5004
Z. Liu et al. / Tetrahedron Letters 51 (2010) 5003–5004
Table 1
References and notes
N-substituted 3,5-bis(substituted-idene)piperidin-4-ones
b
1. (a) Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. J. Comb. Chem. 2005, 7, 147–
Com-
pound
R1
R2
Yielda
(%)
MW
169; (b) Kundu, B. Curr. Opin. Drug Discov. Devel. 2003, 6, 815–826; (c) Feliu, L.;
Vera-Luque, P.; Albericio, F.; Alvarez, M. J. Comb. Chem. 2009, 11, 175–197.
2. Franzen, R. G. J. Comb. Chem. 2000, 2, 195–214.
6a
6b
6c
6d
6e
6f
6g
6h
6i
4-Flourophenyl
4-Flourophenyl
4-Flourophenyl
4-Flourophenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
4-Methoxyphenyl
Benzyl
Methyl
78
67
73
81
76
58
64
86
43
45
52
60
340.4 (M+1)
356.4 (M+1)
432.5 (M+1)
438.4 (M+1)
364.5 (M+1)
380.5 (M+1)
456.5 (M+1)
462.5 (M+1)
332.5 (M+1)
348.5 (M+1)
424.6 (M+1)
430.5 (M+1)
3. Krchnak, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61–92.
2-Hydroxymethyl
2-Phenoxyl methyl
3,4-Difluorophenyl
Methyl
2-Hydroxymethyl
2-Phenoxyl methyl
3,4-Difluorophenyl
Methyl
4. (a) Makarov, M. V.; Leonova, E. S.; Rybalikina, E. Y.; Tongwa, P.; Khrustalev, V.
N.; Timofeeva, T. V.; Odinets, I. L. Eur. J. Med. Chem. 2010, 45, 992–1000; (b) Pati,
H. N.; Das, U.; Quail, J. W.; Kawase, M.; Sakagami, H.; Dimmock, J. R. Eur. J. Med.
Chem. 2008, 43, 1–7; (c) Kumar, R. R.; Perumal, S.; Senthilkumar, P.;
Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009, 44, 3821–3829; (d)
Makarov, M. V.; Rybalkina, E. Y.; Roschenthaler, G. V.; Short, K. W.;
Timafeeva, T. V.; Odinets, I. L. Eur. J. Med. Chem. 2009, 44, 2135–2144; (e)
Das, U.; Sakagami, H.; Chu, Q.; Wang, Q.; Kawase, M.; Selvakumar, P.; Sharma,
R. K.; Dimmock, J. R. Bioorg. Med. Chem. Lett. 2010, 20, 912–917.
5. (a) Kumar, R. R.; Perumal, S.; Kagan, H. B.; Guillot, R. Tetrahedron 2006, 62,
12380–12391; (b) Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron Lett. 1998, 39, 7591–7594.
6. REM resin is a resin which is regenerated after cleavage of the product and is
initially functionalized via a Michael reaction. For more details see Ref. 7.
7. Brown, A. R.; Rees, D. C.; Rankovic, A.; Morphy, J. R. J. Am. Chem. Soc. 1997, 119,
3288–3295.
6j
6k
6l
Benzyl
Benzyl
Benzyl
2-Hydroxymethyl
2-Phenoxyl methyl
3,4-Difluorophenyl
a
Yields are based on the weight of purified product and relative to the initial
loading of the resin (1.1 mmol/g).
b
Determined by ESI-MS.
8. Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Pipko, S. E.; Shivanyuk, A.
N.; Tolmachev, A. A. J. Comb. Chem. 2007, 9, 1073–1078.
To illustrate the versatility of this chemistry, a library of 12
compounds (6a–i) was prepared (Table 1). Three different alde-
hydes and four different alkyl bromides were employed in the syn-
thesis of this library. For most of the compounds (6a–h), a single
configuration (most likely E,E) product was detected by LCMS after
the cleavage, although trace amounts of isomeric product (most
likely E,Z-configuration) were detected in some crude products
(6i–l). In all cases, pure (E,E) N-substituted 3,5-bis(substituted-
idene)piperidin-4-one products were obtained in moderate yields
after the HPLC purification. This is in agreement with reports that
the known 3,5-bis(substituted-idene) piperidin-4-ones are isolated
as thermodynamically more stable E,E-isomers.4a
In summary, we have developed an efficient traceless solid-
phase synthetic approach for the synthesis of N-substituted 3,5-
bis(substituted-idene)piperidin-4-one derivatives. The methodol-
ogy is of value for high throughput synthesis of these potentially
bioactive molecules.
9. General procedure for the synthesis of N-substituted 3,5-bis(substituted-idene)
piperid-4-one derivatives: 100 mg of benzyl alcohol resin (loading: 1.2 mmol/
g) was sealed within a polypropylene mesh packet. Reactions were carried out
in polyethylene bottles. REM resin was prepared following the protocol from
the literature.6 4-Piperidinone hydrate hydrochloride (6 equiv) was tethered to
the resin in the presence of DIEA (6 equiv) with DMF as solvent at room
temperature for 48 h. After washing with DMF (three times), DCM (three
times), and air dried, the resin-bound tertiary amine was reacted with
aldehyde (10 equiv) in DMF using TMCl (1 equiv) as a catalyst at 80 °C for
48 h. The resin was then washed with DMF (three times), 5% DIEA/DCM (three
times), DCM (three times), and MeOH (three times). The afforded resin was
treated with alkyl bromide (6 equiv) in DMF at 65 °C overnight and then
washed with DMF (three times) and DCM (three times). The crude product was
released from the resin by heating at 65 °C overnight in acetonitrile with DIEA
(2 equiv) as a base. The crude product was purified by preparative HPLC10 and
characterized by LC–MS under ESI positive mode and 1H NMR. ESI-MS (m/z) of
6a: 340.4 (M+H); 1H NMR of 6a: (500 MHz, DMSO-d6): d 1.24 (3H, t, J = 7.0 Hz),
2.70 (2H, q, J = 7.0 Hz), 3.63 (4H, s), 6.98 (4H, d, J = 7.6 Hz), 7.61 (2H, s), 8.23
(4H, d, J = 7.6 Hz).
10. The column used was
a Phenomenex (Luna 5u C18(2) 100 Å AX,
150 Â 21.20 mm 5
l
m). A 5–95% gradient of water (0.1% Formic) and ACN
(0.1% Formic) was used at 15 ml/min for 30 min, the fractions were monitored
using a Shimadzu LCMS 2010 ESI positive mode.
Acknowledgments
This work was supported by the State of Florida, Executive
Office of the Governor’s Office of Tourism, Trade and Economic
Development.