.
Several aromatic aldehydes were successfully reacted
with the heterocyclic ketone and found that in all cases,
the reactions proceeded rapidly at room temperature and
complete conversion was observed with the amount of
iodine tested to afford the corresponding α,α'-
dibenzylidene-1-carbethoxy-4-piperidone derivatives in
81–96% yield. Thus the yields were excellent, including
the heteroaromatic aldehyde thiophene-2-carbaldehyde. It
seems that the effect of substituted groups on the aromatic
aldehydes is not very strong; both the electron-donating
[Me, MeO, N(CH3)2] and electron-withdrawing (NO2, Cl)
groups worked well, showing little distinction. The
purifications of these compounds were easily performed
by simple filtration and washing with ethanol.
It is important to note that the cross-Aldol reaction of
aliphatic aldehydes with the ketone (Table 1, entry 8) also
proceeded cleanly to give the corresponding di-Aldol
product in good yield. Under the present conditions, all
reactions were clean and free from any by-products,
whereas, product mixtures were normally observed in
classical reaction conditions [20]. The advantages of the
present protocol are mild reaction conditions, greater
efficiency, shorter reaction times, high yields of products,
and use of inexpensive reagents.
EXPERIMENTAL
All the aldehydes, I2 and acetonitrile were available
commercially. 1-carbethoxy-4-piperidone was obtained from
Merk. Melting points were determined on a Boetius melting
point apparatus. Elemental analyses were performed on a Carlo
1
Erba CHN-S Elemental Analyzer 1108. The H NMR spectra
were obtained using a Bruker AC 300 instrument (1H: 200
MHz). The δ-values are given in ppm, and the internal standard
was tetramethylsilane. Mass spectra were obtained on a Perkin-
Elmer SCIEX API-300 spectrometer (by ion spray using heated
nebulizer). The IR spectra were recorded on a Nicolet 250 FT-IR
spectrophotometer on potassium bromide pellets.
General procedures for the synthesis of α,α'-bis-
(substituted benzylidene)-1-carbethoxy-4-piperidone 3a-3j. A
mixture of an aldehyde (2 mmol), 1-carbethoxy-4-piperidone
(0.17 g, 1 mmol) and iodine (100 mg, 0.79 mmol) in CH3CN (10
mL) was stirred for 6-12 h under N2 atmosphere (the reaction was
monitored by TLC analysis). After completion of the reaction the
solvent was removed under vacuum and the residue was extracted
with EtOAc. The EtOAc extract was washed with a solution of
sodium thiosulfate (2 × 10 mL) and subsequently with water (3 ×
10 mL) and dried over anhydrous Na2SO4. Evaporation of the
solvent under reduced pressure yielded a solid, which was
crystallized from EtOH or MeOH to afford the pure compound.
α,α'-Dibenzylidene-1-carbethoxy-4-piperidone (3a). This
compound was obtained as pale yellow crystals (methyl
alcohol), ir: 3075 (CH SP2), 2978 (CH SP3), 1700 (C=O ester),
It is important to point out that the reaction produces
only one diastereomer as indicated in Scheme 1. The H
NMR proved the presence of olefinic-H proton affected
by the carbonyl group (see the Experimental Section),
since this proton appeared deshielded in the H NMR
1
1
1619 (C=O), 1583 (C=C) cm-1; H nmr (200 MHz, CDCl3): δ
1.14 (t, 3H, COOCH2CH3), 4.11 (q, 2 H, COOCH2CH3), 4.82 (s,
4 H, H-2,6), 7.31-7.42 (m, 10 H, ArH), 7.86 (s, 2 H, 2 C=CH);
ms: m/z 347 [M+], 318, 274. Anal. Calcd. For C22H21NO3: C,
76.06; H, 6.09; N, 4.03. Found: C, 76.01; H, 6.02; N, 3.93.
1
spectra of 3a-j at δ > 7.60. NOE experiments helped to
confirm the proposed structure since irradiation of the
Table 1
Synthesis of α,α'-bis(substituted benzylidene)-1-carbethoxy-4-piperidone catalyzed by molecular iodine.
Entry
Ar
Time (h)
Product
Color
Mp. (°C)
Yield (%)
1
2
C6H5
6
10
8
3a
3b
3c
3d
3e
3f
Pale Yellow
Yellow
152-153
141-142
271-272
162-163
117-118
182-183
198-199
134-135
167-168
171-172
81
96
93
92
93
87
93
92
96
92
p-ClC6H4
3
p-HOC6H4
p-MeOC6H4
o-MeOC6H4
p-NO2C6H4
2-thienyl
Orange
4
12
12
11
9
Pale Yellow
Yellow
5
6
Yellow
7
3g
3h
3i
Orange
8
n-heptyl
7
Pale Yellow
Yellow
9
p-MeC6H4
p-Me2NC6H4
6
10
9
3j
Orange

Mar-Apr 2008 Iodine Catalyzed Synthesis of α,α'-Bis(Substituted Benzylidene)-1-Carbethoxy-4-Piperidone
581
290. Anal. Calcd for C22H37NO3: C, 72.69; H, 10.26; N, 3.85.
Found: C, 72.52; H, 10.11; N, 3.71.
α,α'-Bis(p-chlorobenzylidene)-1-carbethoxy-4-piperidone
(3b). This compound was obtained as yellow crystals (ethyl
1
alcohol), ir: 3084, 2962, 1705, 1629, 1578 cm-1; H nmr (200
α,α'-Bis(p-methylbenzylidene)-1-carbethoxy-4-piperidone
(3i). This compound was obtained as yellow crystals (ethyl
MHz, CDCl3): δ 1.12 (t, 3 H, COOCH2CH3), 4.06 (q, 2 H,
COOCH2CH3), 4.76 (s, 4 H, H-2,6), 7.32-7.39 (m, 8 H, ArH),
7.72 (s, 2 H, 2 C=CH); ms: m/z 415 [M+], 386, 342, 151, 115.
Anal. Calcd for C22H19Cl2NO3: C, 63.47; H, 4.60; Cl, 17.03; N,
3.36. Found: C, 63.36; H, 4.51; Cl, 16.92; N, 3.24.
1
alcohol), ir: 3085, 2985, 1702, 1634, 1565 cm-1; H nmr (200
MHz, CDCl3)::δ 1.09 (t, 3 H, COOCH2CH3), 2.39 (s, 6 H, 2
CH3). 4.12 (q, 2 H, COOCH2CH3), 4.67 (s, 4 H, H-2,6), 7.30-
7.48 (m, 8 H, ArH), 7.83 (s, 2 H, 2 C=CH); ms: m/z 375 [M+],
346, 302. Anal. Calcd for C24H25NO3: C, 76.77; H, 6.71; N, 3.73.
Found: C, 76.61; H, 6.55; N, 3.59.
α,α'-Bis(p-hydroxybenzylidene)-1-carbethoxy-4-piperid-
one (3c). This compound was obtained as orange crystals (ethyl
1
alcohol), ir: 3500, 3070, 2985, 1708, 1623, 1586 cm-1; H nmr
α,α'-Bis(p-N,N-dimethylaminobenzylidene)-1-carbethoxy-
4-piperidone (3j). This compound was obtained as orange
crystals (methyl alcohol), ir: 3082, 2987, 1706, 1634, 1575 cm-1;
1H nmr (200 MHz, CDCl3): δ 1.11 (t, 3 H, COOCH2CH3), 3.04
(s, 12 H, 4 NCH3). 4.14 (q, 2 H, COOCH2CH3), 4.71 (s, 4 H, H-
2,6), 7.33-7.48 (m, 8 H, ArH), 7.78 (s, 2 H, 2 C=CH); ms: m/z
433 [M+], 404, 360. Anal. Calcd for C26H31N3O3 (433.56): C,
72.03; H, 7.21; N, 9.69. Found: C, 71.87; H, 7.03; N, 9.51.
(200 MHz, CDCl3): δ 1.14 (t, 3 H, COOCH2CH3), 4.10 (q, 2 H,
COOCH2CH3), 4.77 (s, 4 H, H-2,6), 7.28-7.41 (m, 8 H, ArH),
7.84 (s, 2 H, 2 C=CH); ms: m/z 379 [M+], 350, 306. Anal. Calcd
for C22H21NO5: C, 69.65; H, 5.58; N, 3.69. Found: C, 69.48; H,
5.39; N, 3.42.
α,α'-Bis(p-methoxybenzylidene)-1-carbethoxy-4-piperid-
one (3d). This compound was obtained as pale yellow crystals
(methyl alcohol), ir: 3082, 2987, 1706, 1634, 1575 cm-1; 1H nmr
(200 MHz, CDCl3): δ 1.09 (t, 3 H, COOCH2CH3), 3.80 (s, 6 H, 2
OCH3). 4.13 (q, 2 H, COOCH2CH3), 4.69 (s, 4 H, H-2,6), 7.33-
7.46 (m, 8 H, ArH), 7.81 (s, 2 H, 2 C=CH); ms: m/z 407 [M+],
378, 334. Anal. Calcd for C24H25NO5: C, 70.75; H, 6.18, N, 3.44.
Found: C, 70.64; H, 6.02, N, 3.31.
α,α'-Bis(o-methoxybenzylidene)-1-carbethoxy-4-piperid-
one (3e). This compound was obtained as yellow crystals
(methyl alcohol), ir: 3070, 2985, 1710, 1642, 1574 cm-1; 1H nmr
(200 MHz, CDCl3): δ 1.11 (t, 3 H, COOCH2CH3), 3.71 (s, 6 H, 2
OCH3). 4.12 (q, 2 H, COOCH2CH3), 4.72 (s, 4 H, H-2,6), 7.29-
7.56 (m, 8 H, ArH), 7.85 (s, 2 H, 2 C=CH); ms: m/z 407 [M+],
378, 334. Anal. Calcd for C24H25NO5: C, 70.75; H, 6.18, N, 3.44.
Found: C, 70.63; H, 6.01, N, 3.31.
REFERENCES AND NOTES
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267.
α,α'-Bis(p-nitrobenzylidene)-1-carbethoxy-4-piperidone
(3f). This compound was obtained as yellow crystals (ethyl
1
alcohol), ir: 3090, 2965, 1706, 1629, 1570 cm-1; H nmr (200
MHz, CDCl3): δ 1.12 (t, 3 H, COOCH2CH3), 4.06 (q, 2 H,
COOCH2CH3), 4.74 (s, 4 H, H-2,6), 7.30-7.39 (m, 8 H, ArH), 7.69
(s, 2 H, 2 C=CH); ms: m/z 437 [M+], 408, 364.. Anal. Calcd for
C22H19N3O7 C, 60.41; H, 4.38; N, 9.61. Found: C, 60.28; H, 4.21;
N, 9.41.
α,α'-Bis(thiophene-2-ylmethylene)-1-carbethoxy-4-piper-
idone (3g). This compound was obtained as orange crystals
(methyl alcohol), ir: 3120, 2990, 1711, 1635, 1575 cm-1; 1H nmr
(200 MHz, CDCl3): δ 1.11 (t, 3 H, COOCH2CH3), 4.08 (q, 2 H,
COOCH2CH3), 4.75 (s, 4 H, H-2,6), 7.16 (t, J = 3.7 Hz, 2 H),
7.39 (d, J = 2.5 Hz, 2 H), 7.54 (d, J = 4.6 Hz, 2 H), 7.79 (s, 2 H,
2 C=CH). ms: m/z 359 [M+], 330, 386. Anal. Calcd for
C18H17NO3S2: C, 60.14; H, 4.77; N, 3.90. Found: C, 60.01; H,
4.62; N, 3.73.
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Changtao Qian, Synthesis 2004, 3060-3064
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Molecular Catalysis A: Chemic, 2006, 247, 182.
α,α'-Dioctylidine-1-carbethoxy-4-piperidone (3h). This
compound was obtained as pale yellow crystals (ethyl alcohol),
1
ir: 2970, 1708, 1639, 1575 cm-1; H nmr (200 MHz, CDCl3): δ
1.08 (br. t, 6 H, 2 CH3), 1.11 (t, 3 H, COOCH2CH3), 1.14-1.60
(m, 20 H, 10 CH2), 4.06 (q, 2 H, COOCH2CH3), 4.74 (s, 4 H, H-
2,6), 7.60 (t, 2 H, J = 8 Hz, 2 C=CH); ms: m/z 363 [M+], 334,
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Ogawa, M. J. Org. Chem. 1987, 52, 2239.