Synthesis of N-substituted 4-trimethylstannyl-3,6-dihydro-2H-pyridines as promising synthons in the preparative chemistry of piperidine

Full text of DOI:10.1134/S1070363213120256

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 12, pp. 2347–2349. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.I. Moskalenko, V.I. Boev, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 12, pp. 2064–2066.
LETTERS
TO THE EDITOR
Synthesis of N-Substituted 4-Trimethylstannyl-3,6-dihydro-
2H-pyridines as Promising Synthons
in the Preparative Chemistry of Piperidine
A. I. Moskalenkoa and V. I. Boevb
a Lipetsk State Pedagogical University, ul. Lenina 42, Lipetsk, 398020 Russia
e-mail: kaf_himii@lspu.lipetsk.ru
b Russian State Agrarian University, Moscow, Russia
Received June 17, 2013
DOI: 10.1134/S1070363213120256
Piperidine derivatives are of interest due to a broad
spectrum of their biological activity [1, 2].
tively available tert-butyl or benzyl 1,2,3,6-tetrahydro-4-
[(trifluoromethyl)sulfonyl]pyridine-1-carboxylates III,
IV [3]. The latter react with hexamethyldistannane in
the presence of catalyst systems Pd(PPh3)4–anhydrous
LiCl [4] under reflux in dioxane for 1.5 h to afford I and
II as pale yellow oily substances in a yield of 80–90%.
In this work, we synthesized previously unknown
piperidine derivatives, N-substituted 4-trimethylstannyl-
3,6-dihydro-2H-pyridines I and II starting from prepara-
SnMe3
OTf
Pd(PPh3)4, LiCl
Me3SnSnMe3
+
N
N
R
R
III, IV
R =
I, II
CH2Ph (Cbz, II, IV).
C
O
O
C
O
O
(Boc, I, III);
CMe3
Organotin compounds are well known [5–7] to be
widely used as convenient synthons for catalytic
synthesis of various functionally substituted organic
compounds. Indeed, we found that compounds I, II
react with a range of electrophilic reagents in the Stille
reaction conditions [8–10] to form the corresponding
piperidine derivatives V–IX in 64–87% yields.
was heated with stirring for 1.5 h under argon. After
cooling, 200 mL of ethyl acetate and 200 mL of
saturated aqueous sodium chloride solution were added
to the mixture. Then the mixture was stirred for 0.5 h,
after which the organic layer was separated. The
aqueous layer was extracted with 150 mL of ethyl
acetate. The combined organic solutions were washed
with water, with saturated sodium chloride, and dried
over anhydrous Na2SO4. After distilling off the solvent
in a vacuum, the residue was purified by chromato-
graphy on silica gel eluting with ethyl acetate–hexane,
1 : 10. Yield 6.45 g (93%). IR spectrum, ν, cm–1: 1686
(C=O), 1632 (C=С). 1Н NMR spectrum, δ, ppm: 0.10 s
(9H, SnMe3, JHSn 27.64 Hz), 1.48 s (9Н, CMe3), 2.28 t
(2Н, СН2, J 9.2 Hz), 3.41 t (2Н, NCH2, J 9.2 Hz), 3.89
d (2Н, NCH2, J 10.4 Hz), 5.78 t (1Н, СН=С, J 10.4 Hz).
Mass spectrum, m/z (Irel, %): 347.13 (100) [M + H]+.
The synthesized compounds V–IX are highly
reactive due to the presence of double bond and labile
protecting groups, therefore they can be used in
preparative molecular design of piperidine derivatives.
tert-Butyl 4-trimethylstannyl-3,6-dihydro-2Н-pyri-
dine-1-carboxylate (I). A mixture of 6.34 g of III [3],
6.56 g of hexamethyldistannane, 2.52 g of anhydrous
lithium chloride, and 1.20 g of tetrakis(triphenyl-
phosphine)palladium in 75 mL of anhydrous dioxane
2347

2348
MOSKALENKO, BOEV
CH2CH=CH2
CH2=CHCH2Br
N
R
V, VI
CH2CH=CHMe
MeCH=CHCH2Br
N
Cbz
Boc
VII
Pd(PPh3)4, LiCl
O
I, II
C
Ph
PhCOCl
N
N
VIII
Me
4-MeC6H4Br
Boc
IX
R = Boc (V), Cbz (VI).
Found, %: С 45.23; Н 7.18; N 3.96. С13Н25NO2Sn.
Calculated, %: С 45.09; Н 7.23; N 4.05. M 346.05.
СН2=С, J 11.9 Hz), 5.05 s (2H, OCH2), 5.38 s (1Н,
СН=СN), 5.75–5.79 m (1Н, СН=С), 7.25–7.34 m (5H,
C6H5). Mass spectrum, m/z (Irel, %): 258.20 (100)
[M + H]+. Found, %: С 74.63; Н 7.28; N 5.51.
С16Н19NO2. Calculated, %: С 74.71; Н 7.39; N 5.45. M
257.33.
Benzyl 4-trimethylstannyl-3,6-dihydro-2Н-pyridine-
1-carboxylate (II) was prepared similarly. Yield 81%.
1
IR spectrum, ν, cm–1: 1693 (C=O), 1635 (C=С). Н
NMR spectrum, δ, ppm: 0.07 s (9H, SnMe3, JHSn
31.26 Hz), 2.21 s (2Н, СН2), 3.48 t (2Н, NCH2, J 8.6 Hz),
3.91 s (2Н, NCH2), 5.04 s (2H, OCH2), 5.77 t (1Н,
СН=С, J 9.6 Hz), 7.26–7.38 m (5H, C6H5). Found, %:
С 50.34; Н 6.17; N 3.75. С16Н23NO2Sn. Calculated, %:
С 50.53; Н 6.05; N 3.68.
Benzyl 4-[(E)-but-2-enyl]-3,6-dihydro-2Н-pyridine-
1-carboxylate (VII) was prepared similarly to V.
Yield 62%, pale yellow solid. IR spectrum, ν, cm–1:
1695 (C=O), 1632, 1620 (C=С). 1Н NMR spectrum, δ,
ppm: 1.61 d (3Н, СН3, J 11.0 Hz), 2.01 s (2Н, СН2),
2.68 d (2Н, СН2С=С, J 7.4 Hz), 3.48 t (2Н, NCH2, J
8.1 Hz), 3.81 d (2Н, NCH2, J 10.6 Hz), 5.01 s (2H,
OCH2), 5.04 t (1Н, СН=СN, J 10.6 Hz), 5.32 t (1На,
СНa=СНb, J 16.4 Hz), 5.72–5.77 m (1Нb, СНa=СНb, J
16.4 Hz), 7.25–7.38 m (5H, C6H5). Mass spectrum, m/z
(Irel, %): 272.23 (100) [M + H]+. Found, %: С 75.09; Н
7.63; N 5.24. С17Н21NO2. Calculated, %: С 75.28; Н
7.75; N 5.17. M 271.35.
tert-Butyl 4-allyl-3,6-dihydro-2H-pyridine-1-car-
boxylate (V) was prepared by procedure [10] using
anhydrous dioxane as solvent. Yield 83%, pale yellow
oil. IR spectrum, ν, cm–1: 1685 (C=O), 1636, 1624
(C=С). 1Н NMR spectrum, δ, ppm: 1.48 s (9Н, CMe3),
2.01 s (2Н, СН2), 2.70 d (2Н, СН2С=С, J 6.7 Hz), 3.48
t (2Н, NCH2, J 8.4 Hz), 3.86 s (2Н, NCH2), 5.01 d
(2Н, СН2=С, J 12.8 Hz), 5.31 s (1Н, СН=СN), 5.76 m
(1Н, СН=С). Mass spectrum, m/z (Irel, %): 224.26 (22)
[M + H]+, 168.33 (100) [M – 57 + 2H]+. Found, %: С
69.87; Н 9.31; N 6.15. С13Н21NO2. Calculated, %: С
69.96; Н 9.42; N 6.28. M 223.31.
tert-Butyl 4-benzoyl-3,6-dihydro-2Н-pyridine-1-
carboxylate (VIII) was prepared by procedure [8].
Yield 78%, pale yellow substance. IR spectrum, ν, cm–1:
1702, 1686 (C=O), 1658 (C=С). 1Н NMR spectrum, δ,
ppm: 1.49 s (9Н, CMe3), 2.02 s (2Н, СН2), 3.54 t (2Н,
NCH2, J 6.7 Hz), 3.92 d (2Н, NCH2, J 8.5 Hz), 6.51 s
(1Н, СН=С), 7.46–7.74 m (5H, C6H5). Mass spectrum,
m/z (Irel, %).: 288.32 (100) [M + H]+. Found, %: С
70.56; Н 7.18; N 4.73. С17Н21NO3. Calculated, %: С
70.83; Н 7.32; N 4.88. M 287.41.
Benzyl 4-allyl-3,6-dihydro-2H-pyridine-1-carboxy-
late (VI) was prepared similarly to V. Yield 80%,
colorless solid. IR spectrum, ν, cm–1: 1695 (C=O),
1
1637, 1626 (C=С). Н NMR spectrum, δ, ppm: 2.01 s
(2Н, СН2), 2.70 d (2Н, СН2С=С, J 6.2 Hz), 3.48 t (2Н,
NCH2, J 7.9 Hz), 3.86 s (2Н, NCH2), 5.01 d (2Н,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 12 2013

SYNTHESIS OF N-SUBSTITUTED 4-TRIMETHYLSTANNYL-3,6-DIHYDRO-2H-PYRIDINES
2349
El-Kouhen, O.F., Donnelly-Roberts, D.L., Namovic, M.T.,
Hollingswort, P.R., Chang, R., Martino, B.R., Wetter, J.M.,
Marsh, K.C., Martin, R., Darbyshire, J.F., Gintant, G.,
Hsieh, G.C., Moreland, R.B., Sullivan, J.P., Brioni, J.D.,
and Stewart, A.O., J. Med. Chem., 2006, vol. 49, no. 24,
p. 7450.
tert-Butyl-4-(p-tolyl)-3,6-dihydro-2Н-pyridine-1-
carboxylate (IX) was prepared by procedure [3].
Yield 81%, pale yellow substance. IR spectrum, ν, cm–1:
1
1687 (C=O), 1618 (C=С). Н NMR spectrum, δ, ppm:
1.49 s (9Н, CMe3), 2.34 s (3Н, СН3), 2.50–2.54 m
(2Н, СН2), 3.49–3.54 m (2Н, NCH2), 4.06 d (2Н,
NCH2, J 7.6 Hz), 6.00–6.04 m (1Н, СН=С), 7.18 d
(2Н, С6Н2, J 8.2 Hz), 7.30 d (2Н, С6Н2, J 8.2 Hz).
Mass spectrum, m/z (Irel, %): 274.48 (100) [M + H]+.
Found, %: С 74.61; Н 8.34; N 5.06. С17Н23NO2.
Calculated, %: С 74.73; Н 8.42; N 5.13. M 273.74.
3. Wustrow, D.J. and Wise, L.D., Synthesis, 1991, no. 11,
p. 993.
4. Wulff, W.D., Peterson, G.A., Bauta, W.E., Chan, K-S.,
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p. 277.
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and Cheng, C.H., Tetrahedron, 2003, vol. 59, no. 12,
p. 3635.
IR spectra were recorded on a Specord 75 IR
instrument from KBr pellets. H NMR spectra were
taken on a Varian Mercury Plus-400 spectrometer
(400 MHz). GC-MS spectra were registered on a
Surveyor MSQ Thermo Finnigan instrument (USA) by
chemical ionization at atmospheric pressure.
1
6. Li, J.H., Liang, Y., Wang, D.P., Liu, W.J., Xie, Y.X.,
and Yin, D.L., J. Org. Chem., 2005, vol. 70, no. 6, p. 2832.
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Chem., 2005, vol. 70, no. 18, p. 8601.
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