Lewis acids as mild and effective catalysts for the synthesis of 3,5-bis[(hetero)arylidene]piperidin-4-ones

Article abstract of DOI:10.1002/hlca.201000005

The aldol-crotonic condensation reactions of N-alkyl- and NH-piperidin-4-one derivatives with (hetero)aromatic aldehydes promoted by Lewis acids or bases were examined. This comparative study has revealed three effective catalytic systems based on Lewis a

Full text of DOI:10.1002/hlca.201000005

1990
Helvetica Chimica Acta – Vol. 93 (2010)
Lewis Acids as Mild and Effective Catalysts for the Synthesis of
3,5-Bis[(hetero)arylidene]piperidin-4-ones
by Evgeniya Leonova, Mihail Makarov, Zinaida Klemenkova, and Irina Odinets*
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova str., Moscow 119991, Russia (phone: þ 74991356166; fax: þ 74991355085;
e-mail: odinets@ineos.ac.ru)
The aldol-crotonic condensation reactions of N-alkyl- and NH-piperidin-4-one derivatives with
(hetero)aromatic aldehydes promoted by Lewis acids or bases were examined. This comparative study
has revealed three effective catalytic systems based on Lewis acids, i.e., LiClO4 and MgBr2 (in the
presence of tertiary amine), and BF3 · Et2O, for the synthesis of N-alkyl-substituted 3,5-bis(heteroar-
ylidene)piperidin-4-ones, including those bearing acid- or base-labile groups both in the (hetero)ar-
omatic groups and in the alkyl substituent at the N-atom. The highest reaction rate was observed for
LiClO4-mediated synthesis. Both MgBr2- and LiClO4-mediated syntheses were inefficient in the case of
NH-piperidin-4-one, while BF3 · Et2O provided the final compounds in high yields. This catalyst is
especially advantageous as it allows simultaneous condensation and deprotection in the case of O-
protected piperidin-4-one.
1. Introduction. – In the last decade, derivatives of bis(heteroarylidene)cycloalka-
nones and the related bis(heteroarylidene)piperidin-4-ones attracted remarkable
interest due to their high and diverse biological activities such as antiviral, antitumor,
radical-scavenging, and antimutagen properties [1], as well as their application as
ligands for the construction of coordination polymers [2]. Regarding the bioactivities,
the conjugated 1,5-di(hetero)aryl-3-oxopenta-1,4-dienyl pharmacophore group in
these compounds is assumed to interact with cellular constituents, since the nature of
the (hetero)aryl substituents and those attached to the heterocyclic N-atom in the
related piperidinone derivatives affects their potency.
The general synthetic approach to these cross-conjugated dienones is based on the
crossed aldol-crotonic condensation of (hetero)aromatic aldehydes with alkanones or
piperidin-4-ones, respectively, which proceeds under the action of strong bases (NaOH/
EtOH) or protic acids (gaseous HCl/AcOH). Therefore, if the starting substrates bear
acid- or base-labile substituents such as CN, P(O)(OR)2, COOR, some heterocyclic
moieties (e.g., furanyl) etc., the use of the above conditions would be unsuitable. Thus,
several improvements have been achieved in the synthesis of bis(heteroarylidene)cy-
cloalkanones by application of KF-supported reagents under microwave or ultrasonic
irradiation [3], Pd/C-mediated synthesis [4], and Lewis acid catalysis including Me3SiI
(TMSI) [5], Yb(OTf)3 [6], LiClO4 in the presence of amines [7], and MgBr2 · Et2O/
MeOH/Et3N [8], as well as SmI3 [9] and FeCl3 [10] in ionic liquids. Strangely enough,
the data concerning improvements of the synthesis of 3,5-bis[(hetero)arylidene]piper-
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 93 (2010)
1991
idin-4-ones, which would be more advantageous for further modifications, are
restricted to only one report on LiClO4-mediated condensation of NH-piperidin-
4-one with aromatic aldehydes and thiophene-2-carbaldehyde in the presence of
Et2NH and under solvent-free conditions [7]. The reported yields of the target
NH-bis[(hetero)arylidene]piperidin-4-ones, achieved over 4 h, were in the range of
90 – 96%. However, in our hands, the attempt to use this procedure in the case of
condensation of piperidin-4-one with 4-fluorobenzaldehyde gave less than 15% yield of
the final product.
Therefore, to improve the synthesis of 3,5-bis[(hetero)arylidene]piperidin-4-ones
bearing acid- or base-labile groups and to elaborate mild, effective, and reproducible
procedures for their synthesis, it seems reasonable to undertake a detailed study on the
applicability of Lewis acids and bases for the condensation of piperidin-4-one
derivatives with (hetero)aromatic aldehydes. Here, we report the results of such
comparative investigations, which revealed three effective catalytic systems based on
Lewis acids.
2. Results and Discussion. – To estimate the activity of Lewis acids and bases as
catalysts for aldol-crotonic condensation of piperidin-4-one derivatives with (hetero)-
aromatic aldehydes, we tested catalytic systems based on Lewis acids such as lithium
perchlorate (LiClO4/TMSNEt2), magnesium bromide (MgBr2 · Et2O/MeOH/Et3N),
and Yb(OTf)3, which provided high yields in the synthesis of 3,5-bis[(hetero)aryl-
idene]cycloalkanones, as well as BF3 · Et2O, silica-supported H2SO4 and trihexyl(te-
tradecyl)phosphonium chloride. As Lewis bases, Bu3P and Ph3P, useful as catalysts for
the Morita – Baylis – Hillman reaction [11], intramolecular aldol condensations [12],
and others, were also used. As a model, the reaction of N-methylpiperidin-4-one (1a)
with 4-fluorobenzaldehyde was chosen as it allowed easy monitoring of the reaction
course by 19F-NMR spectroscopy. In Table 1, the results obtained for this reaction are
collected.
Silica-supported H2SO4 significantly accelerates the reaction only when used in
excess under solvent-free conditions (Table 1, Entries 1 and 2), while its application in a
catalytic amount (20 mol-%) inhibited the reaction. Moreover, the condensation did
not proceed when reactions using this catalyst were performed in CH2Cl2, MeCN, or
EtOH solution, typically used in combination with silica-supported H2SO4. It should be
noted that the sequence of reactant application on the catalyst played a crucial role: the
product was formed only when the aldehyde was applied first.
In general, the catalysts, which provided excellent yields in the case of
bis[(hetero)arylidene]cycloalkanone synthesis, exhibited lower activity for the con-
densation of 1a. Thus, under otherwise equal conditions, the Yb(OTf)3-catalyzed
reaction afforded 2a in low yields even at prolonged reaction time (Table 1, Entries 3
and 4). Similarly, the catalytic system MgBr2 · Et2O/MeOH/Et3N led to a moderate
yield of 37% (63% according to the 19F-NMR data) after 4 h, i.e., the period of time
provided more than 90% yields of bis[arylidene]cycloalkanones [8]. However, a longer
reaction time (14 h) increased the yield up to 86% (97% according to the 19F-NMR
data; Table 1, Entries 5 and 6). More comparative results were achieved using the
LiClO4-based system, which provided 60% isolated yield of 2a (91% according to the
19F-NMR data) already after 4 h.

1992
Helvetica Chimica Acta – Vol. 93 (2010)
Table 1. Condensation of N-Methylpiperidin-4-one (1a) with 4-Fluorobenzaldehyde in the Presence of
Lewis Acids and Bases
Entry
Catalytic system
Solvent
Time [h]
Yield [%]a)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H2SO4/SiO2 (6 equiv.)b)
H2SO4/SiO2 (6 equiv.)b)
Yb(OTf)3 (20 mol-%)
none
none
none
none
none
none
none
BF3 · Et2O
THF
CH2Cl2
MeCN
MeCN
MeCN
CH2Cl2
MeCN
MeCN
4
58
4
14
4
14
4
4
48
48
48
4
5 (12)
55
10 (22)
15 (34)
37 (63)
86 (97)
60 (91)
77c)
Yb(OTf)3 (20 mol-%)
MgBr2 · Et2O (1 equiv.)/MeOH/Et3N (2 equiv.)
MgBr2 · Et2O (1 equiv.)/MeOH/Et3N (2 equiv.)
LiClO4 (1 equiv.)/TMSNEt2(2 equiv.)
BF3 · Et2O (9 equiv.)
BF3 · Et2O (4 equiv.)
BF3 · Et2O (4 equiv.)
13c)
51c)
BF3 · Et2O (4 equiv.)
66c)
BF3 · Et2O (4 equiv.)d)
38 (56)c)
BF3 · Et2O (4 equiv.)d)
9
67c)
(C6H13)3(C14H29)PþClꢀ (20 mol-%)
Ph3P (20 mol-%)
24
24
24
0
0
0
Bu3P (20 mol-%)
a) Yield of isolated 2a (the yield according to the 19F-NMR data is shown in parentheses). b) w/w
Relative to N-methylpiperidin-4-one (1a). c) The product 2a was isolated as HBF4 salt. d) At 808.
Rather good yields were achieved also in the presence of BF3 · Et2O. As
condensation results in the formation of two H2O molecules, application of more than
2 equiv. of BF3 · Et2O was necessary. Moreover, the generation of tetrafluoroboronic
acid resulted in the final product as a BF4 salt. Therefore, 4 mol-equiv. of BF3 · Et2O
were found to be optimal, and this reaction proceeded smoothly in solvents such as
CH2Cl2 and MeCN, while THF inhibited the reaction (Table 1, Entries 9 – 11). In this
context, MeCN is the solvent of choice, as it significantly shortens the reaction time
when the reaction is performed at reflux. It also facilitates the workup due to low
solubility of HBF4 salt formed. The latter can be isolated via simple filtration. Finally,
the reaction could be successfully performed in BF3 · Et2O as a sole solvent (ca. 9
equiv.), and just in this case the highest reaction rate was observed (Table 1, Entry 8).
Neither phosphonium salts ((C6H13)3(C14H29)PþClꢀ) nor phosphines promoted the
reaction. The phosphines underwent rapid oxidation to the corresponding phosphine
oxides even under an inert atmosphere, apparently due to the reaction with aromatic
aldehydes similar to results reported in the literature [13]. This study has revealed three
catalytic systems of comparative potency, namely LiClO4/TMSNEt2 (Method A),
MgBr2 · Et2O/MeOH/Et3N (Method B), and BF3 · Et2O (Method C: 9 equiv.; Method

Helvetica Chimica Acta – Vol. 93 (2010)
1993
D: 4 equiv of BF3 · Et2O in MeCN), which can be successfully used for aldol-crotonic
condensation of 1a. In the above model reaction, the systems provided excellent yields
of the crude product 2a according to the 19F-NMR data; however, loss of the compound
was observed during the purification procedures leading to 2a of pharmaceutical grade.
To our surprise, both MgBr2- and LiClO4-mediated syntheses were inefficient in the
case of NH-piperidin-4-one (1b) used as hydrochloride monohydrate (Table 2, Entries
1 – 3). Moreover, we failed to obtain 3,5-bis(4-fluorobenzylidene)piperidin-4-one (3a)
in a reasonable yield using Et2NH instead of Me3SiNEt2 in LiClO4-mediated synthesis
(Table 2, Entry 3). These data are in contrast to the reported procedure which led to
more than 90% yield in the case of other aromatic aldehydes [8]. Better yields of 3a
were obtained using BF3 · Et2O either in combination with K2CO3 in MeCN solution or
in excess (6 equiv.; 75 and 98% for the crude product, resp.; Table 2, Entries 4 and 5).
Note that these reactions were performed at room temperature as heating accelerated
mostly the side processes. Furthermore, BF3 · Et2O was especially advantageous for the
condensation of the O-protected piperidin-4-one, 2,3-dioxa-8-azaspiro[4.5]decane (1c),
as it provided a reasonable reaction rate at 808 along with simultaneous deprotection of
the ketone group. It should be emphasized that such deprotection usually required
application of strong acidic conditions [14] which affect adversely the labile groups
(Table 2, Entry 6).
Application of the developed procedures for the condensation of 1a and 1b with
other aromatic and heteroaromatic aldehydes (Scheme) afforded the corresponding N-
methyl- or NH-3,5-bis[(hetero)arylidene]piperidin-4-ones 2b – 2f, and 3b in good to
high yields of isolated products. However, the yield of N-methyl-bis(pyridin-2-
ylmethylidene)piperidin-4-one (2g) did not exceed 15%, when condensations of 1a
with pyridine-2-carbaldehyde were performed using the above mentioned systems.
Moreover, we failed to obtain NH-bis(pyridin-2-ylmethylidene)piperidin-4-one. The
Table 2. Condensation of NH-Piperidin-4-one 1b and Its O-Protected Form 1c with 4-Fluorobenzalde-
hyde in the Presence of Different Catalysts
Entry Substrate Catalytic system
Solvent Time [h] Yield [%]a)
1
2
3
4
5
6
1b
1b
1b
1b
1b
1c
MgBr2 · Et2O (1 equiv.)/MeOH/Et3N (2 equiv.) none
14
4
4
8
LiClO4 (1 equiv.)/TMSNEt2 (2 equiv.)
LiClO4 (1 equiv.)/HNEt2 (2 equiv.)
K2CO3/BF3 · Et2O (4 equiv.)b)
BF3 · Et2O (6 equiv.)b)
none
none
MeCN 24
MeCN 24
MeCN 14
traces
13
34 (75)
84 (98)
55
BF3 · Et2O (4 equiv.)b)c)
a) Yield of isolated 3a (the yield according to the 19F-NMR data is shown in parentheses). b) The product
3a was isolated as HBF4 salt. c) At 808.

1994
Helvetica Chimica Acta – Vol. 93 (2010)
condensations of 1a and 1b with pyridine-2-carbaldehyde resulted mostly in complex
mixtures of side-products where 1,2-di(pyridin-2-yl)ethane-1,2-dione was dominating.
Note that such formal dimerization of pyridine-2-carbaldehyde in the presence of
Lewis acids to afford the above mentioned 1,2-dione was reported in literature [15]. It
should be noted that, if BF3 · Et2O was used as a catalyst and at least one of the
reactants possesses poor solubility in this medium (e.g., 4-nitrobenzaldehyde), it was
more preferable to perform the reaction via Method D with MeCN as solvent.
Scheme
In general, the yields of 3,5-bis[(hetero)arylidene]-N-methylpiperidin-4-ones 2a –
2g depend both on the nature of the aldehyde and the catalytic system used. Thus, for
MgBr2-mediated synthesis (Method B) the yields decrease in the series 2-ThCHO > 4-
FꢀC6H4CHO > 4-NCꢀC6H4CHO > 3-PyCHO. For reactions in the presence of
LiClO4 (Method A), the yield of the fluorinated compound 2a sufficiently exceeded
those for 2b – 2f which were approximately equal to each other. However, under other
conditions being equal, the reaction in the presence of LiClO4 proceeds faster than that
using MgBr2 and the comparable yields of the same product were achieved over 4 h
(LiClO4) vs. 14 h (MgBr2).
When BF3 · Et2O was used in the condensation according to the Scheme, the yields
of 2a – 2f decreased in a series of aldehydes as follows: 4-Me2NꢀC6H4CHO > 4-
O2NꢀC6H4CHO > 4-FꢀC6H4CHO > 4-NCꢀC6H4CHO > 3-PyCHO > 2-ThCHO. In
other words, no exact dependence on the electronic properties of the (hetero)aryl
residue in the aldehyde was observed. When BF3 · Et2O was used as a solvent, the
reaction rate at room temperature was even higher compared with that for the LiClO4-
mediated reaction, but substantially decreased when an additional co-solvent was used.
It is also a noteworthy observation of us that the CN group of 4-CNꢀC6H4CHO
remained intact in the condensation with 1a (compound 2d) and NH-piperidin-4-one
1b (compound 3b) in the presence of the above-mentioned Lewis acids. It should be
underlined that, under typical reaction conditions (gaseous HCl/AcOH), the reaction
of 1b with 4-NCꢀC6H4CHO is accompanied by hydrolysis of the CN functionality to
yield the carbamoyl-substituted product (see Exper. Part).
Recently, we demonstrated that introduction of the alkyl phosphonate moiety at the
N-atom of 3,5-bis[(hetero)arylidene]piperidin-4-ones resulted in a dramatic increase

Helvetica Chimica Acta – Vol. 93 (2010)
1995
Table 3. Condensation of Diethyl 2-(4-Oxopiperidin-1-yl)ethylphosphonate 1d and Its O-Protected form
1e with 4-Fluorobenzaldehyde in the Presence of Different Catalysts
Entry Substrate Catalytic system
Solvent
Time [h] Yield [%]a)
1
2
3
4
5
6
7
8
1d
1d
1d
1d
1d
1d
1e
1e
MgBr2 · Et2O (1 equiv.)/MeOH/Et3N (2 equiv.) none
14
4
96
30 (34)
30 (32)
33 (52)
64 (86)
18
33
16 (30)
56 (89)
LiClO4 (1 equiv.)/TMSNEt2 (2 equiv.)
BF3 · Et2O (6 equiv.)
none
MeCN
BF3 · Et2O (9 equiv.)
BF3 · Et2O 96
MgBr2 · Et2O (1 equiv.)/MeOH/Et3N (2 equiv.) none
96
96
96
LiClO4 (1 equiv.)/TMSNEt2 (2 equiv.)
BF3 · Et2O (6 equiv.)
none
MeCN
BF3 · Et2O (9 equiv.)
BF3 · Et2O 96
a) Yield of isolated 4 (the yield according to the 19F-NMR data is shown in parentheses).
of their cytotoxicity and bioavailability [16][17]. However, the syntheses of such
phosphorylated compounds via the condensation of w-aminophosphonates bearing
piperidinone or a protected piperidinone moiety with aromatic aldehydes under the
action of protic acids or strong bases resulted in rather low yields (typically in the range
of 27 – 40%) of the products due to the presence of hydrolytically unstable ester groups
at the P-atom [17]. Therefore, we tested the Lewis acid-mediated synthesis for aldol-
crotonic condensation using b-aminophosphonates 1d, 1e and 4-fluorobenzaldehyde as
model substrate (Table 3).
Similar to the reaction of NH-piperidin-4-one (1b), both MgBr2- and LiClO4-
mediated syntheses provided quite low yields (ca. 30%) of the phosphorylated product
4 independent of the reaction time. When BF3 · Et2O was used, the reaction was rather
sluggish in MeCN but provided the desired product 4 in good yields in the case of both
phosphorylated substrates 1d and 1e using this Lewis acid in excess (Table 3, Entries 4
and 8). According the 31P-NMR spectroscopy of the reaction mixtures, the hydrolysis
of the ester groups at the P-atom was not observed, and the loss of product during the
isolation procedure was connected with the typical retention of the phosphonates on
silica gel.
3. Conclusions. – Aldol-crotonic condensation under the catalytic action of Lewis
acids, present an effective approach to 3,5-bis[(hetero)arylidene]piperidin-4-ones
including those bearing acid- or basic-labile groups. The catalytic system of choice
depends both on the nature of the aldehyde and starting piperidone. LiClO4- and
MgBr2-mediated syntheses are especially advantageous for the condensation of
(hetero)aromatic aldehydes with N-alkylpiperidin-4-ones, while application of
BF3 · Et2O is preferred in the case of NH- and N-(w-phosphorylalkyl)piperidin-4-ones.

1996
Helvetica Chimica Acta – Vol. 93 (2010)
Moreover, the usage of BF3 · Et2O allows simultaneous condensation and deprotection
of O-protected piperidin-4-ones along with easy isolation of the final products as BF4
salts.
Experimental Part
1. General. All commercial reagents were used as purchased without further purification, all solvents
were reagent grade. Diethyl 2-(4-oxopiperidin-1-yl)ethylphosphonate (1d) and diethyl [2-(1,4-dioxa-8-
azaspiro[4.5]dec-8-yl)ethyl]phosphonate (1e) were obtained according to known procedures [17]. The
mixtures were stirred magnetically in round-bottomed flasks, and the reaction course was monitored by
19F- or 31P-NMR technique, or by TLC as appropriate. M.p.: MPA 120 EZ-Melt automated melting point
apparatus; uncorrected. Anal. TLC: Merck silica gel 60 F254 plates; visualization by UV light. IR Spectra:
in KBr pellets on a Fourier-transform spectrometer Magna-IR750 (Nicolet), resolution 2 cmꢀ1, 128 scans.
NMR Spectra: Bruker AMX-400 spectrometer (1H, 400.13; 19F, 376.3; 31P, 161.97; and 13C, 100.61 MHz),
using residual 1H-signals and the 13C-signal of a deuterated solvent as an internal standard rel. to TMS,
and CF3COOH (19F) and H3PO4 (31P) as an external standard; the 13C-NMR spectra were recorded using
the JMODECHO mode; the signals for the C-atom bearing odd and even numbers of H-atoms have
opposite polarities; C-atom numbering used in the 13C-spectra of 3,5-bis(benzylidene)piperidin-4-ones is
shown in Table 1.
2. Synthesis of 3,5-Bis[(hetero)arylidene]piperidin-4-ones in the Presence of Lewis Acids (General
Procedures): Method A. To a mixture of anh. LiClO4 (1 mmol) and TMSNEt2 (2 mmol), the
corresponding aldehyde (2 mmol) and piperidin-4-one 1a – 1e (1 mmol) were added at r.t., and the
mixture was stirred under these conditions until the consumption of the starting reactants (monitoring by
NMR or TLC as appropriate). Then, H2O (10 ml) was added to the mixture, followed by stirring for
30 min. The precipitate was filtered off and recrystallized from AcOEt or EtOH to afford the final 3,5-
bis[(hetero)arylidene]piperidin-4-one.
Method B. The corresponding piperidin-4-one 1a – 1e (1 mmol) was added to a mixture of the desired
aldehyde (2 mmol), MeOH (1 mmol), MgBr2 · OEt2 (1 mmol), and Et3N (2 mmol), and the resulting
mixture was stirred at r.t. until the consumption of the starting reactants (monitoring by NMR or TLC
when appropriate). Further workup was similar to that described in Method A.
Method C. A mixture of the corresponding piperidin-4-one 1a – 1e (1 mmol), aldehyde (2 mmol),
and BF3 · Et2O (9 mmol) was stirred at r.t. The course of the reaction was monitored by TLC or NMR as
appropriate. After completion of the reaction, the mixture was dissolved in hot EtOH. The soln. obtained
was allowed to cool to r.t. The precipitate was filtered off and air-dried to give the final product as a BF4
salt.
Method D. BF3 · Et2O (4 mmol) was added to a soln. of the corresponding aldehyde and piperidin-4-
one 1a – e (1 mmol) in 1 ml of MeCN. Then, the mixture was refluxed over an appropriate period of time
(Tables 1 – 3) or under ambient conditions in the case of compound 4. After chilling of the mixture to
ambient temp., the precipitate formed was filtered off and recrystallized from EtOH to give the final 3,5-
bis[(hetero)arylidene]piperidin-4-one as a BF4 salt.
The structures of the known 3,5-bis[(hetero)arylidene]piperidin-4-ones 2a [18], 2c [19], 2e [20], 2f
[21], and 3a [22] obtained via Methods A and B as free bases were confirmed by the multinuclear NMR
spectra. Their physicochemical constants fit well the available literature data. By Methods C and D, the
products 2a, 2b, 2d, 2f, and 3a were isolated as HBF4 salts forming stable hydrates (see below). In the case
of (3E,5E)-bis[4-(dimethylamino)benzylidene]-1-methylpiperidin-4-one (2c), diethyl (3E,5E)-bis[(4-
fluorobenzylidene)-4-oxopiperidin-1-yl]methylphosphonate (4), and (3E,5E)-bis(pyridin-2-ylmethyli-
dene)-1-methylpiperidin-4-one (2g), their HBF4 salts were converted to the corresponding free bases
via treatment with Na2CO3 soln.
Compound 2c and its BF4 salt represented a dark orange solid, all other products were isolated as
yellow solids.
(3E,5E)-3,5-Bis(4-fluorobenzylidene)-1-methyl-4-oxopiperidinium Tetrafluoroborate (2a · HBF4).
M.p. 220 – 2248. IR (KBr): 3081w, 1667w (C¼O), 1610m (C¼C), 1599s, 1588m, 1512s, 1470w, 1301w,

Helvetica Chimica Acta – Vol. 93 (2010)
1997
1281w, 1243m, 1200m, 1163s, 1106s, 1056s, 1030s, 981w, 844w, 836m, 530m, 495m. 1H-NMR ((D6)DMSO):
3.04 (s, MeN); 4.68 (s, 2 CH2N); 7.40 (dd, 3J(H,F) ¼ 3J(H,H) ¼ 8.8, 4 H); 7.65 (dd, 4J(H,F) ¼ 5.7,
3J(H,H) ¼ 8.4, 4 H); 7.92 (s, 2 HꢀC¼); 10.30 (s, HBF4). 13C-NMR ((D6)DMSO): 42.98 (MeN); 53.92
(C(2), C(6)); 116.45 (d, 2J(C,F) ¼ 21.6, C(10), C(10’), C(12), C(12’)); 127.17 (C(3), C(5)); 130.42 (C(8),
3
1
C(8’)); 133.69 (d, J(C,F) ¼ 8.6, C(9), C(9’), C(13), C(13’)); 139.07 (C(7), C(7’)); 163.36 (d, J(C,F) ¼
249.8, C(11), C(11’)); 181.78 (C(4)). 19F-NMR ((D6)DMSO): ꢀ 108.84; ꢀ 147.98. Anal. calc. for
C20H17F2NO · HBF4 (422.17): C 58.14, H 4.39, N 3.39; found: C 58.11, H 4.21, N 3.21.
(3E,5E)-1-Methyl-3,5-bis(4-nitrobenzylidene)-4-oxopiperidinium Tetrafluoroborate (2b · HBF4).
Yield 80% (Method D). M.p. 233 – 2358. IR (KBr): 3435m, 3188w, 1675w (C¼O), 1615m (C¼C),
1598m, 1518s, 1347s, 1274m, 1200w, 1175m, 1119m, 1084m, 1058m, 856w. 1H-NMR ((D6)DMSO): 2.88 (s,
3
3
MeN); 4.51 (s, 2 CH2N); 7.81 (d, J(H,H) ¼ 8.8, 4 arom. H); 7.95 (s, 2 HꢀC¼); 8.34 (d, J(H,H) ¼ 8.8,
4 H). 13C-NMR ((D6)DMSO): 42.96 (MeN); 53.83 (C(2), C(6)); 124.16 (C(9), C(9’), C(13), C(13’));
130.24 (C(3), C(5)); 132.08 (C(10), C(10’), C(12), C(12’)); 138.08 (C(8), C(8’)); 140.16 (C(11), C(11’));
148.11 (C(7), C(7’)); 181.62 (C(4)). 19F-NMR ((D6)DMSO): ꢀ 148.18. Anal. calc. for C20H17N3O5 ·
HBF4 · 0.75 H3BO3 (513.64): C 46.78, H 3.97, N 8.18; found: C 46.60, H 3.51, N 7.96.
(3E,5E)-3,5-Bis[4-(dimethylamino)benzylidene]-1-methylpiperidin-4-one (2c). The compound was
isolated in 91% yield as the corresponding BF4 salt via the Method D. After isolation, this hygroscopic
product was immediately converted to the corresponding free base 2c in 87% yield by the treatment with
Na2CO3 soln. The precipitate of free base of 2c was filtered off and dried over P2O5 under vacuum
(20 mm Hg, 2 h).
4,4’-[(1-Methyl-4-oxopiperidine-3,5-diylidene)di(E)methylylidene]dibenzonitrile (2d).Yield 47%
(Method A), 60% (Method B). M.p. > 2308 (dec.). Recrystallized from CHCl3/MeOH. IR (KBr):
2946w, 2228s (CN); 1673m (C¼O), 1616s (C¼C), 1604m, 1584, 1501w, 1411w, 1331w, 1270s, 1184s, 1171s,
1127w, 1056w, 987w, 837m, 559s. 1H-NMR ((D6)DMSO): 2.46 (s, MeN); 3.72 (s, 2 CH2N); 7.47 (d,
3J(H,H) ¼ 8.2, 4 H); 7.72 (d, 3J(H,H) ¼ 8.4, 4 H); 7.76 (s, 2 CH¼). 13C-NMR ((D6)DMSO): 44.70
(MeN); 55.82 (C(2), C(6)); 111.14 (C(11), C(11’)); 118.24 (CN); 130.70 (C(9), C(9’), C(13), C(13’));
132.18 (C(10), C(10’), C(12), C(12’)); 132.77 (C(7), C(7’)); 135.98 (C(3), C(5)); 139.01 (C(8), C(8’));
186.21 (C(4)). Anal. calc. for C22H17N3O · CHCl3 · MeOH (490.82): C 58.73, H 4.52, N 8.56; found: C
59.12, H 4.59, N 8.74.
(3E,5E)-3,5-Bis(4-cyanobenzylidene)-1-methyl-4-oxopiperidinium Tetrafluoroborate (2d · HBF4).
Yield 74% (Method D). M.p. 268 – 2708. IR (KBr): 3436w, 3140m, 2225m (CN); 1675w (C¼O), 1619s
(C¼C), 1604m, 1586m, 1415w, 1290w, 1272s, 1198w, 1173w, 1083s, 1074s, 1026s, 941w, 833m, 555m.
1H-NMR ((D6)DMSO): 2.99 (s, MeN); 4.66 (s, 2 CH2N); 7.75 (d, 3J(H,H) ¼ 8.3, 4 H); 7.95 (s, 2 HꢀC¼);
8.03 (d, 3J(H,H) ¼ 8.4, 4 H). 13C-NMR ((D6)DMSO): 42.64 (MeN); 53.53 (C(2), C(6)); 112.23 (C(11),
C(11’)); 118.48 (CN); 129.52 (C(9), C(9’), C(13), C(13’)); 131.28 (C(10), C(10’), C(12), C(12’)); 132.70
(C(7), C(7’)); 138.12 (C(3), C(5)); 137.98 (C(8), C(8’)); 181.38 (C(4)). 19F-NMR ((D6)DMSO): ꢀ
148.18. Anal. calc. for C22H17N3O · HBF4 · 0.5 H2O: C 60.55, H 4.13, N 9.63; found: C 61.11, H 3.92, N 9.59.
(3E,5E)-1-Methyl-3,5-bis(thiophen-2-ylmethylidene)piperidin-4-one (2e). Yield 50% (Method A),
90% (Method B), 50% (Method D, 7 d, r.t., isolated as a free base).
(3E,5E)-1-Methyl-3,5-bis(pyridin-3-ylmethylidene)piperidin-4-one (2f). Yield 52% (Method A),
50% (Method B).
(3E,5E)-1-Methyl-4-oxo-3,5-bis(pyridin-3-ylmethylidene)piperidinium Tetrafluoroborate (2f ·
HBF4). Yield 60% (Method D). M.p. 148 – 1588. IR (KBr): 3436m, 3109w, 2922w, 2693m, 1691w
(C¼O), 1635m (C¼C), 1602w, 1552m, 1467m, 1270m, 1211m, 1175s, 1084s, 1060s, 1034s, 980m, 939w,
804w, 767w, 678m, 534m, 522m. 1H-NMR ((D6)DMSO): 3.03 (s, MeN); 4.74 (s, 2 CH2N); 7.80 (dd,
3J(H,H) ¼ 5.4, 2 H); 7.98 (s, 2 H); 8.24 (d, 3J(H,H) ¼ 8.1, 2 H); 8.80 (d, 3J(H,H) ¼ 7.7, 2 H); 8.92 (s,
2 HꢀC¼); 10.35 (s, HBF4). 13C-NMR ((D6)DMSO): 42.65 (MeN); 53.24 (C(2), C(6)); 127.04 (C of Py);
131.14 (C(7), C(7’)); 132.37 (C of Py); 134.56 (C of Py); 143.64 (C¼CHꢀN), 144.64 (C(3), C(5)); 145.32
(C¼CHꢀN), 180.95 (C(4)). Anal. calc. for C18H17N3O · 3 HBF4 · 1.5 H2O (581.81): C 37.16, H 3.98, N
7.22; found: C 36.98, H 3.65, N 7.21.
(3E,5E)-1-Methyl-3,5-bis(pyridin-2-ylmethylidene)piperidin-4-one (2g). Yield 12% (Method A),
8% (Method B), 15% (Method D). M.p. 135 – 1378. IR (KBr): 2940w, 2772m, 2761m, 1673m (C¼O),
1618m (C¼C), 1592s, 1579s, 1469w, 1430m, 1300w, 1276s, 1165s, 1060w, 980w, 923w, 785m, 738m, 544m.

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Helvetica Chimica Acta – Vol. 93 (2010)
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1H-NMR (CDCl3): 2.52 (s, MeN); 4.16 (s, 2 CH2N); 7.18 (t, J(H,H) ¼ 6.0, 2 H); 7.43 (d, J(H,H) ¼ 7.7,
2 H); 7.60 (s, 2 HꢀC¼); 7.69 (t, J(H,H) ¼ 7.3, 2 H); 8.69 (d, J(H,H) ¼ 3.4, 2 H). 13C-NMR (CDCl3):
45.83 (MeN); 57.57 (C(2), C(6)); 122.56 (C of Py); 127.46 (C of Py); 132.37 (C(7), C(7’)); 136.19 (C of
Py); 137.51 (C(3), C(5)); 149.46 (C¼NꢀCH¼); 154.95 (C¼Nꢀ); 188.70 (C(4)). Anal. calc. for
C18H17N3O (291.35): C 74.20, H 5.88, N 14.42; found: C 73.64, H 6.04, N 14.38.
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(3E,5E)-3,5-Bis(4-fluorobenzylidene)-4-oxopiperidinium Tetrafluoroborate (3a · HBF4). M.p. 233 –
2368. 1H-NMR ((D6)DMSO): 4.51 (s, 2 CH2N); 7.37 (dd, 3J(H,F) ¼ 3J(H,H) ¼ 8.8, 4 H); 7.62 (dd,
4J(H,F) ¼ 5.8, 3J(H,H) ¼ 8.3, 4 H); 7.89 (s, 2 HꢀC¼); 9.17 (s, NH, HBF4). 13C-NMR ((D6)DMSO):
43.94 (C(2), C(6)); 115.71 (d, 2J(C,F) ¼ 21.3, C(10), C(10’), C(12), C(12’)); 127.49 (C(3), C(5)); 130.12
(d, 4J(C,F) ¼ 2.9, C(8), C(8’)); 132.68 (d, 3J(C,F) ¼ 8.8, C(9), C(9’), C(13), C(13’)); 137.97 (C(7), C(7’));
1
162.88 (d, J(C,F) ¼ 250.2, C(11), C(11’)); 182.09 (C(4)). 19F-NMR ((D6)DMSO): ꢀ 109.64; ꢀ 148.16.
Anal. calc. for C19H15F2NO · HBF4 · 0.5 H2O (408.15): C 55.91, H 4.20, N 3.43; found: C 55.50, H 3.84, N
3.34.
(3E,5E)-3,5-Bis(4-cyanobenzylidene)-4-oxopiperidinium Tetrafluoroborate (3b · HBF4). Yield 88%
(Method D). M.p. > 2308 (dec.). IR (KBr): 3430w, 3198w, 3144m, 2226s (CN); 1682m (C¼O), 1608s,
1605s (C¼C), 1500w, 1410m, 1314w, 1290s, 1182s, 1168m, 1082s, 964m, 918m, 852m, 830m, 556m.
1H-NMR ((D6)DMSO): 4.57 (s, 2 CH2N); 7.77 (d, 3J(H,H) ¼ 8.2, 4 H); 7.97 (s, 2 HꢀC¼); 8.04 (d,
3J(H,H) ¼ 8.2, 4 H); 9.44 (s, NH, HBF4). 13C-NMR ((D6)DMSO): 44.25 (C(2), C(6)); 112.31 (C(11),
C(11’)); 118.71 (CN); 130.37 (C(9), C(9’), C(13), C(13’)); 131.30 (C(10), C(10’), C(12), C(12’)); 132.89
(C(7), C(7’)); 137.89 (C(3), C(5)); 138.41 (C(8), C(8’)); 182.37 (C(4)). Anal. calc. for C21H15N3O · HBF4
(413.18): C 61.05, H 3.90, N 10.17; found: C 61.08, H 3.83, N 10.22.
4,4’-{(4-Oxopiperidine-3,5-diylidene)di[(E)-methylidene]}dibenzamide.
NH-Piperidin-4-one
(1 mmol) and 4-formylbenzonitrile (2 mmol) were dissolved in glacial AcOH (3 ml) · HCl (prepared
from NH4Cl, 5 mmol) was bubbled through the soln. The soln. was allowed to stay at r.t. for ca. 24 h.
Then, the mixture was added to aq. NaHCO3 (20 ml) and acetone (3 ml), followed by stirring over 0.5 h.
The light-yellow precipitate was filtered off and recrystallized from DMSO. Yield 92%. M.p. > 2128
(dec.). IR (KBr): 3384m (NH2), 3189m (NH2), 1651s (C¼O), 1613m (C¼C), 1557w, 1417m, 1397m,
1259w, 1184w, 913w, 876w. 1H-NMR ((D6)DMSO): 4.05 (s, 2 CH2N); 7.36 (s, 2 HꢀC¼), 7.57 (d,
3J(H,H) ¼ 7.6, 4 H); 7.95 (d, 3J(H,H) ¼ 7.6, 4 H); 8.32 (s, NH2). Anal. calc. for C21H19N3O3 · 0.5 H2O
(370.41): C 68.10, H 5.44, N 11.34; found: C 67.81, H 5.17, N 11.31.
This work was supported by the program of President of Russian Federation ꢀFor Young PhD
Scientistsꢁ (No MK-2464.2008.3) and the Program of Chemistry and Material Science Division of RAS
and NIH via the RIMI program (grant 1P20MD001104-01). We are grateful to Dr. Oleg Artyushin and
Dr. Pavel Petrovskii (A.N. Nesmeyanov Institute of Organoelement Compounds RAS) for the synthesis
of bis(4-carbamoylbenzylidene)piperidin-4-one and recording the NMR spectra.
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Received January 5, 2010