Intriguing influence of the solvent on the regioselectivity of sulfoxide thermolysis in β-amino-α-sulfinyl esters

Article abstract of DOI:10.1002/1522-2675(200205)85:5<1399::AID-HLCA1399>3.0.CO;2-R

The sulfoxide thermolysis of the diastereoisomeric methyl (3R,4aS, 10aR)-6-methyl-3-methyl-3-(phenyl-sulfinyl)-1,2,3,4,4a,5,10,10a- octahydrobenzo[g]quinoline-3-carboxylates 3a and 3′b in toluene yields, by loss of benzenesulfenic acid, an almost 1:1 mixture of the vinylogous urethane 2b and the isomeric α-aminomethyl enoate 2a. When this elimination is performed in acetic acid, the enoate 2a is formed rather selectively. The same solvent effects on the regioselectivity of the elimination of benzenesulfenic acid are observed with a simple sulfoxide of ethyl piperidine-3-carboxylate (7).

Full text of DOI:10.1002/1522-2675(200205)85:5<1399::AID-HLCA1399>3.0.CO;2-R

Helvetica Chimica Acta Vol. 85 (2002)
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Intriguing Influence of the Solvent on the Regioselectivity of Sulfoxide
Thermolysis in b-Amino-a-sulfinyl Esters
by Markus B‰nziger*a), Solange Kleina), and Grety Rihsb)
a) Chemical & Analytical Development, Novartis Pharma AG, CH-4002 Basel
(Phone: (41) 616964593; fax: (41) 616962711; e-mail: markus.baenziger@pharma.novartis.com)
b) Preclinical Research Core Technology, Novartis Pharma AG, CH-4002 Basel
The sulfoxide thermolysis of the diastereoisomeric methyl (3R,4aS,10aR)-6-methoxy-1-methyl-3-(phenyl-
sulfinyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylates 3a and 3'b in toluene yields, by loss of
benzenesulfenic acid, an almost 1:1 mixture of the vinylogous urethane 2b and the isomeric a-aminomethyl
enoate 2a. When this elimination is performed in acetic acid, the enoate 2a is formed rather selectively. The same
solvent effects on the regioselectivity of the elimination of benzenesulfenic acid are observed with a simple
sulfoxide of ethyl piperidine-3-carboxylate (7).
Introduction. In the course of new product developments, we were interested in
the conversion of methyl (3R,4aR,10aR)-6-methoxy-1-methyl-1,2,3,4,4a,5,10,10a-octa-
hydrobenzo[g]quinoline-3-carboxylate (1) [1] to the corresponding unsaturated methyl
(4aS,10aR)-6-methoxy-1-methyl-1,2,4a,5,10,10a-hexahydrobenzo[g]quinoline-3-car-
boxylate (2a) [2] (Scheme 1).
Scheme 1
Compounds of type 1 and 2a are building blocks of pharmaceutically active
compounds, and we decided to introduce the CˆC bond by benzenesulfenic acid
elimination [3] of the corresponding 3-(phenylsulfinyl)-substituted compound 3.
Synthesis. To accomplish the synthesis, the b-amino ester 1 was deprotonated with
LDA and reacted with diphenyl disulfide [4] to yield intermediate 4 as a single
diastereoisomer in 76% yield after recrystallization. The sulfenylated compound 4
1
bears the ester group in the axial position, as established by H-NMR experiments
(NOE).
The sulfide 4 was oxidized with oxone (potassium hydrogen peroxysulfate) [5] in
acetone to give a ca. 2 :1mixture of the diastereoisomers 3a and 3b (Scheme 2).

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Helvetica Chimica Acta Vol. 85 (2002)
Scheme 2
The two diastereoisomers can be separated by column chromatography; their
structures were determined by X-ray crystallography (see Figs. 1 and 2).
When the diastereoisomer 3a or 3b, or a mixture of both, is heated in toluene or in
toluene containing DBU (ˆ1,8-diazabicyclo[5.4.0]undec-7-ene), a mixture of the two
elimination products 2a and 2b is formed (Scheme 2). The ratio of the regioisomers 2a
and 2b varies from 1:1to 1:3 in favor of 2b, depending upon the precursor 3 and upon
the reaction temperature. In one series of experiments, we also performed the
elimination in AcOH as the solvent. We discovered that 3a is converted at 808 in AcOH
to a 27:1mixture 2a/2b, while the diastereoisomeric compound 3b is transformed to a
12 :1 mixture 2a/2b under these conditions. Thus, the desired compound 2a becomes the
major product, irrespective of the configuration at the S-atom of the starting material.
To the best of our knowledge, the 3-sulfinylpiperidine-3-carboxylic acid system has
only been described once [6], and only one other example of a fused-ring system is
known in the literature [7]. However, the thermolysis of such sulfoxides of six-
membered ring systems is new. An analogous regioselective sulfenic acid elimination
has been described for b-lactams [8].
The thermal instability of sulfoxides is known for a very long time [9]. Sulfoxides
undergo thermal syn-elimination by the Ei mechanism [10]. We had expected to obtain
a mixture of regioisomers 2a and 2b in the thermal sulfenic-acid elimination, with 2b
prevailing, because this elimination product (a vinylogous urethane) should be

Helvetica Chimica Acta Vol. 85 (2002)
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Fig. 1. ORTEP Drawing of compound 3a
Fig. 2. ORTEP Drawing of compound 3b
thermodynamically more stable than the desired compound 2a. Thus, the dramatic
increase of the regioselectivity of the elimination reaction in favor of compound 2a,
when the reaction is conducted in AcOH, is most surprising. A possible explanation for
this effect of AcOH may be that the precursor 3 is doubly protonated in glacial AcOH
at 808 1 008, when the elimination occurs, and that the transition state leading to A is
more favorable then the one generating B.

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Helvetica Chimica Acta Vol. 85 (2002)
Investigations (HPLC) of the course of the sulfoxide thermolysis with both
diastereoisomers 3a and 3b in AcOH or toluene/DBU showed that the ratio with which
the products 2a and 2b are formed remains almost exactly the same during the reaction.
An epimerization at the stereogenic S-center was not observed. The elimination
products 2a or 2b can not be equilibrated with each other by heating in toluene in the
presence of DBU or in AcOH. The addition of 2 equiv. of AcONa to a solution of 3a or
3b in AcOH has no significant influence on the rate of the elimination reaction and
product ratio of 2a/2b.
The same elimination sequence was also performed with ethyl 1-methyl-3-
(phenylsulfinyl)piperidine-3-carboxylate (5) (Scheme 3). The sulfide precursor 6 was
prepared in 52% yield from commercially available ethyl piperidine-3-carboxylate (7)
by N-methylation with aqueous CH2O in MeOH/AcOH under hydrogenation
conditions, followed by treatment of the enolate with diphenyl disulfide. The oxidation
of the sulfide 6 to the sulfoxide 5 (to give a 2 :3 mixture of racemic diastereoisomers)
was carried out with oxone in a similar way as with compound 4. The elimination
experiments with 5 were again performed in toluene/DBU or in AcOH directly with
the mixture of the diastereoisomers. When the sulfoxide 5 was heated at 808 in AcOH,
the ratio in which 8 and 9 are formed was 98 :2 (GC analysis), while it was 2 :3 after
heating in a 1:2 mixture of toluene/DBU at 1108. Thus, similar results were obtained
with the sulfoxide mixture of 5, and with 3a or 3b (Scheme 3).
Scheme 3

Helvetica Chimica Acta Vol. 85 (2002)
1403
Conclusions. The −acetic-acid method× described herein might be a general and
selective way to prepare 1,2,5,6-tetrahydropyridine-3-carboxylates from piperidine-3-
carboxylates via thermolysis of corresponding sulfoxides.
Experimental Part
General. Solvents and reagents were purchased from Fluka. All reactions were performed under N2. The
reactions described are not optimized in respect of yields. Reactions with diphenyl disulfide should be carried
out in a hood, because of the formation of stinking thiophenol. NMR Spectra: Brucker Avance-400
spectrometer; d in ppm. MS: Hewlett-Packard GC-6890 connected to an Agilent 5973 Mass Selective Detector.
Methyl (3R,4aS,10aR)-6-Methoxy-1-methyl-3-(phenylsulfanyl)-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]qui-
noline-3-carboxylate (4). To a soln. of (i-Pr)2NH (23.6 g, 234 mmol) in 120 ml of THF 1.6m BuLi (98.7 g,
226 mmol) were added at À208 within 2 h. After stirring for another h the mixture was cooled to À758, and a
soln. of 45 g (155 mmol) of methyl (3R,4aR,10aR)-6-methoxy-1-methyl-1,2,3,4,4a,5,10,10a-octahydro-ben-
zo[g]quinoline-3-carboxylate (1) [1] in THF (300 ml) was added within 2 h. The mixture was stirred for another
h, and then a soln. of 40.7 g (187 mmol) of diphenyl disulfide in THF (210 ml) was added within 0.5 h. The
mixture was stirred at À758 for 0.5 h and then warmed to 08. Then, 15% aq. NaCl (200 ml) was added, and the
phases were separated. The aq. phase was reextracted with toluene, and the combined org. phase was washed
with H2O. The solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of
300 ml of MeOH and 150 ml of AcOH. By adding 250 g of Et3N the product was precipitated, filtered, washed
with MeOH, and dried in vacuo at 508 to give 4 (47 g, 76%). 1H-NMR ((D6)DMSO): 1.32 1.43 (m, HaxÀC(4));
1.45 1.58 (m, HÀC(4a)); 1.82 1.93 (m, HÀC(10a)); 2.03 2.15 (m, HaxÀC(5)); 2.42 (s, NMe); 2.28 2.43
(m, HaxÀC(2), HeqÀC(4), HaxÀC(10)); 2.69 2.80 (m, HeqÀC(5)); 3.02 3.12 (m, HeqÀC(10)); 3.17 3.24
(m, HeqÀC(2)); 3.54 (s, OMe); 3.74 (s, OMe); 6.65 6.77 (m, HÀC(7), HÀC(9)); 7.03 7.12 (m, HÀC(8));
7.38 7.54 (m, HÀC(5)). Anal. calc. for C23H27NO3S: C 69.49, H 6.85, N 3.52; found: C 69.52, H 6.86, N 3.61.
Methyl (3R,4aS,10aR)-6-Methoxy-1-methyl-3-[(S)-phenylsulfinyl]-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]-
quinoline-3-carboxylate (3a) and Methyl (3R,4aS,10aR)-6-Methoxy-1-methyl-3-[(R)-phenylsulfinyl]-
1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylate (3b). To a mixture of intermediate 4 (10 g,
25 mmol) in acetone (250 ml), a soln. of 15.46 g (25 mmol) of oxone in H2O (60 ml) was added within 0.5 h at 58.
After the addition was complete, the mixture was stirred for another h, and then 10% aq. Na2S2O3 was added.
The acetone was removed in vacuo, and the residue was worked up with CH2Cl2/H2O. The CH2Cl2 phase was
evaporated to dryness, and the diastereoisomers were separated by CC (SiO2; AcOEt/CH2Cl2/25% NH3
800 :600 :6). Yield: 3a: 1 .2 g;3b: 4.9 g. Both diastereoisomers are crystalline and X-ray-crystallographic analysis
was performed.
Data of 3a: 1H-NMR (CDCl3): 1.76 2.01 (m, 2 HÀC(4), HÀC(4a), HÀC(10a)); 2.25 2.32
(m, HaxÀC(5)); 2.41( s, NMe); 2.57 2.64 (m, HaxÀC(10)); 2.77 (d, J ˆ 1
1
,
axHÀC(2)); 2.99 3.02
(m, HeqÀC(5)); 3.12 3.17 (m, HeqÀC(10)); 3.58 (s, OMe); 3.71( d, J ˆ 1 1 , HÀC(2)); 3.84 (s, OMe); 6.67
eq
6.74 (m, HÀC(7)), HÀC( 9 )) ; 7.10 7.14 ( m, HÀC(8)); 7.53 7.59 (m, 5 H). Anal. calc. for C23H27NO4S: C 66.80,
H 6.58, N 3.39; found: C 66.61, H 6.55, N 3.52.
Data of 3b: 1H-NMR (CDCl3): 1.47 1.53 (m, HaxÀC(4)); 1.67 1.77 (m, HÀC(4a)); 1.92 2.04
(m, HÀC(10a)); 2.17 2.29 (m, HeqÀC(4), HaxÀC(5)); 2.41( s, NMe); 2.57 2.62 (m, HaxÀC(2), HaxÀC(10));
2.96 3.01( m, HeqÀC(5)); 3.09 3.15 (m, HeqÀC(10)); 3.49 (s, OMe); 3.63 3.67 (m, HeqÀC(2)); 3.81( s, OMe);
6.64 6.70 (m, HÀC(7), HÀC(9)); 7.07 7.11 (m, HÀC(8)); 7.51 7.58 ( m, HÀC(5)). Anal. calc. for
C23H27NO4S: C 66.80, H 6.58, N 3.39; found: C 66.92, H 6.75, N 3.51.
Crystal-Structure Analyses of 3a and 3b. The intensities of both crystals were collected on an Enraf-
Nonius CAD4 diffractometer using CuKa radiation (l ˆ 1.54178 ä) and w/2q scan. The structures were
solved by direct methods and refined on F2 (SHELXS86 [11] and SHELX93 [12]). H-atoms were treated as
riding1).
1
)
Crystallographic data for the structures reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as deposition No. CCDC-176663 (3a) and -176664 (3b). Copies of the data
can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ UK
(fax: ‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

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Helvetica Chimica Acta Vol. 85 (2002)
Crystals of 3a were grown from an AcOEt/hexane soln. They were orthorhombic, C23H27NO4S, Mr
413.52 g molÀ1, crystal size 0.43  0.32  0.30 mm, space group P212121, a ˆ 11.324(1) ä, b ˆ 13.416(1) ä, c ˆ
14.478(2) ä; Vˆ 2199.5(4) ä3, Z ˆ 4, d(calc.) ˆ 1.249 g/cm3, e ˆ 1.54 mmÀ1, F(000) ˆ 880, No. of reflection
measured ˆ 2542, observed ˆ 2428 (I > 2s(I)), No. of reflections in least squares ˆ 2428, intensity decay ˆ 2%,
qmax ˆ 74.198, No. of refined parameters ˆ 262, R factorˆ 0.060, wR ˆ 0.136, S ˆ 1.151, diff. densitymax ˆ 0.327 e/
ä3, diff. densitymin ˆ À0.494 e/ä3.
Crystals of 3b were grown from an AcOEt/hexane soln. They were orthorhombic, C23H27NO4S,
Mr 413.52 g molÀ1, crystal size 0.67  0.38  0.08 mm, space group P212121, a ˆ 8.255(1) ä, b ˆ 10.779(2) ä,
c ˆ 24.042(4) ä, Vˆ 2139.3(6) ä3, Z ˆ 4, d(calc.) ˆ 1.284 g/cm3, e ˆ 1.58 mmÀ1, F(000) ˆ 880, No. of reflec-
tion measured ˆ 4189, observed ˆ 3558 (I > 2s(I)), No. of reflections in least squares ˆ 3558, intensity
decay ˆ 3%, qmax ˆ 74.238, No. of refined parameters ˆ 262, R factor ˆ 0.060, wR ˆ 0.154, S ˆ 1.257, diff.
densitymax ˆ 0.470 e/ä3, diff. densitymin ˆ 0.171 e/ä3.
Methyl (4aS,10aR)-6-Methoxy-1-methyl-1,4,4a,5,10,10a-hexahydrobenzo[g]quinoline-3-carboxylate (2b).
Sulfide 4 (10 g) was oxidized with oxone as described above. The crude product of 3a and 3b was purified by
the following extractive procedure: It was dissolved in 200 ml of AcOEt and extracted with 1m HCl (5 Â 100 ml).
The pH of the aq. phase was brought to 9 by adding 30% NaOH to the ice cold acidic aq. phase, and the product
was extracted with CH2Cl2 (3 Â 100 ml). The CH2Cl2 phase was dried (MgSO4) and concentrated in vacuo. The
residue (9 g) was dissolved in a mixture of 80 ml of toluene and 80 ml of DBU. This mixture was heated to 808
for 16 h. HPLC control showed a ratio 2a/2b of 1:1.2. Then, it was diluted with 80 ml of toluene and washed with
H2O, followed by 0.3m HCl (to remove DBU and most of 2a) and finally with H2O again. The toluene phase was
evaporated to dryness and the residue was crystallized from toluene/hexane to give 3.5 g of 2b (48%, based on
4). 1H-NMR (CDCl3): 1.87 2.08 (m, HaxÀC(4), HÀC(4a)); 2.24 2.32 (m, HaxÀC(5)); 2.66 2.78
(m, HeqÀC(4), HaxÀC(10)); 3.03 (s, NMe); 3.08 3.16 (m, HÀC(10a)); 3.21 3.37 (m, HeqÀC(5), HeqÀC(10));
3.72 (s, OMe); 3.86 (s, OMe); 6.71 6.78 ( m, HÀC(7), HÀC( 9 )) ; 7.12 7.18 ( m, HÀC(8)); 7.38 (br. s, HÀC(2)).
Anal. calc. for C17H21NO3: C 71.06, H 7.37, N 4.87; found: C 70.86, H 7.29, N 5.09.
Methyl (4aS,10aR)-6-Methoxy-1-methyl-1,2,4a,5,10,10a-hexahydrobenzo[g]quinoline-3-carboxylate (2a).
Sulfide 4 (10 g) was oxidized with oxone as described above. The mixture 3a/3b was purified by the same
extractive procedure as described for the synthesis of 2b. The residue (9 g) of the two diastereoisomeric
sulfoxides 3a and 3b was dissolved in 100 ml AcOH and heated to 808 for 15 h. The HPLC control showed a ratio
2a/2b of 15 :1. Then, the mixture was cooled to r.t., H2O (50 ml) and toluene (100 ml) were added, and the
phases were separated. The toluene phase was extracted 3 times with 1m HCl (180 ml), and the combined aq.
phase was washed once with toluene (50 ml). In the ice bath, the pH was adjusted to 8 by addition of 30%
NaOH (250 g). Finally, the pH was brought to >9 by the addition of 15% aq. Na2CO3 (30 ml). The aq. phase
was extracted 3 times with toluene (200 ml). The combined org. phase was washed twice with H2O (100 ml) and
evaporated to dryness, to yield 6.5 g crude product. Crystallization from toluene/hexane 20 :35 gave 3.9 g pure
product 2a (54% based on 4). 1H-NMR (CDCl3): 2.15 2.36 (m, HaxÀC(5), HÀC(10a)); 2.43 2.58 (m, NMe,
HaxÀC(10)); 2.74 2.82 (m, HÀC(4a)); 2.97 3.23 (m, HaxÀC(2), HeqÀC(5), HeqÀC(10)); 3.68 3.78
(m, HeqÀC(2)); 3.80 (s, OMe); 3.84 (s, OMe); 6.64 6.80 (m, HÀC(7), HÀC(9)); 6.97 (br. s, HÀC(4));
7.10 7.19 ( m, HÀC(8)).
Ethyl 1-Methyl-3-(phenylsulfanyl)piperidine-3-carboxylate (6). A mixture of 51g (324 mmol) of ethyl
piperidine-3-carboxylate (7), 52 g of 37% aq. CH2O (641mmol), AcOH (74 ml), and 5.5 g of Pd/C (5%) in
520 ml of EtOH was hydrogenated at atmospheric pressure and r.t. until no more hydrogen was consumed.
Then, the catalyst was filtered off and washed with 50 ml of EtOH, and the EtOH was evaporated under
reduced pressure. The residue was dissolved in toluene/H2O and the pH was brought to 9 by addition of
20% aq. K2CO3. The phases were separated, the aq. phase was extracted again with toluene, and the combined
toluene phase was washed with H2O. The toluene was evaporated to dryness to give 42.09 g of ethyl 1-methyl-
piperidine-3-carboxylate, which was used without further purification in the next step. 1H-NMR (CDCl3): 1.23
(t, J ˆ 7.2, 3 H); 1.33 1.43 (m, 1 H); 1.53 1.64 (m, 1 H); 1.68 1.75 (m, 1 H); 1.91 1.97 (m, 2 H); 2.07 2.12
(m, 1H); 2.27 ( s, NMe); 2.52 2.60 (m, 1H); 2.68 2.72 ( m, 1H); 2.92 2.95 ( m, 1H); 4.12 ( q, J ˆ 7.2,
2 H).
A mixture of 19.5 g (193 mmol) of (i-Pr)2NH in 110 ml of THF was cooled to À308, and then 110 ml of 1.6m
BuLi (176 mmol; in hexane) were added. The mixture was stirred for 1 h at À308 and then cooled to À708. To
this LDA mixture, a soln. of 27.5 g (161 mmol) of the above ethyl 1-methyl-piperidine-3-carboxylate in 100 ml of
THF was added within 45 min. After stirring for another 45 min, a soln. of 36.8 g (169 mmol) of diphenyl
disulfide in 138 ml of THF was added within 45 min. The mixture was stirred for another 30 min at À708 and
then warmed to 08 within 1h. Then 138 ml of H 2O and 138 ml of brine were added, the phases were separated,

Helvetica Chimica Acta Vol. 85 (2002)
1405
and the aq. phase was re-extracted with toluene. The combined org. phase was washed with brine and then
evaporated to dryness. The residue was purified by dissolution in 300 ml of toluene and extracting the desired
product with 1m HCl (4 Â 200 ml) aq. into the aq. phase. After washing the aq. phase with toluene, the pH was
brought to >9 by adding 30% NaOH, and the product was extracted twice with 200 ml of toluene. The combined
1
org. phase was washed with H2O and evaporated to dryness, to yield 31.4 g of 6 (52% based on 7). H-NMR
(CDCl3): 1.11 (t, J ˆ 7.1, 3 H); 1.48 1.65 (m, 2 H); 1.76 1.81 (m, 1H); 2.05 2.19 ( m, 2 H); 2.23 (s, 3 H); 2.32
2.39 (m, 1H); 2.42 2.52 ( m, 1H); 2.87 2.93 ( m, 1H); 4.04 ( q, J ˆ 7.1, 2 H); 7.29 7.36 (m, 3 H); 7.42 7.45
(m, 2 H).
Ethyl 1-Methyl-3-(phenylsulfinyl)piperidine-3-carboxylate (5). To
a soln. of 10 g (33.8 mmol) of
intermediate 6 in 50 ml of acetone a soln. of 17.6 g (28.7 mmol) of oxone in 67 ml of H2O was added at 0 58
within 20 min. After stirring for another 30 min, 10 ml of 10% aq. Na2S2O3 was added, and the acetone was
evaporated under reduced pressure. To the aq. phase, 100 ml of toluene were added, and the product was
extracted with 0.1m HCl (3 Â 80 ml) into the aq. phase. The pH of the aq. phase was brought to 9 by adding
100 ml of 15% aq. Na2CO3, and the product was extracted with TBME (3 Â 100 ml). The org. phase was washed
with H2O, and the solvent was removed under reduced pressure at 358 to yield 6.7 g of 5 as a 2 :3
diastereoisomeric mixture (63% based on 6), which was used without further purification in the elimination step.
Ethyl 1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (8). A soln. of 1g (3.4 mmol) of the above residue
of 5 in 10 ml of AcOH was heated to 808 for 22 h. Then, the mixture was checked by GC (ratio of 8/9 98 :2) and
cooled to r.t. H2O (20 ml) and toluene (30 ml) were added, the phases were separated, and 8 was extracted from
the org. phase with 0.1m HCl (3 Â 33 ml). The combined aq. phase was washed with 50 ml of toluene, and then
the pH was brought to 9 by adding 80 ml of 15% aq. Na2CO3. The product 8 was extracted with toluene (3 Â
40 ml). The toluene phase was washed with H2O, and then the toluene was evaporated under reduced pressure
to yield 0.61g of crude 8, which was purified by CC (60 g SiO2; AcOEt/toluene/25% NH3 80 :20 :2) to give
370 mg of pure 8 (64%). 1H-NMR (CDCl3): 1.23 (q, J ˆ 7.1, 3 H); 2.19 2.39 (m, 5 H); 2.45 (t, J ˆ 5.6, 2 H);
.
‡
3.09 3.12 (m, 2 H); 4.14 (q, J ˆ 7.1, 2 H); 6.92 6.96 (m, 1H). MS: 169 ( M ), 140, 124, 106, 96, 81, 53.
Ethyl 1-Methyl-1,4,5,6-tetrahydropyridine-3-carboxylate (9). A soln. of 2 g (6.8 mmol) of 5 in 5 ml of
toluene and 5 ml of DBU was heated to 1108 for 1h. Then, the mixture was cooled to r.t., checked by
GC (ratio of 8/9 1:2), diluted with 20 ml of toluene, and washed with 1m HCl (3 Â 10 ml), followed by H2O.
The toluene phase was evaporated to dryness, and the residue was purified by CC (85 g of SiO2; AcOEt) to give
0.4 g of 9 (34% based on 5). 1H-NMR (CDCl3): 1.27 (q, J ˆ 7.1, 3 H); 1.82 1.89 (m, 2 H); 2.27 (t, J ˆ 6.1, 2 H);
.
‡
2.94 (s, 3 H); 3.05 (t, J ˆ 5.7, 2 H); 4.14 (q, J ˆ 7.1 , 2 H); 7.32 s(, 1H). MS: 169 (M ), 154, 140, 124, 106,
96, 81.
The skillfull work of our technical staff (J. Keusch, P. Ritschard) is gratefully acknowledged. We thank Mr.
L. Oberer for the interpretation of the NMR spectra and Ms. G. Rihs and her crew for performing the single-
crystal analyses. We thank also Prof. D. Seebach for many helpful discussions.
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Received January 8, 2002