A highly regioselective indium-mediated allylation of pyridine derivatives: Synthesis of (±)-dihydropinidine from pyridine

Article abstract of DOI:10.1016/S0040-4039(00)01332-0

The preparation of various 1-acyl-1,2-dihydropyridines with high regioselectivity by indium-mediated allylation of the corresponding 1-acylpyridinium salts is demonstrated. This is applied to the synthesis of (±)-dihydropinidines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01332-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7779–7783
A highly regioselective indium-mediated allylation of
pyridine derivatives: synthesis of ( )-dihydropinidine from
pyridine
Teck-Peng Loh,* Pek-Ling Lye, Rui-Bin Wang and Keng-Yeow Sim
Department of Chemistry, The National University of Singapore, 10 Kent Ridge Crescent,
Singapore 119260, Singapore
Received 28 June 2000; revised 17 July 2000; accepted 1 August 2000
Abstract
The preparation of various 1-acyl-1,2-dihydropyridines with high regioselectivity by indium-mediated
allylation of the corresponding 1-acylpyridinium salts is demonstrated. This is applied to the synthesis of
( )-dihydropinidines. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: allylation; 1,2-dihydropyridines; high regioselectivity; indium; ( )-dihydropinidine.
Recently, there has been considerable interest in using 1-acyl-1,2-dihydropyridines as interme-
diates for the synthesis of natural products.1 It has been elegantly shown by Comins, Yamaguchi
and others that dihydropyridines are useful building blocks for alkaloid synthesis.2,3 The most
straightforward method for the synthesis of substituted dihydropyridines is the addition of
Grignard reagents to 1-acylpyridinium salts.4–7 However, this method suffers from the lack of
regioselectivity when pyridine is used as the starting material. For example, it has been shown8
that in the absence of a substituent at the 4-position of the 1-acylpyridinium salt, the reaction
with an allyl Grignard reagent gave a mixture of 2- and 4-substituted dihydropyridines (Scheme
1). Furthermore, functional groups such as an ester or alcohol are not compatible with Grignard
reagents. An alternative method using allyl tributylstannane has also been employed with limited
success.9 Thus, it would be an advantage to use an organometallic reagent that reacts
regioselectively with pyridine without affecting other functional groups such as an ester.
* Corresponding author. Fax: (65)-7791691; e-mail: chmlohtp@nus.edu.sg
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01332-0

7780
Scheme 1.
In this paper, we show that allylic indium reagents can react with 1-acylpyridinium salts to
afford the corresponding 2-substituted 1,2-dihydropyridines in good yields with complete
regioselectivity. In fact, to the best of our knowledge, this is the first example of the reaction of
allylic indiums with pyridinium salts.
The indium-mediated allylation reactions of two different pyridinium salts with various allylic
bromides were investigated (Eq. (1)). The results are summarized in Table 1. In all cases, except
for the allylation reaction on the 1-ethoxycarbonylpyridinium salt (entry 1), the reactions
Table 1
Allylation reactions of pyridine
(1)
Entry
R
Halides
Conditionsa
Yield (%),b selectivity
1
2
3
4
5
6
7
Et
Ph
Ph
Ph
Ph
Ph
Ph
In, DMF, 16 h
In, DMF, 16 h
In, DMF, 16 h
In, DMF, 16 h
In, DMF, 16 h
In, DMF, 16 h
In, DMF, 16 h
23
65
68
70
75 (30:70)c
75 (40:60)c
70 (38:62)c
a For experimental, refer to typical experimental procedure (Ref. 10).
b Purified yield.
c Relative stereochemistry not assigned.

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proceeded smoothly to afford the corresponding products in moderate to high yields. Interest-
ingly, it was found that the indium-mediated allylations of pyridine in the presence of phenyl
chloroformate gave exclusively 2-substituted 1,2-dihydropyridines in DMF at room temperature.
1
No 1,4-product was observed from H NMR analysis. With these results in hand, we applied
this strategy to the synthesis of cis-2,6-disubstituted piperidines. The well-characterized alkaloid
( )-dihydropinidine, which occurs naturally as (+)-dihydropinidine,11 was chosen as the target
for this study (Scheme 2).
1
Scheme 2. The H and 13C NMR data for compound 615 are identical to the reported16 data
Product 2 which was obtained previously was treated with potassium t-butoxide in THF to
afford the N-Boc derivative 3 in 80% yield. Treatment of 3 with n-BuLi and MeI gave
dihydropyridine 4 in 53% yield. Catalytic hydrogenation of 4 with 10% Pd/C and lithium
carbonate in ethyl acetate afforded 5 in 89% yield.12 Finally, subjecting 5 to TMSI furnished the
target compound 6 in 68% yield.12 As far as we know, this is the first method for the synthesis
of ( )-dihydropinidine using pyridine as the starting material, though there have been other
methods applied for the synthesis of (+)- or (−)-dihydropinidine13 and ( )-dihydropinidine.14
Therefore, this new strategy should be amenable to the synthesis of numerous cis-2,6-
dialkylpiperidines.
In conclusion, we have found that indium-mediated allylation of pyridinium salts with various
allylic halides affords the products in moderate to good yields with exclusive 2-regioselectivity.
The efficiency of this new method has been demonstrated with a short and efficient synthesis of
( )-dihydropinidine. Efforts to develop an asymmetric version of this reaction are in progress.
Acknowledgements
This research was assisted financially by grants from the National University of Singapore.

7782
References
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To a solution of pyridine (0.41 mL, 5 mmol) in DMF (3 mL) was added phenylchloroformate (0.63 mL, 5 mmol)
at 0°C. The resulting mixture was stirred at that temperature for a few minutes. The salt solution was
immediately used for the subsequent allylation reactions. (b) Allylation reactions on the 1-acyl-pyridinium salts
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mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The prepared
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oil. The crude product was purified by flash silica gel column chromatography with hexane: ether 8:1 to afford
0.74 g of the pure 1-(phenoxycarbonyl)-2-(2-propenyl)-1,2-dihydropiridine 2 (65% yield).
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1
15. 1H and 13C NMR data for compound 6: H NMR (300 MHz, CDCl3): l 2.63–2.52 (m, 1H), 2.49–2.40 (m, 1H),
1.75–1.66 (m, 1H), 1.61–1.50 (m, 2H), 1.31–0.83 (m, 11H), 1.01 (d, J=6.02 Hz, 3H); 13C NMR (75 MHz, CDCl3):
1
l 56.7, 52.3, 39.5, 34.3, 32.1, 24.7, 22.9, 19.0, 14.1; H NMR (300 MHz, C6D6): l 2.62–2.53 (m, 1H), 2.52–2.42
(m, 1H), 1.80–1.72 (m, 1H), 1.62–1.49 (m, 2H), 1.47–1.22 (m, 8H), 1.09 (d, J=6.27 Hz, 3H), 1.03–0.93 (m, 3H);
13C NMR (75 MHz, C6D6): l 56.8, 52.4, 39.9, 34.7, 32.4, 25.2, 23.1, 19.1, 14.3.

7783
16. 1H and 13C NMR for the reported ( )-dihydropinidine as shown in Ref. 12: 1H NMR (300 MHz, CDCl3): l
2.68–2.56 (m, 1H), 2.55–2.45 (m, 1H), 1.76 (m, 1H), 1.60 (m, 2H), 1.55–0.80 (m, 8H), 1.06 (d, 3H, J=6.6 Hz),
1
0.91 (m, 3H); 13C NMR (75 MHz, CDCl3): l 56.8, 52.5, 39.7, 34.4, 32.2, 24.9, 23.1, 19.1, 14.3; H NMR (300
MHz, C6D6): l 2.52–2.42 (m, 1H), 2.40–2.32 (m, 1H), 1.69 (m, 1H), 1.48 (m, 2H), 1.35–0.80 (m, 8H), 0.99 (d, 3H,
J=6.3 Hz), 0.88 (t, 3H, J=6.3 Hz); 13C NMR (75 MHz, C6D6): l 57.1, 52.7, 40.1, 34.8, 32.5, 25.4, 23.2, 19.3,
14.6.
.