Inter- and intramolecular Horner-Wadsworth-Emmons reactions of 5-(diethoxyphosphoryl)-1-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones

Article abstract of DOI:10.1016/S0040-4039(01)00690-6

Dihydropyridones of the type 1 were converted to their C-5 alkylidene derivatives 2 by a reaction sequence involving phosphorylation, conjugate reduction or addition to provide piperidones 4, and then olefination via a Horner-Wadsworth-Emmons reaction. An

Full text of DOI:10.1016/S0040-4039(01)00690-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4115–4118
Inter- and intramolecular Horner–Wadsworth–Emmons reactions
of
5-(diethoxyphosphoryl)-1-acyl-2-alkyl(aryl)-2,3-dihydro-4-pyridones
Daniel L. Comins* and Christian G. Ollinger
Department of Chemistry, North Carolina State University, Raleigh, NC 27695-8204, USA
Received 8 March 2001; accepted 24 April 2001
Abstract—Dihydropyridones of the type 1 were converted to their C-5 alkylidene derivatives 2 by a reaction sequence involving
phosphorylation, conjugate reduction or addition to provide piperidones 4, and then olefination via a Horner–Wadsworth–
Emmons reaction. An intramolecular version of this method was used to prepare trans-bicyclic enone 13. © 2001 Elsevier Science
Ltd. All rights reserved.
N-Acyldihydropyridones of the type 1 are versatile
building blocks for piperidine, indolizidine, quino-
lizidine, perhydroquinoline and other alkaloid ring sys-
tems.1 These heterocycles (1) can be conveniently
prepared in racemic2 or enantiopure3 form using 1-acyl-
4-methoxypyridinium salt chemistry.4 To enhance the
scope of dihydropyridones 1 as synthetic intermediates,
we are developing methods to add substituents at vari-
ous positions of the heterocyclic ring in a regio- and
stereocontrolled fashion.5 In support of total synthesis
efforts in our laboratories, we have been examining
ways to regioselectively introduce an alkylidene group
at the C-5 position of 1 to provide enones 2.
The preparation of dihydropyridones of the type 3 was
accomplished as shown in Scheme 2. The iododihy-
dropyridones 5 were prepared by C-5 iodination of the
corresponding dihydropyridones using our previously
described procedures.6 To convert 5 to the desired
phosphorus derivatives, we examined Kazankova’s
method7 for converting vinyl halides to phosphonates
and phosphine oxides using a metal-catalyzed cross-
Scheme 1.
The route we chose to investigate first is depicted in
Scheme 1. The plan called for preparation of phospho-
rus derivatives 3, conjugate reduction or addition to
provide piperidones 4, and then olefination via a
modified Wittig reaction to give the desired enones 2.
Scheme 2.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00690-6

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D. L. Comins, C. G. Ollinger / Tetrahedron Letters 42 (2001) 4115–4118
coupling reaction. Initial attempts using triethyl phos-
phite and NiCl2 catalyst in various solvents were not
successful. Fortunately, when the reaction was per-
formed without solvent at 150°C, excellent yields of the
vinyl phosphonates 6 were obtained (6a, R1=Ph, 97%;
6b, R1=i-Pr, 87%). We also could prepare the phos-
phine oxide 7 in high yield (81%) using 5a (R1=Ph),
methyl diphenylphosphinite, and cat. NiCl2 in refluxing
toluene. Product 7 was difficult to purify, however, so
subsequent studies were performed with phosphonates
6.
The double bond in 6 was reduced with K-Selectride to
give phosphonates 8.8 The Horner–Wadsworth–
Emmons (HWE) reaction was examined to convert 8
and various aldehydes to enones 9 (Scheme 3).9 Anion
formation with KOBut in THF, followed by addition of
the aldehyde, and raising the reaction temperature to
35°C gave good yields of the desired enones as shown
in Table 1.
Scheme 3.
Table 1. HWE olefination of 8 with various aldehydes to
give 9
An intramolecular HWE olefination sequence was also
carried out as shown in Scheme 4. Dihydropyridone 6a
was added to Grignard reagent 1010 and CuBr·SMe2 in
THF to provide an 84% yield of the trans-piperidone
11. The stereoselectivity was opposite of that antici-
pated, as 2-substituted N-acyl-2,3-dihydro-4-pyridones
generally give cis-addition with organocuprates.11 The
combination of the C-2 phenyl and C-5 phosphonate
groups on 6a must hinder axial attack via chair confor-
mation A. Axial attack via the higher energy chair
conformation B leads to the observed product (Fig. 1).
Hydrolysis of the acetal 11 was carried out using
aqueous oxalic acid/THF at rt to afford the crude
aldehyde 12 in near quantitative yield. Attempted
purification of 12 by chromatography on silica gel
resulted in partial cyclization to bicyclic enone 13. The
Entrya
8
Aldehyde
9, Yield (%)b
E/Z ratioc
1
2
8a Benzaldehyde
8a Hydrocinnamald-
ehyde
8a Cinnamaldehyde
8a Hexanal
8b Benzaldehyde
8b Hydrocinnamald-
ehyde
8b Cinnamaldehyde
8b Hexanal
92
75
8.3/1
6.4/1
3
4
5
6
64
80
84
74
3.1/1
8.8/1
11.6/1
1.2/1
7
8
61
76
3.6/1
12.3/1
a The reactions were performed on a 1.5–3.0 mmol scale.
b Yield of 9 obtained from radical PLC (silica gel, EtOAc/hexanes) as
a mixture of E,Z isomers.
c Isomer ratios were determined by HPLC.
Scheme 4.

D. L. Comins, C. G. Ollinger / Tetrahedron Letters 42 (2001) 4115–4118
4117
Figure 1. Axial attack on chair conformations A and B.14
SiO2-mediated cyclization could not be improved, and
only 20% of 13 was obtained by this procedure.
3. (a) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am.
Chem. Soc. 1994, 116, 4719; (b) Comins, D. L.; LaMun-
yon, D. H. Tetrahedron Lett. 1994, 35, 7343; (c) Comins,
D. L.; Guerra-Weltzien, L. Tetrahedron Lett. 1996, 37,
3807.
4. For the synthesis of related dihydropyridones using the
aza Diels–Alder reaction, see: Kirschbaum, S.; Wald-
mann, H. J. Org. Chem. 1998, 63, 4936 and references
cited therein.
Several other conditions were used without success to
effect the intramolecular HWE reaction of 12 (e.g.
NaOMe, KOBut, TFA, Amberlyst 15, TEA). Fortu-
nately, Rathke’s method12 using TEA/LiCl in THF led
to a high yield of the desired enone 13. The stereochem-
istry of 13 was confirmed by single crystal X-ray
analysis.13
5. Comins, D. L. J. Heterocyclic Chem. 1999, 36, 1491 and
references cited therein.
In summary, an alkylidene group can be introduced at
the C-5 position of dihydropyridones 1 using a phos-
phorylation, reduction, and an intermolecular HWE
olefination sequence. An intramolecular version of this
method allowed the facile preparation of trans-bicyclic
enone 13 in a highly stereocontrolled fashion.15
6. (a) Comins, D. L.; Joseph, S. P.; Chen, X. Tetrahedron
Lett. 1995, 36, 9141; (b) Comins, D. L.; Hiebel, A.-C.;
Huang, S. Org. Lett. 2001, 3, 769.
7. (a) Kazankova, M. A.; Evgeniy, C. A.; Kochetkov, A.
N.; Efimova, I. V.; Beletskaya, I. P. Tetrahedron Lett.
1998, 39, 573; (b) Kazankova, M. A.; Trostyanskaya, I.
G.; Lutsenko, S. V.; Beletskaya, I. P. Tetrahedron Lett.
1999, 40, 569.
8. NMR analysis in CDCl3 shows that 8 exist as a mixture
of its keto and enol forms.
Acknowledgements
9. (a) Thomas, R.; Boutagy, J. Chem. Rev. 1974, 74, 87; (b)
Wadsworth, Jr., W. S. Org. React. 1977, 25, 73.
10. The Grignard reagent 10 was prepared from 4-chloro-1,1-
diethoxybutane and magnesium powder in THF (reflux, 4
h).
11. Comins, D. L.; Joseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J., Ed.; JAI Press: Greenwich,
CT, 1996; Vol. 2.
The authors express appreciation to the National Insti-
tutes of Health (Grant GM 34442) for financial support
of this research. NMR and mass spectra and X-ray
structure determination of 13 were obtained at NCSU
Instrumentation Laboratories, which were established
by grants from the North Carolina Biotechnology Cen-
ter and the National Science Foundation (Grants CHE-
9121380 and CHE-9509532). The authors would also
like to thank Chirex, Inc. for a generous gift of 4-
chloro-1,1-diethoxybutane.
12. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50,
2624.
13. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 159535. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
14. Molecular modeling program: MacSPARTAN Pro (1.02)
by Wavefunction, Inc. Force field: MMFF. The E values
(kcal/mol) are for the ground-state conformations shown.
15. The structure assigned to each new compound is in
accord with its IR and 1H and 13C NMR spectra and
elemental analysis or high-resolution mass spectra.
Selected characterization data: Compound 6a: white
References
1. For leading references, see: (a) Comins, D. L.; Libby, A.
H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64,
2184; (b) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.;
Goehring, R. R. Org. Lett. 1999, 1, 229; (c) Comins, D.
L.; Fulp, A. B. Org. Lett. 1999, 1, 1941; (d) Kuethe, J. T.;
Comins, D. L. Org. Lett. 2000, 2, 855; (e) Huang, S.;
Comins, D. L. Chem. Commun. 2000, 7, 569.
2. Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27,
4549.

4118
D. L. Comins, C. G. Ollinger / Tetrahedron Letters 42 (2001) 4115–4118
solid; mp 134–135°C; IR (CHCl3): 2985, 1750, 1681,
1584, 1301, 1243, 1024 cm−1 1H NMR (CDCl3, 300
14.2 Hz), 4.97 (q, 1H, J=15.9 Hz), 7.08–7.39 (m, 5H),
;
10.86 (s, 1H); 13C NMR (CDCl3, 75 MHz): l 16.5, 18.4,
19.1, 19.7, 20.3, 29.0, 30.8, 38.0, 39.7, 40.9, 42.2, 42.7,
49.4, 51.1, 55.5, 56.4, 58.9, 59.8, 62.5, 63.1, 63.3, 121.8,
125.5, 129.5, 151.6, 154.1, 202.5. HRMS calcd for
C19H28NO6P: 398.1733 [M+H]+. Found: 398.1729 [M+
H]+.
MHz): l 1.25 (t, 3H, J=6.6 Hz), 1.33 (t, 3H, J=6.6 Hz),
2.95 (d, 1H, J=16.5 Hz), 3.27 (dd, 1H, J=7.3 and 17.1
Hz), 4.10 (m, 4H), 5.90 (d, 1H, J=7.2 Hz), 7.25 (m,
10H), 8.92 (d, 1H, J=14.7 Hz); 13C NMR (CDCl3, 75
MHz): l 16.9, 17.0, 17.1, 42.8, 42.9, 57.5, 63.1, 63.1, 63.2,
63.3, 107.2, 109.7, 121.8, 126.4, 127.4, 129.3, 129.8, 130.4,
137.9, 150.8, 151.6, 152.2, 152.5, 189.7. Anal. calcd for
C22H24NO6P: C, 61.54; H, 5.63; N, 3.26. Found: C,
61.61; H, 5.74; N, 3.23.
Compound 13: white solid; mp 122–123°C; IR (CHCl3):
3031, 2919, 2867, 1724, 1694, 1620, 1490, 1420, 1266,
1
1196 cm−1; H NMR (CDCl3, 300 MHz): l 1.65 (m, 1H),
1.94 (m, 1H), 2.19–2.49 (m, 4H), 3.02 (dd, 1H, J=5.6 and
5.9 Hz), 3.13 (dd, 1H, J=7.6 and 7.7 Hz), 4.51 (m, 1H),
5.52 (t, 1H, J=6.6 Hz), 6.88 (m, 2H), 7.15 (t, 1H, J=7.3
Hz), 7.27–7.42 (m, 8H); 13C NMR (CDCl3, 75 MHz): l
21.2, 25.6, 27.7, 43.1, 54.4, 55.8, 121.8, 125.6, 126.8,
127.9, 129.0, 129.4, 137.3, 138.9, 139.9, 150.9, 154.2,
197.2. Anal. calcd for C22H21NO3: C, 76.06; H, 6.09; N,
4.03. Found: C, 76.06; H, 6.11; N, 3.97.
Compound 8b: colorless oil; IR (CHCl3): 2968, 1715,
1639, 1592, 1417, 1242, 1202, 1160, 1021, 968, 747 cm−1
;
1H NMR (CDCl3, 300 MHz): l 1.02 (d, 6H, J=6.3 Hz),
1.35 (t, 6H, J=5.7 Hz), 1.78 (br s, 1H), 2.04 (br s, 1H),
2.38 (br s, 1H), 2.44 (br s, 1H), 2.65 (d, 2H, J=14.1 Hz),
2.94 (dd, 1H, J=4.3 and 24.0 Hz), 3.06 (m, 1H), 3.22 (m,
1H), 4.15 (m, 4H), 4.44 (m, 1H), 4.68 (dd, 1H, J=6.2 and
.