Regio- and stereoselective addition of allylmetal reagents to pyridinium-π and quinolinium-π complexes

Article abstract of DOI:10.1021/ol070168q

Equation presented Regio- and stereoselective allylation of pyridinium and quinolinium salts was performed by the addition of allylindium and allyltributyltin reagents toward intermediary cation-π complexes. The reaction with allylindium and allyltributyl

Full text of DOI:10.1021/ol070168q

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1477-1480
Regio- and Stereoselective Addition of
Allylmetal Reagents to Pyridinium−π
and Quinolinium−π Complexes
Shinji Yamada* and Mai Inoue
Department of Chemistry, Faculty of Science, Ochanomizu UniVersity, Bunkyo-ku,
Tokyo 112-8610, Japan
yamada.shinji@ocha.ac.jp
Received January 23, 2007
ABSTRACT
Regio- and stereoselective allylation of pyridinium and quinolinium salts was performed by the addition of allylindium and allyltributyltin
reagents toward intermediary cation−π complexes. The reaction with allylindium and allyltributyltin reagents afforded a 1,2-adduct, whereas
the addition of a prenylindium reagent gave a 1,4-adduct with good regio- and stereoselectivities. X-ray structural analysis, 1H NMR studies,
and DFT calculations elucidated the intermediary cation−π complex formation with face-to-face orientation.
The piperidine ring system constitutes a number of natural
products and biologically active compounds. Approaches
toward the efficient synthesis of the ring system are therefore
a continuing challenge in organic synthesis.1 One of the most
promising ways is an approach through dihydropyridines2
or dihydropyridones3 because they are easily accessible to a
variety of piperidine derivatives4 and alkaloids.3,5
Various types of chiral dihydropyridines,6 dihydroquino-
lines,7 and dihydroisoquinolines8 possessing an aryl, alkyl,
and cyano group have been prepared by the nucleophilic
addition toward pyridinium, quinolinium, and isoquinolinium
salts, respectively. On the other hand, little is reported for
stereoselective allylation of pyridinium and quindinium rings
except for the reaction with chiral allylsilane9 and allylcopper
reagents.10 We focused on the synthesis of allyl-substituted
chiral dihydropyridines and dihydroquinolines because they
are significantly important as the synthetic intermediates of
natural products and related compounds.11
Since allylation generally occurs at the γ-position of the
allylmetal reagent, it is often accompanied with lower face-
(1) For reviews, see: (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
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L.; Huang, S.; McArdle, C. L.; Ingalls, C. L. Org. Lett. 2001, 3, 469.
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Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M.
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M. Miyazaki, M.; Ohsawa, A. Synlett 1999, 1154.
10.1021/ol070168q CCC: $37.00
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Published on Web 03/16/2007

selectivity for pyridine systems.8h We anticipated that the
stereoselective allylation of a pyridinium would be performed
based on our previous strategy of the face-selective addition
reaction as shown in Scheme 1:12 Conversion of a pyridine
of one side of the pyridinium face by the phenyl ring enables
allyl metal reagents to attack the complex only from the open
side, leading to 1,2- and 1,4-dihydropyridines stereoselec-
tively. We report here that allylation of pyridinium and
quinolinium salts with allylindium or allyltributyltin reagents
provides 1,2- and 1,4-adducts regio- and stereoselectively.
As substrates, we prepared nicotinic amides 1,12 4, and 5,
quinolinic amides 2 and 3, and the corresponding N-methyl
salts 6-9 as reference compounds for the geometrical studies.
Among various allylmetal reagents, we focused on allyl-
indium and allyltributyltin reagents as nucleophiles because
of the establishment of their regioselectivity in the addition
to pyridinium and quinolinium salts.13,14 Attempted addition
reaction of allylindium reagent to 1 in the presence of methyl
chloroformate in DMF and CH2Cl2 gave no adduct (Table
1, entries 1 and 2). On the other hand, the reaction was
Scheme 1. Strategy for the Stereoselctive Addition of Allyl
Reagents
Table 1. Face-Selective Addition Reaction of Allylmetal
Reagents to a Cation-π Complex
derivative A into a pyridinium salt with methyl chloroformate
will give a cation-π complex B. The selective face shielding
(6) (a) Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8, 5325.
(b) Comins, D. L.; King, L. S.; Smith, E. D.; Fe´vrier, F. C. Org. Lett. 2005,
7, 5059. (c) Bennasar, M.-L.; Zulaica, E.; Alonso, Y.; Bosch, J. Tetrahe-
dron: Asymmetry 2003, 14, 469. (d) Yamada, S.; Misono, T.; Ichikawa,
M.; Morita, C. Tetrahedron 2001, 57, 8939. (e) Ohno, A.; Oda, S.;
Yamazaki, N. Tetrahedron Lett. 2001, 42, 399. (f) Beckett, R. B.; Burgess,
V. A.; Davies, S. G.; Whittaker, M. Tetrahedron Lett. 1993, 34, 3617. (g)
Ge´nisson, C.; Marazano, C.; Das, B. C. J. Org. Chem. 1993, 58, 2052. (h)
Gosmini, R.; Mangeney, P.; Alexakis, A.; Commerc¸on, M.; Normant, J.-F.
Synlett 1991, 111. (i) Meyers, A. I.; Oppenlaender, T. J. Am. Chem. Soc.
1986, 108, 1989. (j) Schultz, A. G.; Flood, L.; Springer, J. P. J. Org. Chem.
1986, 51, 838. 4. (k) Meyers, A. I.; Oppenlaender, T. J. Chem. Soc., Chem.
Commun. 1986, 920. (l) Meyers, A. I.; Natale, N. R.; Wettlaufer, D. G.
Tetrahedron Lett. 1981, 22, 5123.
(7) (a) Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005,
1491. (b) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6327.
1
a Determined by H NMR spectra. b The de values are reported for the
major products unless otherwise noted. c Phenyl chloroformate was used
(8) (a) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2005, 44, 6700. (b) Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, A. K.
Angew. Chem., Int. Ed. 2005, 44, 6058. (c) Pauvert, M.; Collet, S. C.;
Bertrand, M.-J.; Guingant, A. Y.; Evain, M. Tetrahedron Lett. 2005, 46,
2983. (d) Youte, J.-J.; Barbier, D.; Al-Mourabit, A.; Gnecco, D.; Marazano,
C. J. Org. Chem. 2004, 69, 2737. (e) Surygina, O.; Ehwald, M.; Liebscher,
J. Tetrahedron Lett. 2000, 41, 5479. (f) Rezgui, F.; Mangeney, P.; Alexakis,
A. Tetrahedron Lett. 1999, 40, 6241. (g) Yamaguchi, R.; Tanaka, M.;
Matsuda, T.; Fujita, K.-I. Chem. Commun. 1999, 2213. (h) Nakamura, M.;
Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489.
instead of methyl chloroformate. d The de value is reported for 12b.
successfully performed in THF to give 1,2-adduct 10a as a
major product in 84% de (entry 3). Using phenyl chlorofor-
mate instead of methyl chloroformate improved the stereo-
(9) Yamaguchi, R.; Tanaka, M.; Matsuda, T.; Okano, T.; Nagura, T.;
Fujita, K. Tetrahedron Lett. 2002, 43, 8871.
(10) Mangeney, P.; Gosmini, R.; Raussou, S.; Commerc¸on, M.; Alexakis,
A. J. Org. Chem. 1994, 59, 1877.
(11) (a) Loh, T.-P.; Lye, P.-L.; Wang, R.-B.; Sim, K.-Y. Tetrahedron.
Lett. 2000, 41, 7779. (b) Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.;
Kawanisi, M. J. Org. Chem. 1985, 50, 287.
(12) Yamada, S.; Morita, C. J. Am. Chem. Soc. 2002, 124, 8184.
(13) (a) Lee, J. H.; Kweon, J. S.; Yoon, C. M. Tetrahedron Lett. 2002,
43, 5771. (b) Lee, S. H.; Park, Y. S.; Nam, M. H.; Yoon, C. M. Org. Biomol.
Chem. 2004, 2, 2170.
(14) Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. J. Org.
Chem. 1988, 53, 3507.
1478
Org. Lett., Vol. 9, No. 8, 2007

selectivity (entry 4). Addition of an allylzinc reagent resulted
in much lower regioselectivity with similar stereoselectivity
to the case of entry 3 (entry 5). Allyltributyltin also served
as a good nucleophile to afford 10a in good regio- and
stereoselectivity (entry 6). The nucleophile dependence on
the regioselectivity can be explained by the HSAB rule;
harder allylation reagent preferentially attacks the harder
2-position than the 4- and 6-position.
oxazolidine moiety. Kanemasa and his co-workers have
reported the effectiveness of this chiral auxiliary for asym-
metric Diels-Alder reactions, where the gem-dimethyl
groups help the benzyl group to block the diene moiety by
the steric repulsion.18 Addition of an allyltributyltin reagent
to the pyridinium salt of 4 gave 16a as a major product in
91% de (Scheme 3). On the other hand, the reaction with
Methallyl- and prenylindium reagents are also reported to
serve as nucleophiles to a pyridinium salt.13 Although
regioselectivity was scarcely observed in the reaction with
a methallylindium reagent (entry 7), the addition of a
prenylindium reagent preferentially gave 1,4-adduct 13b in
good regio- and stereoselectivities (entry 8). This regiose-
lectivity is in agreement with that of the reaction with
prenyltributyltin reported by Yamaguchi.14 To the best of
our knowledge, this is the first example of the stereoselective
allylation at the 4-position. It is worthwhile to note that the
chiral auxiliary of the adducts can be removed by the
reduction with Cp2Zr(H)Cl15 to give the corresponding
aldehydes.
Scheme 3
This allylation is applicable to the synthesis of dihydro-
quinoline derivatives. The addition of an allylmetal reagent
to a quinolinium was carried out under similar reaction
conditions described above (Scheme 2). Allylation of 2 with
the prenylindium reagent gave a 1,4-adduct 17b in 90% de.
These results clearly show the effectiveness of this chiral
auxiliary on the stereoselectivity. The stereogenic center of
1,4-adduct 17b was also assigned to be S by X-ray analysis.19
To elucidate the role of a cation-π interaction on the
Scheme 2
1
conformation of the intermediate pyridinium salt, H NMR
studies of 2-9 and X-ray structural analysis of 6 were carried
out. Table 2 lists the ∆δ values for the quinoline and
Table 2. ∆δ Values (ppm) for 2, 4, 6, and 8a,b
∆δ2
∆δ6
∆δ4
∆δ8
H2
H4
H5
H6
-0.15
-0.20
0.26
-0.59
-0.42
-0.69
-0.30
-0.19
-1.45
-0.50
-0.18
0.23
a Measured at 400 MHz in CDCl3. b ∆δ2 ) δ2 - δ3, ∆δ4 ) δ4 - δ5,
∆δ6 ) δ6 - δ7, ∆δ8 ) δ8 - δ9.
allyltributyltin exclusively yielded 2-allyldihydroquinoline
14a in 78% de. On the other hand, the reaction with a
prenylindium reagent gave 1,4-adduct 15b as a major
product, the stereoselectivity of which is 78% de. It is
interesting to note that this regioselectivity contrasts with
the indium-mediated prenylation of 2-ethoxy-1-(ethoxycar-
bonyl)-1,2-dihydroquinoline that yields 1,2-adduct as a major
product.13
The absolute configuration of the stereogenic center was
determined by X-ray structural analysis. Crystals suitable for
X-ray analyses were obtained for 1,2-dihydropyridine 11a16
and 1,2-dihydroquinoline 14a.17 The X-ray structures clarified
that both stereogenic centers have S configuration.
To improve the stereoselectivity, we used a chiral auxiliary
possessing gem-dimethyl groups at the 4-position of the
quinolinium protons of 2 and 6, and those for the pyridine
and pyridinium protons of 4 and 8, which are the differences
(16) Crystal data for 11a: C28H30N2O4, M ) 458.56, orthorhombic, space
group P212121, a ) 12.557(2) Å, b ) 21.638(3) Å, c ) 9.4914(15) Å, V )
2578.8(7) Å3, Z ) 4, Dcalcd ) 1.181 g cm-3, m ) 0.6369 mm-1 (Cu KR,
λ ) 1.54178 Å), T ) 293 K. R1 ) 0.0431 and wR2 ) 0.1335 for 3034
unique reflections > 2σ(I).
(17) Crystal data for 14a: C27H30N2O4, M ) 446.54, monoclinic, space
group P21, a ) 9.7426(10) Å, b ) 10.9058(12) Å, c ) 11.6685(12) Å, â
) 91.856(6)°, V ) 1239.1(2) Å3, Z ) 2, Dcalcd ) 1.197 g cm-3, m ) 0.6482
mm-1 (Cu KR, λ ) 1.54178 Å), T ) 293 K. R1 ) 0.0376 and wR2 )
0.1195 for 4065 unique reflections > 2σ(I).
(18) Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8631.
(19) Crystal data for 17b: C27H36N2O4, M ) 452.59, monoclinic, space
group P21, a ) 10.3437(11) Å, b ) 11.8652(14) Å, c ) 11.4054(12) Å, â
) 117.248(7)°, V ) 2293.5(13) Å3, Z ) 2, Dcalcd ) 1.208 g cm-3, m )
0.646 mm-1(Cu KR, λ ) 1.54178 Å), T ) 293 K. R1 ) 0.0718 and wR2
) 0.2041 for 11934 unique reflections > 2σ(I).
(15) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000,
122, 11995.
Org. Lett., Vol. 9, No. 8, 2007
1479

in the chemical shifts between their δ values and those of
reference compounds 3, 5, 7 and 9, respectively.
As can be seen from Table 2, ∆δ6 values for H2 and H6
are significantly different from those of the ∆δ2 values. The
H2 remarkably shifts to higher field and H4 shifts to lower
field. Similarly, ∆δ values of 8 are significantly different
from those of 4. These results suggest a significant confor-
mational difference between the neutral and the cationic
compounds; the quinoline and the pyridine rings of 2 and 4
may be apart from the benzyl ring, whereas the quinolinium
and pyridinium rings of 6 and 8 would be close to the benzyl
group.
The opposite tendency in the chemical shift change
between ∆δ6 and ∆δ8 may be due to the difference in the
shielding and deshielding area by the phenyl ring. The much
larger absolute values of ∆δ8 would be responsible for the
effective shielding of the benzyl group by introducing gem-
dimethyl groups.
X-ray analysis of compound 6 clearly shows the effective
blocking of the quinolinium plane by the benzyl group
through an intramolecular cation-π interaction (Figure 1).20
Figure 2. Structural optimization of quinolinium cation.
stereoselectivity. The predicted absolute configuration of the
stereogenic center is in agreement with that determined by
the X-ray analysis. The coordination of the carbonyl oxygen
toward metal reagents during the addition reaction may also
help this face selectivity.
Figure 3. Working model for face-selective addition to a cation-π
complex.
In summary, regio- and stereoselective allylation of
pyridinium and quinolinium salts was performed based on
the strategy through a cation-π complex. The reaction with
allylindium and allyltributyltin reagents afforded 1,2-adducts,
whereas the addition of a prenylindium reagent gave 1,4-
adducts in good regio- and stereoselectivities. The key feature
in this reaction is that the cation-π complex formation plays
an essential role in the face-selective allylation reaction.
Figure 1. ORTEP drawing of compound 6.
The quinolinium and the phenyl rings lie parallel to each
other, and the two rings are arranged face-to-face, the
distance between which is about 3.4 Å.
DFT calculations of the intermediate N-CO2Me quino-
linium cation at the B3LYP/6-31G* level21 predict the
preference of conformer II to I; conformer II is 2.99 kcal/
mol more stable than conformer I (Figure 2). The geometrical
difference between the crystal structure of 6 and conformer
II may be due to the difference in the N-substituent or
packing effect in the crystal.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research (B) (No. 13650901)
from the Japan Society for the Promotion of Science. We
gratefully acknowledge to Prof. Shuji Kanemasa (Kyushu
University) for his suggestion about an effective chiral
auxiliary.
Note Added after ASAP Publication. The structures of
compounds 1-9 were omitted in the version published ASAP
March 16, 2007; the corrected version was published ASAP
March 21, 2007.
These results lead to a working model outlined in Figure
3. The equilibrium between conformers I and II favors II.
Allylmetal reagents would attack the conformer II from the
less-hindered side to give a chiral dihydropyridine with good
Supporting Information Available: Crystallographic
data for 6, 11a, 14a, and 17b. Synthetic procedures and
(20) Crystal data for 6: C23H25N2O2Br, M ) 441.37, triclinic, space group
P1, a ) 6.8268(8) Å, b ) 12.5858(14) Å, c ) 14.2335(16) Å, R ) 79.547-
(7)°, â ) 12.5858(14)°, γ ) 14.2335(16)°, V ) 1158.2(2) Å3, Z ) 2, Dcalcd
) 1.266 g cm-3, m ) 2.564 mm-1 (Cu KR, λ ) 1.54178 Å), T ) 293 K.
R1 ) 0.0537 and wR2 ) 0.1518 for 4068 unique reflections > 2σ(I).
(21) DFT calculations were carried out by using PC SPARTAN ’06.
The optimized energies of I and II are -840742.707 kcal/mol and
-840745.695 kcal mol-1, respectively.
1
spectral data and H NMR spectra for 2-17. Optimized
structures for three rotamers of the N-CO2Me cation of 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070168Q
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Org. Lett., Vol. 9, No. 8, 2007