Tetrabutylammonium triphenyldifluorosilicate (TBAT) initiated intramolecular addition of allylsilanes to 2,3-dihydro-4-pyridones. A novel route for the stereoselective construction of indolizidine systems

Article abstract of DOI:10.1016/S0040-4039(03)01678-2

A general and preparatively simple access to multisubstituted indolizidines has been developed. The key step involves the fluoride ion induced intramolecular reaction of 2,3-dihydro-4-pyridones with allylsilane located in the side-chain.

Full text of DOI:10.1016/S0040-4039(03)01678-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6629–6632
Tetrabutylammonium triphenyldifluorosilicate (TBAT) initiated
intramolecular addition of allylsilanes to 2,3-dihydro-4-pyridones.
A novel route for the stereoselective construction of
indolizidine systems
Bartłomiej Furman* and Magdalena Dziedzic
Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
Received 14 May 2003; revised 27 June 2003; accepted 3 July 2003
Abstract—A general and preparatively simple access to multisubstituted indolizidines has been developed. The key step involves
the fluoride ion induced intramolecular reaction of 2,3-dihydro-4-pyridones with allylsilane located in the side-chain.
© 2003 Elsevier Ltd. All rights reserved.
Allylsilanes have been applied as nucleophilic compo-
nents in the formation of carbon–carbon bonds.1 The
reactions of allylsilanes with conjugated enones
(Sakurai reaction) in the presence of Lewis acids lead to
the formation of d,o-enones.2 Examples of both inter-
and intramolecular Sakurai reactions have been
reported.3 These allylation reactions generally require
stoichiometric or greater amounts of Lewis acids to
obtain an acceptable yield of products. A catalytic
version of this reaction is possible when InCl3 (10
mol%) in the presence of TMSCl is used.4 Reactions of
allylsilanes with enones can be also carried out in a
1,4-fashion in the presence of fluoride ions.5
In this article, we describe a fluoride ion induced
intramolecular reaction between the allylsilyl functional
group and 2,3-dihydro-4-pyridones, as a key reaction
within a proposed general approach to a variety of
indolizidines (Scheme 1).
The key allylsilane amine 27 can be obtained more
effectively, in three steps, starting from allyl alcohol 18
using known methods9 in 82% overall yield (Scheme 2).
The aldimine 3 obtained from amine 2 and benzalde-
hyde reacted smoothly with Danishefsky’s diene in the
presence of a catalytic amount of Yb(OTf)3 to afford
the 2,3-dihydro-4-pyridone 4 in good yield (Scheme 3).
Not surprisingly, the five-membered ring product 5 was
not detected.10
Numerous natural products contain an azabicyclic
skeleton as a structural element.6 Indolizidine alkaloids
belong to this class of compounds. As they often
exhibit marked pharmacological activity and because
new members of this class of compounds continue to be
discovered in Nature, the stereoselective synthesis of
indolizidines is of great importance.
Many imines, in particular those derived from aliphatic
aldehydes are not particularly stable. It appeared desir-
able, from the synthetic point of view, to generate the
Scheme 1.
* Corresponding author. Fax: 44-22-632-66-81; e-mail: furbar@icho.edu.pl
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01678-2

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B. Furman, M. Dziedzic / Tetrahedron Letters 44 (2003) 6629–6632
Scheme 2. Reagents and conditions: (a) TsCl, (C2H5)3N, 0°C,
3 h; (b) NaN3, DMF, rt, 2 h; (c) PPh3, THF/H2O, 20 h, rt.
Scheme 4.
tions with isolated aldimines. The respective dihydro-4-
pyridones were obtained using a wide range of
aldehydes, including aromatic, olefinic and heteroaro-
matic aldehydes, even in the presence of water (entry 9).
intermediate aldimines in situ and allow them to react
with the appropriate diene under one-pot reaction con-
ditions. Recently, Kobayashi11 has reported that a cata-
lytic amount of Yb(OTf)3 (15–20%) effectively mediates
the aza-Diels–Alder reaction between Danishefsky’s
diene and aldimines generated in situ from aliphatic
aldehydes and p-anisidine. Also, Akiyama12 reported
that in the presence of montmorillonite K10, a three
component aza-Diels–Alder reaction can be performed
effectively.
The 4-pyridones thus obtained were subjected to a
Lewis acid mediated intramolecular Sakurai reaction.
Unfortunately, numerous attempts using TiCl4, SnCl4,
BF3·Et2O, EtAlCl2, InCl3/TMSCl all failed to promote
the intramolecular conjugated addition and resulted
only in the protodesilylation product 7 (Scheme 4).
We studied the three-component synthesis of the dihy-
dro-4-pyridone derivatives by a one-pot aza-Diels–
Alder reaction. As shown (Table 1), the one-pot
reaction afforded the corresponding adducts 6 in good
yield.13
We also examined various fluoride ion sources as pro-
moters of the Sakurai reaction. The use of anhydrous
Bu4NF in the DMF/HMPT (3:1) mixture5b afforded
the expected indolizidines in 20% yield, along with a
significant amount of desilylated product. Other
fluoride ion sources such as CsF or TASF failed
to promote the cyclization at all. However, the use
of the soluble, anhydrous, non-hygroscopic tetra-
The average yield of the cyclo-condensation reactions
was comparable to that obtained from analogous reac-
Scheme 3.
Table 1. Results of the three-component aza-Diels–Alder reaction
Entry
R
Solvent
Yield of 6, %
1
2
3
4
5
6
7
8
9
C6H5
4-MeOC6H4
2-Pyridyl
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN/H2O
96
85
80
70
78
70
56
68
60
BnOCH2
CH3CH2CH2
(CH3)2CH
(CH3)3C
CH3(CH2)8
(CH3O)2CH

B. Furman, M. Dziedzic / Tetrahedron Letters 44 (2003) 6629–6632
6631
Table 2. TBAT initiated intramolecular addition of allylsilane to 2,3-dihydro-4-pyridones
Entry
R
Yield of 8, %
Yield of 9, %
1
2
3
4
5
6
7
8
9
Ph
81
70
82
63
84
59
56
77
67
0
0
0
7
8
0
5
0
0
4-MeOC6H4
2-Pyridyl
BnOCH2
CH3CH2CH2
(CH3)2CH
(CH3)3C
CH3(CH2)8
(CH3O)2CH
Scheme 5.
butylammonium triphenyldifluorosilicate (TBAT)14 as
the fluoride source (2 equiv.) gave much better results
(Table 2).15
References
1. (a) Fleming, I. In Comprehensive Organic Synthesis;
Trost, B. H.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp. 563–593; (b) Brook, M. A. In Silicon in
Organic, Organometallic and Polymer Chemistry; Wiley:
New York, 2000.
2. (a) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99,
1673–1675; (b) Hosomi, A. Acc. Chem. Res. 1988, 21,
200–206; (c) Fleming, I.; Dunognes, J.; Smithers, R. Org.
React. 1989, 37, 57–181; (d) Langkopf, E.; Schinzer, D.
Chem. Rev. 1995, 95, 1375–1408.
For all entries in Table 2, treatment of the 2-substituted
2,3-dihydro-4-pyridones with 2 equiv. of TBAT in THF
at 30°C led to the desired indolizidines in good yields as
a single detectable diastereomer, as estimated from the
1H and 13C NMR data.16 The relative stereochemistry
at C5 and C9 was established with the aid of NOE
experiments. The stereochemical outcome observed in
these cyclizations is rationalized in Scheme 5.
3. (a) Schinzer, D.; Solyom, S.; Becker, M. Tetrahedron
Lett. 1985, 26, 1831–1834; (b) Blumenkopf, T. A.; Heath-
cock, C. H. J. Am. Chem. Soc. 1983, 105, 2354–2358; (c)
Jeroncic, L. O.; Cabal, M.-P.; Danishefsky, S. J.; Schulte,
G. M. J. Org. Chem. 1991, 56, 387–395; (d) Kuhnert, N.;
Peverley, J.; Robertson, J. Tetrahedron Lett. 1998, 39,
3215–3216.
We suggest that the reaction proceeds through the
transition state 10 where the bulky substituent R is
located in the equatorial position, while the nitrogen
electron pair is in the axial orientation. The nucle-
ophilic terminal of the double bond enters exclusively
anti to the R substituent to provide compound 8 with
the trans orientation between the C5 and C9 protons.
4. Lee, P. H.; Lee, K.; Sung, S.-y.; Chang, S. J. Org. Chem.
2001, 66, 8646–8647.
In conclusion, we have demonstrated a general and
efficient stereospecific synthesis of indolizidines. Work
is currently in progress to apply this methodology to
the diastereo- and enantioselective synthesis of
indolizidines.
5. (a) Majetich, G.; Hull, K.; Desmond, R. Tetrahedron
Lett. 1985, 26, 2751–2754; (b) Majetich, G.; Desmond, R.
W.; Soria, J. J. J. Org. Chem. 1986, 51, 1753–1769.
6. (a) Michael, J. P. Nat. Prod. Rep. 1998, 15, 571–606; (b)
Michael, J. P. Nat. Prod. Rep. 2002, 19, 719–741.

6632
B. Furman, M. Dziedzic / Tetrahedron Letters 44 (2003) 6629–6632
7. (a) Kavash, R. W.; Mariano, P. S. Tetrahedron Lett.
154.2, 142.2, 138.7, 128.9, 128.2, 126.9, 110.7, 98.2, 60.8,
59.4, 43.5, 23.6, −1.5; HRMS (ESI) calcd for C18H26NOSi
(M+H+) 300.1778, found 300.1791.
1989, 30, 4185–4188; (b) Lin, X.; Kavash, R. W.; Mari-
ano, P. S. J. Org. Chem. 1996, 61, 7335–7347.
8. Trost, B.; Chan, D. M. T.; Nanninga, T. N. Org. Synth.
1984, 62, 58–66.
14. Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem.
Soc. 1995, 117, 5166–5167.
9. Rubiralta, M.; Diez, A.; Miguel, D.; Remuson, R.; Gelas-
Mialhe, Y. Synth. Commun. 1992, 22, 359–367.
10. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976,
734–736.
11. Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995,
1195–1202.
15. Typical experimental procedure for TBAT mediated
cyclocondensation: The 2,3-dihydro-4-pyridones (0.1
mmol) and TBAT (0.2 mmol) were dissolved in THF (5
mL). After 10 min, the reaction turned orange, and after
1 h, the reaction was complete. The THF was removed
under reduced pressure, the residue was redissolved in 10
mL of 1:1 Et2O/EtOAc, and filtered. The filtrate was
concentrated, and the crude material obtained was
purified by column chromatography to give the desired
product. Representative data for 2-methylene-5-phenyl-
hexahydro-indolizin-7-one (Table 2, entry 1): 1H NMR
(500 MHz, CDCl3) l 7.35–7.15 (m, 5H), 4.90 (m, 2H),
4.33 (dd, 1H, J=6.3 and 4.3 Hz), 3.47 (dd, 1H, J=13.7
and 1.4 Hz), 3.20 (m, 1H), 3.13 (ddd, 1H, J=13.7, 2.3
and 1.0 Hz), 2.88 (ddd, 1H, J=15.3, 6.3 and 1.0 Hz), 2.73
(ddd, 1H, J=15.3, 4.3 and 1.6 Hz), 2.67 (ddd, 1H,
J=14.9, 3.9 and 1.6 Hz), 2.60 (m, 1H), 2.44 (ddd, 1H,
J=14.9, 9.9 and 0.8 Hz), 2.25 (m, 1H); 13C NMR (125
MHz, CDCl3): 209.4, 146.0, 138.3, 128.4, 128.2, 127.6,
106.2, 60.1, 55.3, 55.2, 46.0, 45.2, 38.4; HRMS (EI) calcd
for C15H17NO 227.13101, found 227.13189.
12. Akiyama, T.; Matsuda, K.; Fuchibe, K. Synlett 2002, 11,
1898–1900.
13. The typical experimental procedure for the ytterbium
triflate mediated reaction: The aldehyde (0.2 mmol),
amine 2 (0.2 mmol) and Danishefsky’s diene (0.22 mmol)
were dissolved in MeCN (5 mL) at rt and Yb(OTf)3 (0.02
mmol, 10 mol%) was added in one portion. The reaction
mixture was stirred for 10–15 h, then water was added
and the product was extracted with CH2Cl2 (10 mL×3).
After usual work-up, the crude material obtained was
chromatographed on silica gel to give the final product.
Representative data for 2-phenyl-1-(2-trimethylsilanyl-
methyl-allyl)-2,3-dihydro-1H-pyridin-4-one (Table 1,
entry 1): 1H NMR (500 MHz, CDCl3) l 7.43–7.25 (m,
5H), 7.13 (d, 1H, J=7.6 Hz), 5.03 (d, 1H, J=7.6 Hz),
4.79 (m, 2H), 4.62 (m, 1H), 3.52 (m, 2H), 2.94 (dd, 1H,
J=16.5 and 7.3), 2.68 (dd, 1H, J=16.5 and 7.1), 1.44 (s,
2H), −0.04 (s, 9H); 13C NMR (125 MHz, CDCl3): 190.1,
16. All new compounds were fully characterized by 1H and
13C NMR spectroscopy and by HRMS analysis.