Synthesis of aza analogs of the herbicide sindone B

Article abstract of DOI:10.1007/PL00010224

The synthesis of a series of quinoline and isoquinoline derivatives via condensation of 1,3-dicarbonyl compounds with enaminonitrile 1 is described yielding hydrophilic analogs of the herbicide Sindone B.

Full text of DOI:10.1007/PL00010224

Monatshefte fuÈr Chemie 130, 441±450 (1999)
Synthesis of Aza Analogs of the Herbicide
Sindone Ba
2
Peter Stanetty1;Ã and Gerhard Purstinger
È
1
Institute of Organic Chemistry, Vienna University of Technology, A-1060 Vienna, Austria
2
Institute of Pharmaceutical Chemistry, University of Innsbruck, A-6020 Innsbruck, Austria
Summary. The synthesis of a series of quinoline and isoquinoline derivatives via condensation of
1,3-dicarbonyl compounds with enaminonitrile 1 is described yielding hydrophilic analogs of the
herbicide Sindone B.
Keywords. Herbicides; Sindones; Quinolines; Isoquinolines.
Synthese von Azaanaloga des Herbizids Sindone B
Zusammenfassung. Die Synthese einer Reihe von Chinolin- und Isochinolinderivaten uÈber
Kondensation von 1,3-Dicarbonylverbindungen mit dem Enaminonitril 1 wird beschrieben, wobei
hydrophile Analoga des Herbizids Sindone B erhalten wurden.
Introduction
Some time ago, a new type of herbicidal compounds ± later called sindones ± has
been found by chance in the course of routine biological screening of a series of
products originally aimed as ¯avouring compounds and fragrances from the musk
type [1a]. The compound showing biologically most interesting results within this
class was Sindone B, a product with good selectivity against grass weeds.
Unfortunately, adequate herbicidal activity has been reached only at application
rates of about 2 kg/ha, too much for a modern herbicide. In 1994 we have
Scheme 1
a
Dedicated to Prof. Dr. Gottfried Heinisch on the occasion of his 60th birthday
Ã
Corresponding author

442
P. Stanetty and G. PuÈrstinger
published the synthesis of N,N-dimethyl-isobenzofuranamines as isosteric analogs
of Sindone B [1b]. In the present paper we report the synthesis of some quinoline
and isoquinoline derivatives of the general formulae A and B designed as even
more hydrophilic analogs of Sindone B.
Results and Discussion
Our synthetic strategy towards the target compounds was based on the reaction
of enaminonitrile 1 with various 1,3-dicarbonyl compounds 2 derived from
cyclopentanone or cyclohexanone. It can be considered as a useful modi®cation of
a procedure published previously [2] where various enaminoaldehydes and
-ketones were reacted with ꢀ-ketoesters and symmetrical 1,3-diketones. There
are two synthetic approaches described in the literature that lead to the desired
enaminonitrile 1 [3a, 3b]. Using a slightly modi®ed procedure of Ref. [3a], we
could achieve an almost quantitative yield by performing this reaction in THF
instead of diethyl ether with LDA as base. NMR data show that in CDCl3 solution 1
exists in an equilibrium with its imine tautomer (see Experimental).
In a model reaction, acetylacetone was chosen to react with 1. Reaction of the
resulting nitrile 3a with EtMgBr yielded the corresponding imine which
subsequently was hydrolyzed to the propanone 4a.
So far not being commercially available, the 1,3-dicarbonyl compounds
required for the construction of the target compounds were synthesized mainly
using published procedures [4a±f]. The diketone 2d was made available by the
approach shown in Scheme 4.
In our ®rst experiments, 2-acetylcyclohexanones 2c±e were reacted with 1 and
a catalytic amount of ammonium acetate, yielding a mixture of the corresponding
quinoline and isoquinoline derivatives in each case. As we failed to separate the
isomers by chromatographic methods, only the isoquinoline-4-carbonitriles 3c±e
could be isolated in modest yields by recrystallization of the crude mixture. Taking
into account the chosen reaction conditions, the mechanism of the reaction should
Scheme 2
Scheme 3

Aza Analogs of Sindone B
443
Scheme 4
Scheme 5
consist of an initial Knoevenagel condensation of the enamino moiety with one of
the carbonyl groups followed by the attack of the amino group at the second
carbonyl group, thus leading to cyclization. The formation of the isoquinoline
isomer as the main product re¯ects the higher reactivity of the ring carbonyl group.
The nitriles 3c±e were now easily transformed to the propanones 4c±e in the
reaction mentioned for 4a (Scheme 5). Attempts to perform an analogous
cyclization of 1 with 2-acetylcyclopentanone (2b) were very disappointing as only
tars were obtained.
Taking into account the results so far, the availability of the corresponding
quinoline derivatives as main products became an interesting issue. In order to
achieve this, we had to interchange the reactivity of the two carbonyl groups
starting with 2-formylcyclohexanones 2f±i that exist mainly as the 2-hydroxy-
methylene tautomers. In our ®rst attempt we reacted 1 with 2-hydroxymethylene-
cyclohexanone (2f) under the same reaction conditions and isolated a mixture of
the expected carbonitriles 3f and the corresponding carboxamide 5f which could
be easily isolated by crystallization. As this caboxamide was easily dehydrated to
the carbonitrile by POCl3, its isolation was not necessary. Instead, the crude
mixtures of 3 and 5 were subsequently reacted with POCl3 leading to the pure
carbonitriles 3. The following transformation was again performed with an excess

444
P. Stanetty and G. PuÈrstinger
Scheme 6
of EtMgBr and yielded the target compounds 4f±i upon hydrolysis of the imine
intermediates.
Experimental
1H and 13C NMR spectra were recorded from CDCl3 solutions on a BRUKER AC 200 or a JEOL FX
90 Q NMR spectrometer and related to TMS (ꢁ ˆ 0 ppm). Melting points were determined on a
Ko¯er hot stage microscope and are uncorrected. Elemental analyses were performed at the Institute
of Physical Chemistry, University of Vienna; the data for C, H, N were within 0.3% of the calculated
values. Reactions were monitored by TLC using alumina backed silica 60 F254 plates (Merck 5554)
and visualized using UV light. Column chromatography was performed using Kieselgel 60
(0.040±0.063 mm, Merck 9385). All solvents were distilled prior to use.
Acetylacetone (2a), 2-acetylcyclopentanone (2b), and 2-acetylcyclohexanone (2c) are commer-
cially available and were used without further puri®cation. The following compounds utilized as
starting materials were prepared according to the Refs. cited: 2-acetyl-4,4-dimethyl-cyclohexanone
(2e) [4d], 2-hydroxymethylenecyclohexanone (2f) [4b], 2-hydroxymethylene-6,6-dimethylcyclo-
hexanone (2g) [4e], 2-hydroxymethylene-5,5-dimethylcyclohexanone (2h) [4b, 4c], and 2-hydroxy-
methylene-4,4-dimethylcyclohexanone (2i) [4b, 4f].
3-Amino-4-methyl-2-pentenenitrile (1, C6H10N2)
A 2.5 M n-BuLi solution in hexane (61.4 ml, 152.4 mmol) was slowly added to a solution of 15.52 g
(152.4 mmol) (i-Pr)2NH in 150 ml of dry THF under nitrogen at ꢀ10ꢁC. After stirring for 30 min at
this temperature, the solution was cooled to ꢀ80ꢁC and treated with 6.00 g (146.2 mmol) of CH3CN
dissolved in 15 ml of dry THF. After 10 min, 10.10 g (146.2 mmol) of isobutyronitrile dissolved in
20 ml of dry THF were added dropwise. The suspension was warmed to room temperature, stirred
overnight, and poured on ice/water. After evaporation of the organic solvent, the remaining emulsion
was extracted twice with 100 ml of diethyl ether. The combined organic layers were dried over

Aza Analogs of Sindone B
445
anhydrous sodium sulfate, ®ltered, and evaporated. The resulting crude product was puri®ed by
Kugelrohr distillation to give 15.62 g (97%) of a pale yellow, partially crystalline oil.
1
B.p.: 75±80ꢁC/0.05 mbar (Ref. [3a]: 92±94ꢁC/0.5 mbar); H NMR (CDCl3, ꢁ, 90 MHz): 4.60
(bs, enamine-NH2 and imine-NH), 3.90 and 3.80 (2s, CH2CN and C=CHCN), 3.20 and 2.38 (2 sept,
1H, imine- and enamine-CH(CH3)2, J ˆ 9 Hz), 1.19 and 1.14 (2d, 6H, imine- and enamine-(CH3)2,
J ˆ 9 Hz) ppm.
2-Acetyl-6,6-dimethylcyclohexanone (2d, C10H16O2)
A solution of 39.70 g (314.6 mmol) 6-methyl-5-hepten-2-one and 83.18 g (943.5 mmol) ethyl acetate
in 150 ml of dry diethyl ether was added under nitrogen to a mechanically stirred suspension of
42.46 g (755.4 mmol) sodium ethanolate in 250 ml of dry diethyl ether over a period of 3 h while
keeping the temperature between ꢀ25 and ꢀ20ꢁC. The cooling bath was then removed, and the
mixture was stirred for another 20 h. The reaction mixture was hydrolyzed with 400 ml of ice/water
and extracted with 200 ml of diethyl ether. The organic layer was extracted with 100 ml of 2 N
sodium hydroxide, the combined aqueous layers were acidi®ed to pH ˆ 1 by addition of conc.
hydrochloric acid and extracted twice with 250 ml of diethyl ether. The combined ether layers were
dried over anhydrous sodium sulfate, ®ltered, and evaporated. The product was puri®ed by distil-
lation to give 33.77 g (64%) of 4-hydroxy-8-methyl-3,7-nonadien-2-one (which is in a tautomeric
equilibrium with 8-methyl-7-nonen-2,4-dion) as a colorless liquid.
B.p.: 102±103.5ꢁC/13 mbar (Ref. [4c]: 105±107ꢁC/15 mbar); 1H NMR (CDCl3, ꢁ, 90 MHz): 5.49
(s), 5.16±4.92 (m, 1H, H-7), 3.70±3.54 (m), 2.60±2.49 (m), 2.31 (s), 2.30 (s), 2.23 (s), 2.17 (s), 2.11
(s), 2.04 (s), 1.70 and 1.63 (2s, 3H each, C-9 and 8-CH3) ppm.
To a solution of 30.00 g (178.3 mmol) of 4-hydroxy-8-methyl-3,7-nonadien-2-one in 250 ml of
dry dichloromethane, 11.62 g (44.6 mmol) SnCl4 in 50 ml of dry dichloromethane were added under
nitrogen at 0ꢁC. After the addition was completed, the resulting solution was stirred for 20 h at room
temperature. Then another 11.62 g (44.6 mmol) SnCl4 in 50 ml of dry dichloromethane were added at
once. After 1 h of stirring the reaction was hydrolyzed by addition of 200 ml of water. The aqueous
layer was extracted with 100 ml of dichloromethane, and the combined organic layers were dried
over sodium sulfate, ®ltered, and evaporated. The product was puri®ed by distillation to give 25.20 g
(84%) of 2-acetyl-6,6-dimethyl-cyclohexanone (2d) as a colorless liquid.
1
B.p.: 98±100ꢁC/13 mbar (Ref. [4c]: 107±108ꢁC/16 mbar); H NMR (CDCl3, ꢁ, 90 MHz): 3.44
(s, 1H, H-2), 2.75±1.25 (m, 6H, H-4, H-5 and H-6), 2.24 (s, 3H, COCH3), 1.07 and 0.98 (2s, 3H
each, (CH3)2, cis and trans) ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 207.0 and 204.2 (2s, 2 CO), 73.9
(d, C-2), 38.7 (t, C-4), 38.6 (s, C-3), 34.8, 32.8, 27.4, 25.1 (q, COCH3), 21.3 (t, C-5) ppm; the NMR
data are given for the main tautomer (diketo form).
Method A: General procedure for the condensation of enaminonitrile 1
with 1,3-dicarbonyl compounds 2
A mixture of 25.0 mmol 1, 25.0 mmol 2, and 25.0 mmol ammonium acetate was heated overnight at
110ꢁC. After cooling to room temperature, 100 ml of diethyl ether were added. The resulting mixture
was dried over anhydrous sodium sulfate, ®ltered, and evaporated. The crude products were puri®ed
by recrystallization, Kugelrohr distillation, or column chromatography as stated below.
4,6-Dimethyl-2-(1-methylethyl)-3-pyridinecarbonitrile (3a, C11H14N2)
The product was puri®ed by Kugelrohr distillation and by column chromatography (petroleum
ether:ethyl acetate ˆ 15:1). Yield: 76%; colorless crystals; m.p.: 49±50.5ꢁC, b.p.: 70±75ꢁC/
1
0.08 mbar; H NMR (CDCl3, ꢁ, 90 MHz): 6.88 (s, 1H, H-5), 3.49 (m, 1H, CH(CH3)2, J ˆ 7 Hz),

446
P. Stanetty and G. PuÈrstinger
2.56 and 2.50 (2s, 3H each, 4-CH3 and 6-CH3), 1.32 (d, 6H, (CH3)2, J ˆ 7 Hz) ppm; 13C NMR
(CDCl3, ꢁ, 50 MHz): 169.1 (s, C-2), 161.2 (s, C-6), 150.7 (s, C-4), 121.4 (d, C-5), 116.2 (s, CN),
105.4 (s, C-3), 34.5 (d, CH(CH3)2), 24.5 (q, 6-CH3), 21.5 (q, (CH3)2), 20.0 (q, 4-CH3) ppm.
5,6,7,8-Tetrahydro-1-methyl-3-(1-methylethyl)-4-isoquinolinecarbonitrile (3c, C14H18N2)
The crude product was ®rst puri®ed by Kugelrohr distillation and by column chromatography
(petroleum ether:ethyl acetate ˆ 15:1) to give 69% of a pale yellow, partially crystalline isomer
mixture consisting of approximately 80% 3c and 20% 5,6,7,8-tetrahydro-4-methyl-2-(1-methyl-
ethyl)-3-quinolinecarbonitrile. This mixture was recrystallized from 80% MeOH to give 38% of 3c.
Colorless crystals; m.p.: 44.5±46ꢁC; b.p.: 80±85ꢁC/0.004 mbar; 1H NMR (CDCl3, ꢁ, 90 MHz):
3.70±3.25 (m, 1H, CH(CH3)2, J ˆ 7 Hz), 3.00±2.80 (m, 2H, H-5), 2.75±2.50 (m, 2H, H-8), 2.47
(s, 3H, 1-CH3), 2.00±1.75 (m, 4H, H-6 and H-7), 1.30 (d, 6H, (CH3)2, J ˆ 7 Hz) ppm; 13C NMR
(CDCl3, ꢁ, 50 MHz): 165.4 (s, C-3), 160.0 (s, C-1), 148.4 (s, C-4a), 128.1 (s, C-8a), 116.0 (s, CN),
105.2 (s, C-4), 33.9 (d, CH), 28.0 (t, C-5 and C-8), 25.3 (q, 1-CH3), 22.4 and 22.0 (2t, C-6 and C-7),
21.3 (q, (CH3)2) ppm.
5,6,7,8-Tetrahydro-1,5,5-trimethyl-3-(1-methylethyl)-4-isoquinolinecarbonitrile (3d, C16H22N2)
The crude product was submitted to a Kugelrohr distillation (85±150ꢁC/0.001 mbar). The yellow,
milky distillate was then puri®ed chromatographically (petroleum ether:ethyl acetate ˆ 20:1) and
®nally recrystallized from 80% MeOH. Yield: 36%; colorless crystals; m.p.: 60.5±63.5ꢁC; 1H NMR
(CDCl3, ꢁ, 90 MHz): 3.42 (hpt, 1H, CH(CH3)2, J ˆ 7 Hz), 3.05±2.80 (m, 2H, H-5), 2.48 (s, 3H,
1-CH3), 1.95±1.55 (m, 4H, H-6 and H-7), 1.42 (s, 6H, (CH3)2), 1.31 (d, 6H, CH(CH3)2, J ˆ 7 Hz)
ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 165.2 (s, C-3), 161.0 (s, C-1), 149.5 (s, C-4a), 136.8 (s, C-8a),
116.8 (s, CN), 105.9 (s, C-4), 42.7 (t, C-7), 34.0 (d, CH), 33.3 (s, C-8), 30.6 (t, C-5), 28.6 (q, (CH3)2),
27.2 (q, CH3), 21.6 (q, CH(CH3)2), 18.0 (t, C-6) ppm.
5,6,7,8-Tetrahydro-1,7,7-trimethyl-3-(1-methylethyl)-4-isoquinolinecarbonitrile (3e, C16H22N2)
The product was puri®ed by column chromatography (petroleum ether:diethyl ether ˆ 2:1) and by
1
recrystallization from ethanol. Yield: 41%; yellow powder; m.p.: 85±87ꢁC; H NMR (CDCl3, ꢁ,
90 MHz): 3.43 (hpt, 1H, CH(CH3)2, J ˆ 7 Hz), 2.90 (t, 2H, H-5), 2.45 (s, 3H, CH3), 2.33 (s, 2H, H-8),
1.58 (t, 2H, H-6), 1.28 (d, 6H, CH(CH3)2), 1.00 (s, 6H, (CH3)2) ppm; 13C NMR (CDCl3, ꢁ, 50 MHz):
165.7 (s, C-3), 160.7 (s, C-1), 147.7 (s, C-4a), 127.9 (s, C-8a), 116.5 (s, CN), 105.1 (s, C-4), 39.4
(t, C-8), 34.1, 33.9, 29.0 (s, C-7), 28.0 (q, (CH3)2), 25.6 (q, CH3), 22.9 (q, C-5), 21.6 (q, CH(CH3)2)
ppm.
Method B: General procedure for the synthesis of 3f±i
The crude products derived from method A or the isolated intermediates 5f, g were treated with 30 ml
of POCl3 and the resulting mixture was heated under re¯ux for 1 h. Then, the excess reagent was
distilled off and the residue was hydrolyzed with ice/water. After adjusting to pH ˆ 9 with 2 N
NaOH, the resulting mixture was extracted twice with 100 ml of diethyl ether. The combined organic
layers were dried over anhydrous sodium sulfate, ®ltered, and evaporated. The crude products were
puri®ed by column chromatography and/or Kugelrohr distillation as mentioned below.
5,6,7,8-Tetrahydro-2-(1-methylethyl)-3-quinolinecarbonitrile (3f, C13H16N2)
The partially crystalline crude product was recrystallized from ethyl acetate yielding pure 5,6,7,8-
tetrahydro-2-(1-methylethyl)-3-quinolinecarboxamide (5f): Yield: 34%; colorless crystals; m.p.:

Aza Analogs of Sindone B
447
185±186.5ꢁC; 1H NMR (CDCl3, ꢁ, 90 MHz): 7.34 (s, 1H, H-4), 5.90 (bs, 2H, CONH2), 3.47 (hpt, 1H,
CH(CH3)2, J ˆ 6.8 Hz), 3.00±2.60 (m, 4H, H-5 and H-8), 2.00±1.70 (m, 4H, H-6 and H-7), 1.30
(d, 6H, (CH3)2, J ˆ 6.8 Hz) ppm; 13C NMR (DMSO-d6, ꢁ, 50 MHz): 170.5 (s, CO), 160.0 (s, C-2),
156.5 (s, C-8a), 135.1 (d, C-4), 128.8 and 128.1 (2s, C-3 and C-4a), 32.2 (t, C-8), 31.2 (d, CH), 27.5
(t, C-5), 22.6 and 22.4 (2t, C-6 and C-7), 22.4 (q, (CH3)2) ppm.
The mother liquor from the recrystallization was evaporated and the residue submitted to column
chromatography (petroleum ether:ethyl acetate ˆ 15:1) and then puri®ed by Kugelrohr distillation.
1
Yield: 31% 3f; colorless crystals; m.p.: 39±40.5ꢁC, b.p: 80±85ꢁC/0.007 mbar; H NMR (CDCl3, ꢁ,
90 MHz): 7.51 (s, 1H, H-4), 3.44 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 3.05±2.70 (m, 4H, H-5 and H-8),
2.00±1.70 (m, 4H, H-6 and H-7), 1.33 (d, 6H, (CH3)2, J ˆ 6.8 Hz) ppm; 13C NMR (CDCl3,
ꢁ, 50 MHz): 165.6 (s, C-2), 161.1 (s, C-8a), 139.8 (d, C-4), 129.3 (s, C-4a), 116.9 (s, CN),
104.2 (s, C-3), 33.8 (d, CH), 32.8 (t, C-8), 27.6 (t, C-5), 22.2 and 21.9 (2t, C-6 and C-7), 21.2
(q, (CH3)2) ppm.
5,6,7,8-Tetrahydro-8,8-dimethyl-2-(1-methylethyl)-3-quinolinecarbonitrile (3g, C15H20N2)
The partially crystalline crude product was recrystallized from diisopropyl ether to give pure 5,6,7,8-
Tetrahydro-8,8-dimethyl-2-(1-methylethyl)-3-quinolinecarboxamide (5g). Yield: 26%; colorless
crystals; m.p.: 159±160ꢁC; 1H NMR (CDCl3, ꢁ, 90 MHz): 7.32 (s, 1H, H-4), 6.05 and 5.75
(2 bs, CONH2), 3.46 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.78±2.67 (m, 2H, H-5), 1.90±1.70 (m, 4H,
H-6 and H-7), 1.31 (s, 6H, (CH3)2), 1.28 (d, 6H, CH(CH3)2, J ˆ 6.8 Hz) ppm; 13C NMR (CDCl3, ꢁ,
50 MHz): 170.7 (s, CONH2), 162.9 (s, C-8a), 159.6 (s, C-2), 134.3 (d, C-4), 127.3 and 126.2 (2s, C-3
and C-4a), 37.8 (t, C-7), 35.9 (s, C-8), 30.9 (d, CH), 29.3 (q, (CH3)2), 28.5 (t, C-5), 21.9
(q, CH(CH3)2), 18.4 (t, C-6) ppm.
The mother liquor from the recrystallization was evaporated and subsequently submitted to
Kugelrohr distillation (75±110ꢁC/0.001 mbar) and column chromatography (petroleum ether:ethyl
acetate ˆ 25:1). Yield: 21% 3g; colorless crystals; m.p.: 47±49ꢁC; b.p.: 80±85ꢁC/0.003 mbar;
1H NMR (CDCl3, ꢁ, 90 MHz): 7.49 (s, 1H, H-4), 3.41 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.76±2.67
(m, 2H, H-5), 1.88±1.70 (m, 4H, H-6 and H-7), 1.32 (s, 6H, (CH3)2), 1.30 (d, 6H, CH(CH3)2,
J ˆ 6.8 Hz) ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 168.1 (s, C-8a), 166.1 (s, C-2), 140.3 (d, C-4),
128.5 (s, C-4a), 117.6 (s, CN), 104.2 (s, C-3), 38.2 (t, C-7), 37.4 (s, C-8), 34.3 (d, CH), 29.9
(q, (CH3)2), 29.3 (t, C-5), 21.9 (q, CH(CH3)2), 19.0 (t, C-6) ppm.
5,6,7,8-Tetrahydro-7,7-dimethyl-2-(1-methylethyl)-3-quinolinecarbonitrile (3h, C15H20N2)
The product was puri®ed by Kugelrohr distillation. Yield: 32%; yellow oil; b.p.: 85±90ꢁC/0.02 mbar;
1H NMR (CDCl3, ꢁ, 90 MHz): 7.55 (s, 1H, H-4), 3.41 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.78 (t, 2H,
H-5), 2.70 (s, 2H, H-8), 1.58 (t, 2H, H-6), 1.29 (d, 6H, CH(CH3)2, J ˆ 6.8 Hz), 1.00 (s, 6H, (CH3)2)
ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 166.4 (s, C-2), 161.1 (s, C-8a), 140.1 (d, C-4), 128.1 (s, C-4a),
117.4 (s, CN), 104.5 (s, C-3), 46.7 (t, C-8), 34.8 (t, C-6), 34.2 (d, CH), 29.8 (s, C-7), 27.9 (q, (CH3)2),
24.8 (t, C-5), 21.6 (q, CH(CH3)2) ppm.
5,6,7,8-Tetrahydro-6,6-dimethyl-2-(1-methylethyl)-3-quinolinecarbonitrile (3i, C15H20N2)
The product was puri®ed by Kugelrohr distillation. Yield: 81%; yellow oil; b.p.: 75±80ꢁC/0.02 mbar;
1H NMR (CDCl3, ꢁ, 90 MHz): 7.49 (s, 1H, H-4), 3.43 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.93 (t, 2H,
H-8), 2.50 (s, 2H, H-5), 1.66 (t, 2H, H-7), 1.29 (d, 6H, CH(CH3)2), 1.00 (s, 6H, (CH3)2) ppm;
13C NMR (CDCl3, ꢁ, 50 MHz): 166.0 (s, C-2), 160.5 (s, C-8a), 140.6 (d, C-4), 128.7 (s, C-4a), 117.2
(s, CN), 104.5 (s, C-3), 41.7 (t, C-5), 35.1 (t, C-7), 34.0 (d, CH), 29.9 (t, C-8), 29.0 (s, C-6), 27.5
(q, (CH3)2), 21.6 (q, CH(CH3)2) ppm.

448
P. Stanetty and G. PuÈrstinger
Method C: General procedure for the synthesis of 1-pyridinyl-1-propanones 4
To a solution of 100 mmol EtMgBr in 70 ml of diethyl ether (prepared from magnesium turnings and
EtBr in the usual manner), a solution of 20 mmol carbonitrile 3 in 30 ml of dry diethyl ether was
added at ambient temperature. Then the resulting mixture was heated under re¯ux (35 h for 4a, 4c±e,
3 h for 4f±i). After evaporating the solvent, 10 ml of water and 150 ml of 2 N HCl were added. After
heating to re¯ux (20 h for 4a, 4c±e, 2 h for 4f±i) the mixture was cooled to room temperature, and the
pH was adjusted to 9 by addition of 2 N NaOH. The resulting mixture was extracted twice with
100 ml of diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate,
®ltered, and evaporated. The resulting crude products were puri®ed by Kugelrohr distillation, column
chromatography, or recrystallization (see below).
1-(4,6-Dimethyl-2-(1-methylethyl)-3-pyridinyl)-1-propanone (4a, C13H19NO)
The product was puri®ed by Kugelrohr distillation. Pale yellow oil; b.p.: 75±80ꢁC/1.3 mbar; 1H NMR
(CDCl3, ꢁ, 90 MHz): 6.73 (s, 1H, H-5), 2.85±2.55 (m, 3H, CH(CH)3)2 and CH2CH3), 2.48 (s, 3H,
6-CH3), 2.14 (s, 3H, 4-CH3), 1.25 (d, 6H, (CH3)2, J ˆ 7 Hz), 1.19 (t, 3H, CH2CH3, J ˆ 7.3 Hz) ppm;
13C NMR (CDCl3, ꢁ, 50 MHz): 209.2 (s, CO), 160.2 and 157.6 (2s, C-2 and C-6), 141.7 (s, C-4),
133.6 (s, C-3), 121.6 (d, C-5), 38.3 (t, CH2CH3), 33.4 (d, CH(CH3)2), 23.9 (q, 6-CH3), 22.2
(q, (CH3)2), 18.3 (q, 4-CH3), 7.4 (q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-1-methyl-3-(1-methylethyl)-4-isoquinolinyl)-1-propanone (4c, C16H23NO)
The product was ®rst puri®ed by column chromatography (petroleum ether:ethyl acetate ˆ 15:1) and
then by Kugelrohr distillation. Colorless crystals, m.p.: 71±72ꢁC; b.p.: 80±85ꢁC/0.02 mbar; 1H NMR
(CDCl3, ꢁ, 90 MHz): 2.90±2.40 (m, 7H, CH(CH3)2, CH2CH3, H-5 and H-7), 2.44 (s, 3H, 1-CH3),
1.90±1.65 (m, 4H, H-6 and H-7), 1.24 (d, 6H, (CH3)2, J ˆ 6.8 Hz), 1.20 (t, 3H, CH2CH3, J ˆ 7.2 Hz)
ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 209.6 (s, CO), 156.4 and 155.9 (2s, C-1 and C-3), 140.0 (s, C-
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4a), 133.4 (s, C-4), 127.4 (s, C-8a), 38.2 (t, CH2CH3), 32.9 (d, CH), 26.3 (t, C-5), 25.7 (t, C-8),
22.3, 22.2, (q, (CH3)2), 22.1, 21.6, 7.3 (q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-1,5,5-trimethyl-3-(1-methylethyl)-4-isoquinolinyl)-1-propanone
(4d, C17H25NO)
The crude product was ®rst puri®ed by Kugelrohr distillation and then submitted to column
chromatography (petroleum ether:ethyl acetate ˆ 35:1). Pale yellow crystals; m.p.: 68.5±69.5ꢁC;
1
b.p.: 90±100ꢁC/0.005 mbar; H NMR(CDCl3, ꢁ, 90 MHz): 2.77±2.43 (m, 5H, CH(CH3)2, CH2CH3
and H-5), 2.68 (s, 3H, 1-CH3), 1.80±1.60 (m, 4H, H-6 and H-7), 1.38 (s, 6H, (CH3)2), 1.24 (d, 6H,
CH(CH3)2, J ˆ 7.0 Hz), 1.20 (t, 3H, CH2CH3, J ˆ 7.2 Hz) ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 210.7
(s, CO), 157.1 and 155.5 (2s, C-1 and C-3), 140.6 (s, C-4a), 136.0 (s, C-8a), 133.7 (s, C-4), 42.5
(t, C-7), 38.3 (t, CH2CH3), 33.2 (s, C-8), 32.9 (d, CH), 28.8 (q, (CH3)2), 28.3 (t, C-5), 26.7
(q, 1-CH3), 22.3 (q, CH(CH3)2), 18.3 (t, C-6), 7.4 (q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-1,7,7-trimethyl-3-(1-methylethyl)-4-isoquinolinyl)-1-propanone
(4e, C17H25NO)
The crude product was puri®ed by column chromatography (petroleum ether:ethyl acetate ˆ 35:1).
1
Pale yellow crystals; m.p.: 66±68ꢁC; H NMR (CDCl3, ꢁ, 90 MHz): 2.87±2.42 (m, 5H, CH(CH3)2,
CH2CH3 and H-8), 2.95 (s, 2H, H-5), 2.48 (s, 3H, 1-CH3), 1.80±1.72 (m, 2H, H-7), 1.28 (s, 6H,
(CH3)2), 1.22 (d, 6H, CH(CH3)2, J ˆ 7.0 Hz), 1.20 (t, 3H, CH2CH3, J ˆ 7.2 Hz) ppm; 13C NMR

Aza Analogs of Sindone B
449
(CDCl3, ꢁ, 50 MHz): 210.4 (s, CO), 156.7 and 154.5 (2s, C-1 and C-3), 140.5 (s, C-4a), 141.2 (s, C-
8a), 133.7 (s, C-4), 42.4 (s, C-7), 38.3 (t, CH2CH3), 33.2 (s, C-6), 32.9 (d, CH), 28.8 (q, (CH3)2), 28.3
(t, C-5), 26.7 (q, 1-CH3), 23.3 (t, C-8), 22.4 (q, CH(CH3)2), 7.4 (q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-2-(1-methylethyl)-3-quinolinyl)-1-propanone (4f, C15H21NO)
The product was puri®ed by Kugelrohr distillation. Colorless crystals; m.p.: 55±58ꢁC; b.p.: 75±80ꢁC/
0.015 mbar; 1H NMR (CDCl3, ꢁ, 90 MHz): 7.37 (s, 1H, H-4), 3.36 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz),
3.00±2.65 (m, 6H, CH2CH3, H-5 and H-8), 2.00±1.70 (m, 4H, H-6 and H-7), 1.25 (d, 6H, (CH3)2,
J ˆ 6.8 Hz), 1.18 (t, 3H, CH2CH3, J ˆ 7.2 Hz) ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 204.5 (s, CO),
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161.4 (s, C-2), 158.6 (s, C-8a), 135.1 (d, C-4), 130.8 (s, C-3), 128.1 (s, C-4a), 35.2 (t, CH2CH3),
32.3 (d, CH), 31.6 (t, C-8), 28.0 (t, C-5), 22.6 and 22.4 (2t, C-6 and C-7), 22.2 (q, (CH3)2), 8.0
(q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-8,8-dimethyl-2-(1-methylethyl)-3-quinolinyl)-1-propanone (4g, C17H25NO)
The product was puri®ed by Kugelrohr distillation and subsequent recrystallization from MeOH.
1
Colorless crystals; m.p.: 69±70.5ꢁC; b.p.: 80±85ꢁC/0.003 mbar; H NMR (CDCl3, ꢁ, 90 MHz): 7.37
(s, 1H, H-4), 3.39 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.86 (q, 2H, CH2CH3, J ˆ 7.2 Hz), 2.78±2.70 (m,
2H, H-5), 1.85±1.75 (m, 4H, H-6 and H-7), 1.33 (s, 6H, (CH3)2), 1.25 (d, 6H, CH(CH3)2, J ˆ 6.8 Hz),
1.18 (t, 3H, CH2CH3, J ˆ 7.2 Hz) ppm; 13C NMR (CDCl3, ꢁ, 50 MHz): 205.3 (s, CO), 165.5 (s, C-
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8a), 161.8 (s, C-2), 135.6 (d, C-4), 130.5 (s, C-3), 127.2 (s, C-4a), 38.6 (t, C-7), 37.0 (t, C-8), 35.4
(t, CH2CH3), 32.2 (d, CH), 30.0 (q, (CH3)2), 29.6 (t, C-5), 22.6 (q, CH(CH3)2), 19.4 (t, C-6), 8.4
(q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-7,7-dimethyl-2-(1-methylethyl)-3-quinolinyl)-1-propanone (4h, C17H25NO)
The product was puri®ed by Kugelrohr distillation and subsequent column chromatography
(petroleum ether:ethyl acetate ˆ 5:1). Pale yellow oil; b.p.: 80±85ꢁC/0.01 mbar; 1H NMR (CDCl3, ꢁ,
90 MHz): 7.38 (s, 1H, H-4), 3.34 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.83 (q, 2H, CH2CH3,
J ˆ 7.2 Hz), 2.73 (t, 2H, H-5), 2.67 (s, 2H, H-8), 1.56 (t, 2H, H-6), 1.22 (d, 6H, CH(CH3)2,
J ˆ 6.8 Hz), 1.18 (t, 3H, CH2CH3, J ˆ 7.2 Hz), 1.00 (s, 6H, (CH3)2) ppm; 13C NMR (CDCl3, ꢁ,
50 MHz): 205.2 (s, CO), 161.8 (s, C-2), 158.4 (s, C-8a), 135.1 (d, C-4), 131.0 (s, C-3), 126.8 (s, C-
4a), 46.4 (t, C-8), 35.4 (t, CH2CH3), 35.1 (d, CH), 31.8 (t, C-6), 29.8 (s, C-7), 28.0 (q, (CH3)2), 25.1
(t, C-5), 22.4 (q, CH(CH3)2), 8.2 (q, CH2CH3) ppm.
1-(5,6,7,8-Tetrahydro-6,6-dimethyl-2-(1-methylethyl)-3-quinolinyl)-1-propanone (4i, C17H25NO)
The product was puri®ed by Kugelrohr distillation. Pale Yellow oil; b.p.: 86±90ꢁC/0.02 mbar;
1H NMR (CDCl3, ꢁ, 90 MHz): 7.34 (s, 1H, H-4), 3.34 (hpt, 1H, CH(CH3)2, J ˆ 6.8 Hz), 2.90 (t, 2H,
H-8), 2.85 (q, 2H, CH2CH3, J ˆ 7.2 Hz), 2.50 (s, 2H, H-5), 1.65 (t, 2H, H-7), 1.25 (d, 6H, CH(CH3)2,
J ˆ 6.8 Hz), 1.17 (t, 3H, CH2CH3, J ˆ 7.2 Hz), 0.99 (s, 6H, (CH3)2) ppm; 13C NMR (CDCl3,
ꢁ, 50 MHz): 205.2 (s, CO), 161.7 (s, C-2), 157.9 (s, C-8a), 135.8 (d, C-4), 131.1 (s, C-3), 127.5
(s, C-4a), 42.2 (t, C-5), 35.5 (t, CH2CH3), 35.4 (d, CH), 31.8 (t, C-7), 29.6 (t, C-8), 29.2 (s, C-6), 27.7
(q, (CH3)2), 22.4 (q, CH(CH3)2), 8.2 (q, CH2CH3) ppm.
Acknowledgments
We are grateful for generous ®nancial support for this research work given by Novartis, Basel.

450
P. Stanetty and G. PuÈrstinger: Aza Analogs of Sindone B
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Received September 15, 1998. Accepted (revised) October 12, 1998