The synthesis is reported of chiral substituted 2-methylpyridines, in which the pyridine rings are

annulated at the 5,6-positions to the chiral frameworks originating from (-)-β-pinene,

(-)-isopinocampheol and (+)-camphor. Two procedures have been evaluated for their

preparation

Chelucci, Giorgio Adolfo

Orrù, Gianmauro

Soccolini, Francesco

English

UnissResearch

General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 44 ©ARKAT USA, Inc 
Synthesis of chiral 2-methyl-5,6,7,8-tetrahydroquinolines from 
naturally occurring monoterpenes 
 
Giorgio Chelucci,* Gianmauro Orrù, and Franco Soccolini 
 
Dipartimento di Chimica, Università di Sassari, via Vienna 2, I-07100 Sassari, 
Italy 
E-mail: chelucci@ssmain.uniss.it 
(received 17 Mar 04; accepted 09 Aug 04; published on the web 22 Aug 04) 
 
Abstract 
The synthesis is reported of chiral substituted 2-methylpyridines, in which the pyridine rings are 
annulated at the 5,6-positions to the chiral frameworks originating from (-)-β-pinene,  
(-)-isopinocampheol and (+)-camphor. Two procedures have been evaluated for their 
preparation. 
 
Keywords: Chiral tetrahydroquinolines, chiral pyridines, chiral nitrogen heterocycles, Kröhnke 
annulation 
 
 
 
Introduction 
 
During our study on the synthesis of chiral P,N-ligands with pyridine N-donors,1,2 we needed a 
set of chiral substituted 2-methylpyridines bearing a stereogenic centre on the carbon bonded to 
the 6-position of the heterocycle. Since these compounds should be obtained from inexpensive 
chiral compounds, monoterpenes, easily available building blocks originating from the chiral 
pool, were selected as appropriate starting materials. 
Herein, we wish to report the synthesis of the three chiral substituted 2-methylpyridines 1-3 
in which the pyridine rings are annulated at the 5,6-positions to chiral frameworks originating 
from (-)-β-pinene, (-)-isopinocampheol and (+)-camphor. 
 
N
2
N
3
N
1  
 
 
 
General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 45 ©ARKAT USA, Inc 
Results and Discussion 
 
At the start of our investigation, we envisaged that the most direct approach to 
tetrahydroquinolines 1-3 could involve the Kröhnke methodology for the synthesis of pyridines.3 
This route demands the reaction of a β-ketoalkylpyridinium salt with an α,β-unsaturated 
carbonyl compound in the presence of ammonium acetate/acetic acid. Thus, to test the feasibility 
of this idea, 1-(2-oxopropyl)pyridinium bromide (6)4 was prepared by reaction of bromoacetone 
5 with pyridine (Scheme 1). 
An attempt to prepare the analogue iodide by reaction of acetone with iodine in pyridine, as 
reported by Saxena et al.5 failed. Instead we obtained 1,3-(dipyridinium-1-yl)propan-2-one 
diiodide (7) in 15% yield (Scheme 1). Salt 6 was then treated with the α-methylene ketone 96 
which was selected as a typical substrate to develop optimal reaction conditions. Compound 9 
was prepared in two steps from the ketone 8 obtained in turn by oxidation of (-)-β-pinene7 
(Scheme 2). The Kröhnke-type cyclization gave the expected pyridine 1 but in low yield. 
Although many permutations of conditions were explored, in no case the yield of the desired 
pyridine was >15%. 
 
6
O
N+
Br-
Br
O
O
NN
O
+ +
I-I-
5
7
4
a
b
c
a: Br2, Na2CO3, CCl4 ;  b: pyridine, Et2O;  c: I2, pyridine, MeOH.  
 
Scheme 1 
 
The unsatisfactory outcome of these experiments prompted us to examine an alternative 
procedure8 (Scheme 2). Accordingly, dimethylhydrazone 10, prepared by treatment of the (+)-
nopinone (8) with N,N-dimethylhydrazine, was deprotonated (n-BuLi, THF, -78 °C, 2 h) and 
then quenched with 2-(2-bromoethyl)-2,5,5-trimethyl-[1,3]dioxane (12). The alkylation product 
11 was not isolated, but directly converted into the tetrahydroquinoline 1 by heating in carbitol 
(35% yield based on 10). The overall yield (31% yield based on 8) of this process was much 
higher than that obtained following the Kröhnke-type cyclization (10% yield based on 8). 
Having obtained the desired pyridine 1, the alkylation-azaannulation-aromatization sequence 
was extended to the bicyclic ketones 14, prepared by oxidation of (-)-isopinocampheol, and (+)-
General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 46 ©ARKAT USA, Inc 
camphor (17) (Scheme 3 and 4). Thus, the dimethylhydrazones 15 and 18, afforded pyridines 2 
and 3 in 32 and 17% yield, respectively. 
 
N
10
8
b
Br
12
O
c
O
N N
11
N
O
O
(-)-β-pinene 9 1
a d
e
f
g
a: TMO, OsO4, Py, t-BuOH/H2O, then NaIO4, r.t., reflux, 2h, 66%;  
b: NaNH2, Bz, reflux, 15h; then isopentyl formate, r.t., 4h, finally HCl, 
71%;  c: Na2CO3, HCHO, r.t., 40 min, 99%;  d: 6, MeOH, AcONH4, 
reflux, 20h, 15%;  e: H2NNMe2, EtOH, reflux;  f: n-BuLi, THF, -78 C 
then 12;  g: carbitol, HCl, reflux, 6h.
O
O
N
 
 
Scheme 2 
 
The overall yield of the process was comparable for pyridines 1 and 2 (32-35%), but much 
lower (17%) for pyridine 3 derived from camphor. This result can be attributed to the steric 
hindrance of the camphor carbonyl group that reduces the ability of this ketone to undergo the 
azaannulation step.9 
O
N
b
2
N
N
14 15
d
a
OH
(-)-isopinocampheol 13
N
N
16
O
O
c
 
a: CrO3, H2SO4, acetone, 82%; b: H2NNMe2, EtOH, reflux; c: n-BuLi, THF, -78 
oC then 12;
d: carbitol, HCl, reflux, 6h  
 
Scheme 3 
General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 47 ©ARKAT USA, Inc 
NO N
N
c
(+)-camphor 17
3
a
18
b
N
N
19
O
O
 
a: H2NNMe2, EtOH, reflux; b: n-BuLi, THF, -78 
oC then 12; c: carbitol, HCl, reflux, 6h  
 
Scheme 4 
 
With the pyridines 1-3 in hand, we attempted to transform them into the related pyridine-
phosphine ligands 20 (Scheme 5). Unexpectedly, several attempts to prepare 20 by metallation of 
the 2-methyl group of compounds 1-3 with various bases (LDA, n-BuLi, PhLi, etc.), followed by 
treatment with chlorodiphenylphosphine, failed.10 
 
R R
PPh2* *
1-3 20
N N
 
 
Scheme 5 
 
 
Conclusions 
 
Although the synthesis of the pyridine-phosphines of the type 20 has been unsuccessful, we have 
explored two procedures for preparing chiral substituted 2-methylpyridines from monoterpenes, 
making available new chiral pyridines which could be useful chiral building blocks for the 
synthesis of more complex heterocycles.11 
 
 
Experimental Section 
 
General Procedures. All reagents and solvents were purchased from Aldrich and used as 
received. THF was distilled from sodium-benzophenone ketyl and degassed thoroughly with dry 
nitrogen directly before use. Melting points were determined on a Büchi 510 capillary apparatus 
and are uncorrected. The 1H-NMR spectra were obtained with a Varian VXR-300 spectrometer 
at 300 MHz. Chemical shifts are reported in ppm downfield from internal Me4Si in CDCl3 if not 
otherwise stated. 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. 
General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 48 ©ARKAT USA, Inc 
1-(2-Oxopropyl)pyridinium bromide (6) was prepared according to a reported procedure.4 
(1R,5R)-6,6-Dimethylbicyclo[3.1.1]heptan-2-one ((+)-nopinone, 8) and (1R,2S,5S)-2,6,6-
trimethylbicyclo[3.1.1]heptan-3-one (14) were prepared by oxidation of (-)-β-pinene (99% pure, 
Aldrich)7 and (-)-isopinocampheol (98% pure, 95% ee by GLC, Aldrich),12 respectively. 
(1R,5R)-6,6-Dimethyl-3-methylenebicyclo[3.1.1]heptan-2-one (9) was prepared from (+)-
nopinone (8).7 (+)-Camphor (17) and 2-(2-bromoethyl)-2,5,5-trimethyl-[1,3]-dioxane (12) were 
purchased from Aldrich. 
 
General procedure for the preparation of N,N-Dimethylhydrazones13 
A solution of the ketone (0.02 mol), N,N-dimethylhydrazine (2.7 g, 0.045 mol) and catalytic 
amount of 4-toluenesulfonic acid in absolute EtOH (25 mL) was heated under reflux for 7 days. 
The solvent was removed and the residue taken up with cold (0 °C) 5% HCl (2 x 15 mL) and 
Et2O (20 mL). The aqueous layer was separated, basified with 10% solution of NaOH (40 mL) 
and extracted with Et2O (2 x 20 mL). The organic extracts were dried over anhydrous Na2SO4 
and the solvent was evaporated. The residue was purified by distillation under reduced pressure 
to give pure N,N-dimethylhydrazones. 
(1R,5R)-N,N-Dimethyl-N'-(6,6-dimethylbicyclo[3.1.1]hept-2-ylidene) hydrazine (10). This 
compound was obtained in 93% yield based on the converted ketone 8: bp 100 °C (10 mm Hg), 
1H-NMR: δ 2.65-2.42 (m, 3H), 2.45 (s, 6H), 2.30-1.80 (m, 4H), 1.43 (d, 1H, J = 9.9 Hz), 1.28 (s, 
3H), 0.78 (s, 3H). Calcd for C11H20N2: C, 73.28; H, 11.18; N, 15.54. Found: C, 73.32; H, 11.14; 
N, 15.51. 
(1R,2S,5S)-N,N-Dimethyl-N'-(2,6,6-trimethylbicyclo[3.1.1]hept-3-ylidene) hydrazine (15). 
This compound was obtained in 93% yield based on the converted ketone 14: bp 115 °C (10 mm 
Hg), 1H-NMR: δ 2.88-280 (m, 1H), 2.75-2.68 (m, 2H), 2.46 (s, 6H), 2.31-2.22 (m, 1H), 2.02-
1.91 (m, 1H), 1.86-1.78 (m, 1H), 1.25 (s, 3H), 1.18 (d, 3H, J = 7.2 Hz), 1.08 (d, 1H, J = 10.5 Hz), 
0.83 (s, 3H). Anal. Calcd for C12H22N2: C, 74.17; H, 11.41; N, 14.42. Found: C, 74.22; H, 11.48; 
N, 14.38. 
N,N-Dimethyl-N'-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)hydrazine (18). This 
compound was obtained in 87% yield based on the converted camphor: bp 65 °C (4 mm Hg), 1H-
NMR: δ 2.58-2.47 (m, 1H), 2.45 (s, 6H), 2.00 (d, 1H, J = 18 Hz), 1.93-1.76 (m, 2H), 1.68 (dt, 
1H, J = 12, 4 Hz), 1.37 (dt, 1H, J = 12, 4 Hz), 1.21 (dt, 1H, J = 12, 4 Hz), 1.03 (s, 3H), 0.97 (s, 
3H), 0.82 (s, 3H). Calcd for C12H22N2: Anal. Calcd for C12H22N2: C, 74.17; H, 11.41; N, 14.42. 
Found: C, 74.12; H, 11.37; N, 14.47. 
1,3-(Dipyridinium-1-yl)propan-2-one diiodide (7). A solution of iodine (101.6 g, 0.4 mol) 
acetone (29.3 mL, 0.4 mol), pyridine (80.9 mL, 1.0 mol) in MeOH (600 mL) was heated under 
reflux for 10 h. The formed solid was filtered off and recrystallized from 50% aqueous methanol 
to give white crystals: 14.0 g (15% yield based on the iodine), mp 227-228 °C. 1H-NMR 
((CD3)2SO): δ 8.72 (d, 4H, J = 5.4 Hz), 8.75 (t, 2H, J = 7.8 Hz), 8.75 (t, 4H, J = 6.9 Hz), 6.02 (s, 
4H). Anal. Calcd for C13H14I2N2O: C 33.36, H 3.01, N 5.98. Found: C 33.45, H 3.09, N 5.68. 
General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 49 ©ARKAT USA, Inc 
(6R,8R)-(+)-5,6,7,8-Tetrahydro-2,7,7-trimethyl-6,8-methanoquinoline (1). A mixture of 1-(2-
oxopropyl)pyridinium bromide (6) (2.16 g, 0.01 mol), ammonium acetate (7.7 g, 0.1 mol) and 
(1R,5R)-6,6-dimethyl-3-methylenebicyclo[3.1.1]heptan-2-one (9) (1.5 g, 0.01 mol) in absolute 
MeOH (50 mL) was heated under reflux for 20 h. After cooling the solvent was evaporated and 
the residue was taken up in H2O (200 mL) and extracted with Et2O (3 x 30 mL). The ethereal 
phase was extracted with a 10% solution of HCl (3 x 10 mL). The aqueous phase was basified 
with a 10% solution of NaOH (40 mL) and extracted with Et2O (2 x 50 mL). The combined 
organic phases were dried over anhydrous (Na2SO4), the solvent was evaporated and the residue 
was purified by flash chromatography (petroleum ether/ethyl acetate = 9/1) to give pure 1 as a 
pale yellow oil: 0.28 g (15%), [α]
25
D (c = 3.12, CHCl3): -25.3.
 1H-NMR: δ 7.21 (d, 1H, J = 6.9 
Hz), 6.84 (d, 1H, J = 6.9 Hz), 2.87 (t, 1H, J = 5.7 Hz), 2.80 (s, 2H), 2.64-2.57 (m, 1H), 2.40 (s, 
3H), 2.25-2.20 (m, 1H), 1.32 (s, 3H), 1.18 (d, 1H, J = 9.6 Hz), 0.58 (s, 3H). 13C NMR: δ 169.2, 
153.1, 137.7, 127.8, 120.1, 52.3, 49.4, 46.5, 33.3, 34.4, 24.5, 23.2, 19.2. Anal. Calcd for 
C13H17N: C 83.37, H 9.15, N 7.48. Found: C 83.46, H 9.17, N 7.50. 
 
General procedure for the preparation of chiral 2-methyl-5,6,7,8-tetrahydroquinolines 
A solution of the proper N,N-dimethylhydrazone (0.02 mol) in anhydrous THF (5 mL) was 
added dropwise to a cooled (-78 °C) solution of n-butyllithium (0.02 mol, 12.5 mL of a 1.6 M 
solution in hexane) in anhydrous THF (50 mL). The resulting solution was stirred at -78 °C for 2 
h and then at 0 °C for 1 h. After cooling at -78 °C, a solution of 2-(2-bromoethyl)-2,5,5-
trimethyl-[1,3]dioxane (12) (5.47 g, 0.02 mol) in anhydrous THF (5 mL) was added dropwise. 
After 15 min at -78 °C, the solution was allowed to reach slowly room temperature (overnight) 
and were then quenched with H2O. The mixture was extracted with ethyl ether. The organic 
phase was separated, dried (Na2SO4) and the solvent was evaporated. The flask was connected to 
a distillation head and heated under reduced pressure (0.1 mm Hg) to distill off unconverted 
hydrazone and dioxane. The residue was taken up with carbitol (30 mL), acidified with a few 
drops of HCl and heated under reflux for 6 h. After cooling, the mixture was taken up with H2O 
(500 mL) and extracted with ethyl ether (3 x 50 mL). The ethereal phase was extracted with a 
10% solution of HCl (3 x 50 mL). The aqueous phase was basified with a 10% solution of NaOH 
and extracted with ethyl ether. The organic phase was dried on anhydrous Na2SO4, and the 
solvent was evaporated. The residue was distilled under reduced pressure (13 mm Hg) collecting 
the fraction distilling between 160-180 °C. The distillate was finally purified by flash 
chromatography (petroleum ether/ethyl acetate = 9/1) to give pure tetrahydroquinolines. 
(6R,8R)-(+)-5,6,7,8-Tetrahydro-2,7,7-trimethyl-6,8-methanoquinoline (1). Yield: 1.31 g 
(35%). The 1H-NMR spectrum was identical to that obtained in the above reported method.  
(5R,7R,8S)-(-)-5,6,7,8-Tetrahydro-2,6,6,8-tetramethyl-5,7-methanoquinoline (2). Yield: 
1.28g (32%), oil, [α]
25
D (c = 1.18, CHCl3): -0.61. 
1H-NMR: δ 7.06 (d, 1H, J = 7.5 Hz), 6.81 (d, 
1H, J = 7.5 Hz), 3.21-3.10 (m, 1H), 2.68 (q, 1H, J = 6.3 Hz), 2.55-2.44 (m overlapping, 1H), 2.51 
(s, 3H), 2.16-2.08 (m, 1H), 1.39 (s, 3H), 1.37 (d, 3H, J = 7.2 Hz), 1.28 (d, 1H, J = 9.9 Hz), 0.62 
General Papers ARKIVOC 2004 (xiv) 44-50 
ISSN 1424-6376 Page 50 ©ARKAT USA, Inc 
(s, 3H). 13C NMR: δ 168.9, 154.2, 137.4, 128.5, 119.9, 56.5, 49.8, 45.3, 33.5, 31.2, 25.3, 24.8, 
21.9, 21.3. Anal. Calcd for C14H19N: C 83.53, H 9.51, N 6.96. Found: C 83.61, H 9.53, N 6.94. 
(5S,8R)-(+)-5,6,7,8-Tetrahydro-2,8,9,9-tetramethyl-5,8-methanoquinoline (3).
8
 Yield: 0.68 g 
(17%), oil, [α]
20
D (c = 1.44, CHCl3): +23.2. 
1H-NMR: δ 7.22 (d, 1H, J = 7.2 Hz), 6.80 (d, 1H, J = 
7.2 Hz), 2.79 (d, 1H, J = 4.2 Hz), 2.51 (s, 3H), 2.13-2.03 (m, 1H), 1.83 (dt, 1H, J = 12.3, 3.6 Hz), 
1.32 (s, 3H), 1.26-1.04 (m, 2H), 0.97 (s, 3H), 0.54 (s, 3H). 13C NMR: δ 169.6, 153.8, 137.8, 
128.1, 119.5, 56.5, 53.9, 51.0, 31.6, 26.2, 26.1, 24.1, 19.8, 19.1. Anal. Calcd for C14H19N: C 
83.53, H 9.51, N 6.96. Found: C 83.48, H 9.49, N 6.98. 
 
 
Acknowledgements 
 
Financial support from MIUR (PRIN 2003033857-Chiral ligands with nitrogen donors in 
asymmetric catalysis by transition metal complexes. Novel tools for the synthesis of fine 
chemicals) and from the University of Sassari is gratefully acknowledged by G. C. 
 
 
References 
 
1. For a recent review on pyridine-phosphine ligands, see: Chelucci, G.; Orrù , G.; Pinna, G. A. 
Tetrahedron  2003, 59, 9471. 
2. Chelucci, G.; Saba, A.; Soccolini, F. Tetrahedron 2001, 57, 9989. 
3. Kröhnke, F. Synthesis 1976, 1 and references therein. 
4. Kröhnke, F.; Schmidt, E.; Zecher, W. Chem. Ber. 1964, 97, 1163. 
5. Saxena, J. P.; Gelra, M. A. Aust. J. Chem. 1967, 20, 1171. 
6. Gianini, M.; von Zelewsky, A. Synthesis 1996, 702. 
7. (a) Grimshaw, N.; Grimshaw, J. T.; Juneja, H. R. J. Chem. Soc., Perkin Trans. 1 1972, 50. 
(b) Brown, H. C.; Weissman, S. A.; Perumal,  P. T.; Dhokte, U. P. J. Org. Chem 1990, 55, 
1217. 
8. Chelucci, G.; Gladiali, S.; Marchetti, M. J. Heterocyclic Chem. 1988, 25, 1761. 
9. Chelucci, G.; Delogu, G.; Gladiali, S.; Soccolini, F. J. Heterocyclic Chem. 1986, 23, 1395. 
10. For the method on related 2-picoline, see: Newkome, G. R. Chem. Rev. 1993, 93, 2067. 
11. For references on the synthesis of chiral pyridine derivatives, see: Chelucci, G.; Thummel, 
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Synthesis of chiral 2-methyl-5,6,7,8-tetrahydroquinolines from naturally occurring monoterpenes

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