New synthetic route to C2-symmetric 2,2′-bipyridines: Synthesis of (6R,6′R,8R,8′R)-6,8,6′, 8′-bismethano-7,7,7′,7′-tetramethyl- 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-biquinoline

Article abstract of DOI:10.1081/SCC-100105892

A generalizable procedure to C₂-symmetric 2,2′-bipyridines based on two consecutive constructions of the pyridine rings is reported. As an example of this strategy the title bipyridine has been prepared in four steps from 3-benzyloxy-2-butanone

Full text of DOI:10.1081/SCC-100105892

This article was downloaded by: [Mount Allison University 0Libraries]
On: 05 October 2014, At: 13:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
NEW SYNTHETIC ROUTE TO C2-SYMMETRIC 2,2′-
BIPYRIDINES: SYNTHESIS OF (6R,6′R,8R,8′R)-6,8,6′,
8′-BISMETHANO-7,7,7′,7′-TETRA-
METHYL-5,5′,6,6′,7,7′,8,8′-OCTAHYDRO- 2,2′-
BIQUINOLINE
Giorgio Chelucci a & Antonio Saba a
a Dipartimento di Chimica , Universita' di Sassari , Via Vienna 2, Sassari, 07100, Italy
Published online: 16 Aug 2006.
To cite this article: Giorgio Chelucci & Antonio Saba (2001) NEW SYNTHETIC ROUTE TO C2-SYMMETRIC 2,2′-BIPYRIDINES:
SYNTHESIS OF (6R,6′R,8R,8′R)-6,8,6′, 8′-BISMETHANO-7,7,7′,7′-TETRA- METHYL-5,5′,6,6′,7,7′,8,8′-OCTAHYDRO-
2,2′-BIQUINOLINE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:20, 3161-3166, DOI: 10.1081/SCC-100105892
To link to this article: http://dx.doi.org/10.1081/SCC-100105892
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(20), 3161–3166 (2001)
NEW SYNTHETIC ROUTE TO
C2-SYMMETRIC 2,20-BIPYRIDINES:
SYNTHESIS OF (6R,60R,8R,80R)-6,8,60,
80-BISMETHANO-7,7,70,70-TETRA-
METHYL-5,50,6,60,7,70,8,80-OCTAHYDRO-
2,20-BIQUINOLINE
Giorgio Chelucci* and Antonio Saba
Dipartimento di Chimica, Universita’ di Sassari,
Via Vienna 2, 07100 Sassari, Italy
ABSTRACT
A generalizable procedure to C2-symmetric 2,20-bipyridines
based on two consecutive constructions of the pyridine rings
is reported. As an example of this strategy the title bipyridine
has been prepared in four steps from 3-benzyloxy-2-butanone
and (1R,5R)-3-methylenenopinone.
Chiral derivatives of 2,20-bipyridines and in particular those provided
of C2-symmetry are finding increased utility as auxiliaries for metal cata-
lyzed asymmetric catalysis.1,2 Notwithstanding this, relatively few chiral
C2-symmetric bipyridine ligands has been reported and used in asymmetric
*Corresponding author.
3161
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
3162
CHELUCCI AND SABA
catalysis.3 One reason associated with this problem is the lack of efficient
and alternative synthetic routes to them. In fact, the nickel-mediated homo-
coupling of 2-halopyridines is the sole method reported so far.2
The difficulties associated with the preparation of 2-halopyridines have
led us to explore new procedures for obtaining such ligands. Here we
describe a generalizable procedure for the preparation of C2-symmetric
bipyridines, specifically, the synthesis of the pinano-fused bipyridine 64
from (þ)-nopinone which was selected as a prototype from which to develop
the basic methodology.
The synthesis of 2,20-bipyridine 6 began with racemic 3-benzyloxy-2-
butanone 2 which was prepared from the dimeric ketal 1 by heating
under reflux a mixture of benzyl alcohol and concentrated hydrochloric
acid in toluene on a Dean-Stark apparatus5 (Scheme 1). Then, the pyridine
3 was obtained by conjugate addition of the lithium enolate of the benzylk-
etone 2 with (1R,5R)-3-methylenenopinone (7), in turn obtained from (-)-b-
pinene6 (Scheme 1, at the bottom), followed by azaanellation of unisolated
1,5-dicarbonyl intermediate with the ammonium acetate/acetic acid system
(23% overall yield). Catalytic hydrogenolysis of the benzyl derivative
3 (Pd/C at 3 atm.) gave the carbinol 4 (92%) which was oxidized under
the condition of Swern reaction to ketone 5 (93%). Starting from this
key intermediate, the bipyridine 6 was prepared by building up the
second pyridine ring in a similar way to that used to prepare 3 from 2
(35% overall yield).
Scheme 1.

ORDER
REPRINTS
C2-SYMMETRIC 2,20-BIPYRIDINES
3163
In conclusion, the present protocol to C2-symmetric bipyridines
offers an useful alternative to the method based on the homocoupling of
2-halopyridines.
EXPERIMENTAL SECTION
Boiling points are uncorrected. Melting points were determined on a
Buchi 510 capillary apparatus and are uncorrected. The 1H-NMR
(300 MHz) spectra were obtained with a Varian VXR-300 spectrometer.
Chemical shifts are reported in ppm downfield from internal Me4Si.
Optical rotations were measured with a Perkin-Elmer 241 polarimeter
in a 1 dm tube. Elemental analyses were performed on a Perkin-Elmer
240 B analyser. Tetrahydrofuran (THF) was freshly distilled over LiAlH4
under argon. 3-Hydroxy-2-butanone dimer and lithium diisopropylamine
(LDA, 2M solution in heptane/THF/ethylbenzene) were purchased
from Aldrich Chemical Co. (1R,5R)-3-Methylenenopinone (7) was prepared
from (-)-b-pinene (99% pure, Aldrich) according to a reported procedure.6
3-(Phenylmethoxy)-2-butanone (2): A solution of 1 (17.1 g, 0.1 mol) and
benzyl alcohol (32.4 g, 0.3 mol) in toluene (40 ml) containing concentrated
hydrochloric acid (10 ml) was refluxed for 45 min on a Dean-Stark appara-
tus. Then the toluene was evaporated and the oily residue was distilled in
vacuo to give 2 (10.5 g, 59%): bp2 110ꢀC; H-NMR (CDCl3) d: 7.38–7.29
1
(m, 5H), 4.56 (d, 1H, J ¼ 11.7 Hz), 4.49 (d, 1H, J ¼ 11.7 Hz), 3.90 (q, 1H,
J ¼ 6.8 Hz), 2.20 (s, 3H), 1.34 (d, 3H, J ¼ 7.1). Anal. Calcd for C11H14O2: C,
74.13; H, 9.92. Found: C, 74.25; H, 9.97.
(6R,8R)-6,8-Methano-7,7-dimethyl-2-[(1-phenylmethoxy)ethyl]-5,6,7,8-
tetrahydroquinoline (3): A solution of 2 (8.16 g, 46 mmol) in anhydrous
THF (5 ml) was added dropwise at ꢁ78ꢀC to a solution of lithium diisopro-
pylamine (46 mmol) in anhydrous THF (230 ml) under an argon atmos-
phere. The resulting solution was stirred at ꢁ40ꢀC for 2 h and then
a solution of 3-methylenenopinone (7) (6.9 g, 46 mmol) in THF (20 ml)
was added dropwise at ꢁ40ꢀC. After 15 min at ꢁ40ꢀC, the solution was
allowed to reach slowly room temperature and then poured into a mixture
of ammonium acetate (71 g, 50 mmol) and acetic acid (230 ml). The flask was
connected with a distillation head and the THF was distilled off over a 3-h
period. Most part of the acetic acid was removed under reduced pressure
and the residue taken up with H2O and extracted with ethyl ether. The
organic phase was separated and extracted with a 10% HCl solution. The
acid solution was neutralized with a 5% NaOH solution and extracted with
ethyl ether. The organic phase was dried on anhydrous Na2SO4, the solvent

ORDER
REPRINTS
3164
CHELUCCI AND SABA
was evaporated and the residue was purified by flash chromatography
(petroleum ether/ethyl acetate ¼ 9/1) to give 3 as a mixture of diastereomers
1
(in a ratio 6/4): 3.25 g (23%); oil; H-NMR (CDCl3); major isomer, d: 7.43
(d, 1H, J ¼ 7.8), 7.37–7.22 (m, 6H), 4.59 (m, 1H), 4.46 (m, 2H), 2.97 (m, 1H),
2.93 (s, 2H), 2.33 (m, 1H), 1.50 (d, 3H, J ¼ 6.6 Hz), 1.42 (s, 3H), 1.31 (d, 1H,
J ¼ 9.6 Hz), 0.66 (s, 3H). Minor isomer, d: 7.43 (d, 1H, J ¼ 7.8), 7.37–7.22
(m, 6H), 4.59 (m, 1H), 4.46 (m, 2H), 2.97 (m, 1H), 2.93 (s, 2H), 2.33 (m, 1H),
1.51 (d, 3H, J ¼ 6.6 Hz), 1.42 (s, 3H), 1.30 (d, 1H, J ¼ 9.6 Hz), 0.67 (s, 3H).
Anal. Calcd for C21H25NO: C, 82.03; H, 8.20; N, 4.56. Found: C, 82.15; H,
8.06; N, 4.66.
(6R,8R)-2-[(1-hydroxy)ethyl]-6,8-methano-7,7-dimethyl-5,6,7,8-tetrahy-
droquinoline (4): A mixture of 3 (3.07 g, 10 mol), 10% palladium on carbon
in 95% ethanol (40 ml) was hydrogenated at room temperature and 3 atm in
a Parr apparatus. Hydrogen absorption ceased after the uptake of one
equivalent of Hydrogen. The mixture was filtered and the filtrate evaporated
at reduced pressure to give an oil. Purification of this oil by chromatography
on SiO2 (petroleum ether/ethyl acetate ¼ 7/3) gave 4 as a mixture of diaster-
eomers (in a ratio 6/4) (2.0 g, 92%): oil;1H-NMR (CDCl3); major isomer,
d: 7.40 (d, 1H, J ¼ 7.5), 7.04 (d, 1H, J ¼ 7.5 Hz), 4.82 (q, 1H, J ¼ 6.6 Hz), 4.65
(s broad, 1H), 2.98 (t, 1H, J ¼ 5.7 Hz), 2.92 (d, 2H, J ¼ 2.4 Hz), 2.70 (m, 1H),
2.33 (m, 1H), 1.48 (d, 3H, J ¼ 6.6 Hz), 1.42 (s, 3H), 1.28 (d, 1H, J ¼ 9.6), 0.64
(s, 3H). Minor isomer, d: 7.40 (d, 1H, J ¼ 7.5), 7.02 (d, 1H, J ¼ 7.5 Hz), 4.82
(q, 1H, J ¼ 6.6 Hz), 4.65 (s broad, 1H), 2.98 (t, 1H, J ¼ 5.7 Hz), 2.92 (d, 2H,
J ¼ 2.4 Hz), 2.70 (m, 1H), 2.33 (m, 1H), 1.48 (d, 3H, J ¼ 6.6 Hz), 1.42 (s, 3H),
1.27 (d, 1H, J ¼ 9.6 Hz), 0.65 (s, 3H). Anal. Calcd for C14H19NO: C, 77.37;
H, 8.82; N, 6.45. Found: C, 77.55; H, 8.92; N, 6.33.
(6R,8R)-(ꢁ)-2-ethanoyl-6,8-methano-7,7-dimethyl-5,6,7,8-tetrahydroqui-
noline (5): A solution of dimethyl sulfoxide (0.82 g, 10.5 mmol) in anhydrous
CH2Cl2 (3 ml) was added dropwise to a solution of oxalyl chloride (0.66 g,
5.3 mmol) in CH2Cl2 (13 ml) at ꢁ60ꢀC. After stirring for 5 min a solution of
4 (0.87 g, 4 mmol) in CH2Cl2 (5 ml) was added. The cloudy mixture was
stirred at ꢁ60ꢀC for 50 min and Et3N (2.03 g, 20 mmol) was added dropwise.
The resulting mixture was warmed to room temperature and stirred for 1 h.
The mixture was poured into H2O and extracted with CH2Cl2. The organic
phase was dried on anhydrous Na2SO4, the solvent was evaporated and the
residue was purified by flash chromatography (petroleum ether/ethyl acet-
ate ¼ 7/3) to give 5: 0.8 g (93%); oil; [a]2D5-20.2. (c 2.3, CHCl3). H-NMR
1
(CDCl3) d: 7.85 (d, 1H, J ¼ 7.8 Hz), 7.52 (d, 1H, J ¼ 7.8 Hz), 3.06 (t, 1H,
J ¼ 5.7 Hz), 3.00 (d, 2H, J ¼ 2.7 Hz), 2.76 (m, 1H), 2.69 (s, 3H), 2.35 (m, 1H),
1.44 (s, 3H), 1.29 (d, 1H, J ¼ 9.6 Hz), 0.66 (s, 3H). Anal. Calcd for
C14H17NO: C, 78.09; H, 7.96; N, 6.51. Found: C, 78.23; H, 7.84; N, 6.61.

ORDER
REPRINTS
C2-SYMMETRIC 2,20-BIPYRIDINES
3165
(6R,60R,8R,80R)-(þ)-6,8,60,80-Bismethano-7,7,70,70-tetramethyl-5,50,6,
60,7,70,8,80-octahydro-2,20-biquinoline (6): Following the procedure used for
the preparation of 3 and starting from 5 (0.78 g, 36 mmol) a crude mixture
was obtained (1 g). Purification of this mixture by chromatography on neu-
tral aluminium oxide (petroleum ether/ethyl acetate ¼ 9/1) gave 6 (436 mg,
35%): mp 163–164ꢀC; [a]D25þ41.3 (c 1.1, CHCl3). H-NMR (CDCl3) d: 8.07
1
(d, 2H, J ¼ 8.1 Hz), 7.50 (d, 2H, J ¼ 8.1 Hz), 3.10 (t, 2H, J ¼ 5.7 Hz), 2.97
(d, 4H, J ¼ 2.7 Hz), 2.74 (m, 2H), 2.33 (m, 2H), 1.42 (s, 6H), 1.35 (d, 2H,
J ¼ 9.6 Hz), 0.67(s, 6H). Anal. Calcd for C24H28N2: C, 83.67; H, 8.20;
N, 8.14. Found: C, 83.77; H, 8.29; N, 8.05.
ACKNOWLEDGMENT
Thanks are due to Mr. Mauro Mucedda for experimental assistance.
Financial support by M.U.R.S.T. and by Regione Autonoma Sardegna is
gratefully acknowledged.
REFERENCES
1. For non C2-symmetric 2,20-bipyridine, see: Chelucci, G.; Gladiali, S.;
Sanna, M.G.; Brunner, H. Tetrahedron: Asymmetry 2000, 11, 3419.
Chelucci, G.; Gladiali, S.; Saba, A.; Sanna, G.; Soccolini, F.
Tetrahedron: Asymmetry 2000, 11, 3427. Chelucci, G.; Pinna, G.A.;
Saba, A. Tetrahedron: Asymmetry 1998, 9, 531. Collomb, P.; von
Zelewsky, A. Tetrahedron: Asymmetry 1998, 9, 3911. Duboc-Toia,
C.; Menage, S.; Lambeaux, C.; Fontecave, M. Tetrahedron Lett.
1997, 38, 3727. Chelucci, G.; Cabras, M.A.; Botteghi, C.; Basoli, C.;
Marchetti, M. Tetrahedron: Asymmetry 1996, 7, 885. Chen, C.;
Tagami, K.; Kishi, Y. J. Org. Chem. 1995, 60, 5386.
2. For C2-symmetric 2,20-bipyridine, see: (a) Malkov, A.V.; Bella, M.;
Langer, V.; Kocovsky, P. Organic Lett. 2000, 2, 3047. (b) Wong,
H.L.; Tian, Y.; Chan, K.S. Tetrahedron Lett., 2000, 41, 7723. Rios,
R., Liang, J.; Lo, M.M.-C.; Fu, G.C. Chem. Commun. 2000, 377.
Chelucci, G.; Culeddu, N.; Saba, A.; Valenti, R. Tetrahedron:
Asymmetry 1999, 10, 3537. Fletcher, N.C.; Keene, F.R.; Ziegler, M.;
Stoeckli-Evans, H.; Viebrock, H.; von Zelewsky, A. Helv. Chim. Acta
1996, 79, 119. Ito, K.; Yoshitake, M.; Katsuki, T. Tetrahedron 1996,
3905. Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857. Chelucci, G.;
Falorni, M.; Giacomelli, G. Tetrahedron 1992, 48, 3653. Ito, K.;
Tabuchi, S.; Katsuki, T. Synlett 1992, 575. Ito, K.; Tabuchi, S.;

ORDER
REPRINTS
3166
CHELUCCI AND SABA
Katsuki, T. Tetrahedron Lett. 1992, 575. Bolm, C.; Zehnder, M.; Bur,
D. Angew. Chem. Int. Ed. Engl. 1990, 29, 205.
3. For a review, see: Chelucci, G. Gazz. Chim. Ital. 1992, 122, 89. See also
ref. 1 and ref. 2.
4. During the preparation of this manuscript the preparation of 6 through
coupling of a 2-chloropyridine has been reported by Kocovsky’s group;
ref. 2a.
5. Kossolapoff, G.M.C.A., 1964, 61, 1770. Wu, Y.-J.; Ding, W.-L.; Du,
C.-X. Tetrahedron: Asymmetry 1998, 9, 4035.
6. Gianini, M.; von Zelewsky, A. Synthesis 1996, 702.
Received in the Netherlands January 2, 2001

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC100105892