A synthetic approach to perhydro-3-isoquinolinones bearing an angular methyl group via organocuprate addition

Article abstract of DOI:10.1007/PL00010187

The addition of organocuprates to the activated C-C double bond in 2H-3,3a,4,5,6,7-hexahydro-2-indenone followed by trapping of the anionic intermediate with Mel as electrophile is reported. Structural assignment of the resulting product was carried out v

Full text of DOI:10.1007/PL00010187

Monatshefte fuÈr Chemie 130, 1257±1268 (1999)
A Synthetic Approach to Perhydro-3-
isoquinolinones Bearing an Angular Methyl
Group via Organocuprate Addition
Peter Stanetty1;Ã, M. Hassan Bahardoust1, Marko D. Mihovilovic1,
and Kurt Mereiter2
1
Institute of Organic Chemistry, Vienna University of Technology, A-1060 Vienna, Austria
2
Institute of Mineralogy, Crystallography, and Structural Chemistry, Vienna University of Technology,
A-1060 Vienna, Austria
Summary. The addition of organocuprates to the activated C±C double bond in 2H-3,3a,4,5,6,7-
hexahydro-2-indenone followed by trapping of the anionic intermediate with MeI as electrophile is
reported. Structural assignment of the resulting product was carried out via its oxime using X-ray
diffraction. A subsequent Beckmann rearrangement gave the desired title compound.
Keywords. Organocuprate addition; Michael-type addition; Beckmann rearrangement; Ergosterol
biosynthesis inhibitors; X-Ray diffraction.
È
Ein Syntheseweg zu Perhydro-3-isochinolinonen mit angularer Methylgruppe
uÈber Organocuprat-Addition
Zusammenfassung. Die Addition von Organocupraten an die aktivierte C±C Doppelbindung in 2H-
3,3a,4,5,6,7-Hexahydro-2-indenon, gefolgt von einer Abfangreaktion des anionischen Zwischenpro-
È
dukts mit MeI als Elektrophil, wurde untersucht. Die Strukturaufklarung des erhaltenen Produktes
È
erfolgte mittels Rontgendiffraktion seines Oxims. Eine anschlieûende Beckmann-Umlagerung lieferte
die gewuÈnschte Titelverbindung.
Introduction
A major target for highly selective fungicides in agrochemical disease control is
represented by the biosynthesis of ergosterol [1]. The generally accepted mode of
action of these compounds is the inhibition of the enzyme Á8-Á7-isomerase which
is responsible for the isomerization reaction from fecosterol (1) to episterol (2)
(Scheme 1) [2]. Especially perhydrated heterocyclic molecules with lipophilic side
chains such as phenpropimorph (3), fenpropidine (4), or tridemorph (5) exhibit
high biological activity and have been successfully introduced as commercial
products [3].
Ã
Corresponding author

1258
P. Stanetty et al.
Scheme 1
Scheme 2
Compared to the monocyclic series, the ®eld for potential bicyclic inhibitors is
by far not as well investigated [4]. In an effort to close this gap we have recently
started to develop synthetic routes to perhydro-quinolinones 6 and perhydro-
quinolinoles 7 using hetero-Diels-Alder methodology [5] and reductive cyclization
techniques [6] (Scheme 2). We have expected to improve the af®nity of the
inhibitor for the active site of the target enzyme by introducing an angular methyl
group as a general structural feature. Hence, these products act as a heterocyclic
mimic for parts of the steroidal skeleton.
Expanding our research in this ®eld on isoquinolines of type 8 with an angular
methyl group, we now present our ®rst approach towards the key intermediate 9.
Retrosynthetic analysis of the system suggested access by a ring expansion reaction
of the Beckmann type (Scheme 3). For the synthesis of the precursor 10 we
envisioned a double addition technique starting from enone 11 as acceptor for a
Scheme 3

Perhydro-3-isoquinolinones with Angular Methyl Group
1259
conjugate 1,4-addition and introducing the angular group via an organocuprate.
Quenching of the intermediate anion with a suitable electrophile would then enable
access to the system substituted in position 1 in one step.
Results and Discussion
Synthetic aspects
The synthesis of the Michael acceptor 11 was initiated by Stork alkylation of
cyclohexanonenamine 12 or 13 with 3-chloro-2-methylpropene to give 14 (Scheme
4) [7]. Best results were obtained in the presence of one equivalent of NaI. The
optimized procedure reported for this conversion minimizes troublesome side
reactions such as double alkylation. Ozonolysis of 14 gave the diketone 15 in
excellent yield. This two-step procedure allows substantially improved access to 15
avoiding alternative routes using readily decomposing iodides [8] or expensive
reagents [9]. Subsequent condensation of precursor 15 under basic reaction
conditions led to the Michael acceptor 11 [10].
Michael type addition with Me2CuLi prepared in situ followed by hydrolysis
‡
(E ˆ H , R ˆ H) gave ketone 10a with cis-annelation of the cyclic system as
expected from similar results in the literature [11] (Scheme 5). Since we
encountered some problems when we tried to trap the intermediate anion with an
alkyliodide (E ˆ MeI, R ˆ Me), HMPA was added to the reaction mixture after the
initial addition of Me2CuLi in order to enhance the reactivity of the intermediate
species. With this modi®cation the conversion to one single compound 10b [12]
was improved signi®cantly.
The stereochemistry of 10b was established after conversion to the
corresponding oxime 16b. X-Ray diffraction of a crystal (Fig. 2) con®rmed that
the initial attack of the organometallic species occurs cis to the proton at the
annelation site. In contrast to our expectations, the position of the second methyl
group was found to be cis to the angular substituent. This result is remarkable since
in similar reactions the effect of steric hindrance usually directs the attack of the
electrophile into the trans position [13].
Conversion of the ketone 10b to the corresponding oxime proved to be very
sensitive to the reaction conditions. Depending on the base used, substantial
amounts of the epimeric compound 17b were isolated (Table 1, entry 2). In an
optimization process (entries 1, 3±5) this undesired side reaction could be
suppressed completely, maximizing the yield of 16b (entry 6). According to the
Scheme 4

1260
P. Stanetty et al.
Scheme 5
Table 1. Product ratio for the oxime formation from ketone 11b
Entry
Conditions
16b
17b
1
2
3
4
5
6
H2NOH Á HCl/HCl/EtOH
H2NOH Á HCl/NaOAc
15%
45%
47%
38%
55%
97%
0%
13%
0%
H2NOH Á HCl/MeOH
H2NOH Á HCl/NaOH
0%
H2NOH Á HCl/NaOH/MeOH
H2NOH Á HCl/pyridine/MeOH
0%
0%
crystal structure determination, the OH-group of the oxime 16b is in anti-position
to C9 (labeling according to Fig. 2). Hence, both electronic and steric aspects favor
migration of this center, leading to the desired 1,8a-dimethyl-3-isoquinolinone 9b.
However, the ring expansion reaction under standard Beckmann rearrangement
conditions using strong mineral (Table 2, entry 1) or organic (entry 2) acids gave
only small amounts of the desired target compound 9b. The yield of heterocyclic
material was successfully increased by improving the leaving group quality of the
Table 2. Optimization of the Beckmann ring expansion reaction depending on the starting material
(SM)
Entry
Condition
SM
Yield
1
2
3
4
5
conc. H2SO4
16b
16b
16b
11b
11b
13%
32%
96%
55%
77%
MeSO3H
TsCl/pyridine
one-pot: H2NOTs/HCOOH
one-pot: H2NOH Á HCl/TsCl/pyridine

Perhydro-3-isoquinolinones with Angular Methyl Group
1261
OH-moiety via tosylation in the presence of a base (entry 3). X-Ray diffraction of
the obtained product 9b con®rmed that the rearrangement proceeded as expected
with the sterically more demanding group to migrate giving a single isomer (Fig. 3).
Expanding the above methodology to a one-pot procedure for the direct
conversion of ketone 10b to the isoquinolinone system, we used TsONH2 in the
presence of concentrated formic acid. Although the reaction gave the expected
compound after re¯uxing for several hours, the yield of 9b was only fair (entry 4).
Much better results were obtained when hydroxylamine was used to prepare
the oxime, followed by in situ tosylation with TsCl in the presence of pyridine
(entry 5). These conditions gave clean conversion to 9b without formation of any
other isomer.
Comparison of the molecular and crystal structures of 17b, 16b, and 9b
Atomic coordinates of the non-hydrogen atoms of 17b, 16b, and 9b are compiled
in Table 3. The molecular structures as encountered in the crystalline state and the
adopted crystallographic atom numberings are shown in Figs. 1, 2, and 3. In the
three compounds, the six-membered rings C(3) through C(8) adopt normal chair-
conformations. The ®ve-membered rings in 17b and 16b as well as the six-
membered lactam ring in 9b display envelope or half-chair conformations with
essentially planar parts formed by C(1), C(2), C(3), C(9), N, and O, from which the
Ê
ring atom C(8) deviates by about 0.60±0.64 A. This envelope conformation is
stabilized by the presence of sp2-hybridized C(1) atoms in the ®ve-membered rings
and by two sp2-hybridized atoms C(1) and N in the six-membered ring.
Although the two oximes 17b and 16b differ formally only in the cis- and trans-
disposition of their methyl groups C(10)H3 and C(11)H3, the molecular structures of
the two compounds show marked stereochemical differences in their bicyclic ring
systems (Figs. 1 and 2). Despite the cis/trans-isomerism, the methyl groups C(11)H3
adopt equatorial positions at the ®ve-membered rings of both compounds with the
result that the torsion angles C(11)±C(9)±C(8)±C(10) are of comparable size,
measuring ꢀ73ꢁ in 17b and ꢀ50ꢁC in 16b. This is achieved by a reversal in the
conformation of the bicyclic system. In 17b the angular methyl group C(10)H3 is
oriented axially relative to the six-membered ring and equatorially relative to the
®ve-membered ring, whereas in 16b the situation is reversed. Hence, the annelation
of the ®ve-membered to the six-membered ring is axial for C(2) and equatorial for
C(9) in 17b, whereas in 16b it is equatorial and axial. In that context, the envelope-
shaped 5-ring is exo-oriented in 17b and endo-oriented in 16b.
The lactam 9b retains the main conformational features of 16b (Fig. 3).
Surprisingly, this analogy between 16b and 9b is not limited to the molecular
structure, but holds also for the arrangement and interaction of the molecules in
their crystal structures despite the signi®cant differences between the functional
groups >C=NOH (16b) and -HN-(C=O)- (9b). This is achieved in both compounds
by the formation of cyclically hydrogen-bonded dimers of symmetry Ci: in the
oxime 16b by molecular dimers linked via a six-membered ring Á Á ÁN±O±HÁ Á ÁN0±
O0±H0Á Á Á (primed atoms are inversion related to unprimed ones, dots indicate
hydrogen bonds), in the lactam 9b by molecular dimers linked via an eight-
membered ring Á Á ÁO±C(1)-N±HÁ Á ÁO0±C(1)0-N0±H0Á Á Á. The hydrogen bond

1262
P. Stanetty et al.
Table 3. Atomic coordinates of cis-lactam C11H19NO (9b), cis-oxime C11H19NO (16b), and trans-
oxime C11H19NO (17b)
x
y
z
cis-lactam C11H19NO (9b)
N
0.4351(7)
0.7657(5)
0.6563(9)
0.7660(7)
0.6234(7)
0.6153(8)
0.4847(9)
0.2530(8)
0.2541(8)
0.3910(7)
0.2826(7)
0.4079(9)
0.0667(7)
0.1509(5)
0.1670(5)
0.2213(6)
0.3589(7)
0.4430(6)
0.6133(6)
0.7014(7)
0.5599(7)
0.3849(6)
0.2912(6)
0.2040(6)
0.1401(7)
0.0328(7)
0.3852(3)
0.4951(3)
0.4133(4)
0.3385(4)
0.2580(4)
0.3331(4)
0.2516(5)
0.1846(4)
0.1142(4)
0.1924(3)
0.2933(4)
0.1035(4)
0.2458(4)
O
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
cis-oxime C11H19NO (16b)
O
0.7386(2)
0.5131(2)
0.5221(2)
0.7342(2)
0.6358(2)
0.6395(3)
0.4983(3)
0.2469(3)
0.2327(2)
0.3874(2)
0.3038(2)
0.4004(5)
0.0874(3)
0.1655(2)
0.1443(2)
0.2538(2)
0.3852(2)
0.4647(2)
0.6534(2)
0.7189(2)
0.5779(2)
0.3892(2)
0.3142(2)
0.2532(2)
0.1494(3)
0.0740(2)
0.4951(1)
0.4328(1)
0.3680(1)
0.3469(2)
0.2516(1)
0.3110(2)
0.2259(2)
0.1782(2)
0.1127(1)
0.1852(1)
0.2910(1)
0.0992(2)
0.2602(2)
N
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
trans-oxime C11H19NO (17b)
N
0.0573(1)
0.1813(2)
0.0377(2)
0.3299(2)
0.3603(3)
0.5541(3)
0.5558(3)
0.3936(4)
0.4152(4)
0.4008(3)
0.5639(2)
0.5002(3)
0.7852(3)
0.4434(4)
0.4548(1)
0.3883(1)
0.4169(1)
0.3167(1)
0.3149(1)
0.2365(2)
0.2500(2)
0.3431(2)
0.4209(1)
0.4128(1)
0.4739(1)
0.4380(2)
0.5738(1)
O
0.0075(1)
0.1094(1)
0.1273(2)
0.2051(1)
0.2847(2)
0.3780(2)
0.4412(2)
0.3613(1)
0.2654(1)
0.1690(1)
0.3102(2)
0.1995(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)

Perhydro-3-isoquinolinones with Angular Methyl Group
1263
Fig. 1. Molecular structure of 17b in the crystalline state with crystallographic atom numbering
(20% ellipsoids)
Fig. 2. Molecular structure of 16b in the crystalline state with crystallographic atom numbering
(20% ellipsoids)
Fig. 3. Molecular structure of 9b in the crystalline state with crystallographic atom numbering
(20% ellipsoids)

1264
P. Stanetty et al.
Fig. 4. Packing plots of the crystal structures of 16b (left) and 9b (right) viewed along the a axes;
C-bonded H-atoms omitted for clarity, H-bonds as broken line; the comparison shows the hydrogen
bonded dimers and visualizes that the two compounds are pseudo-isostructural
0
Ê
Ê
distances NÁ Á ÁO are 2.833 A in 16b and 2.920 A in 9b. As shown in Fig. 4, the
H-bonded dimers of 16b and 9b are analogous in shape and spatial arrangement
ꢀ
and, hence, also in the triclinic unit cells, space group P 1. Consequently, the
compounds can be regarded as pseudo-isostructural.
A generally accepted crystallographic proof for this view is the fact that both
crystal structures can be successfully re®ned with the atomic parameters of its
congener as the starting values. The largest shifts in these re®nements concern
C(1), N, and O. In comparison to 9b and 16b, oxime 17b likewise forms hydrogen
0
Ê
bonded dimers of inversion symmetry with OÁ Á ÁN ˆ 2.814 A, but the spatial
arrangement is different and leads to a unit cell with monoclinic symmetry, space
group P21/c, and a doubled unit cell content.
Experimental
General
All solvents were distilled prior to use. Dry CH2Cl2 was prepared by distillation from P2O5, dry
MeOH by distillation from Mg, dry diethyl ether by distillation from Na/benzophenone, dry acetone
and dry acetonitrile by distillation from dry K2CO3. Dry pyridine (Aldrich) was stored over
Ê
molecular sieves (4A). Methyllithium was obtained from Aldrich as 1.5 M solution in diethyl ether.
TLC was performed on Merck precoated silica gel plates (5554) and ¯ash column chromatography
on silica gel 60 from E. Merck (40±63 mm, 9385).
Melting points were determined using a Ko¯er hot stage microscope and are uncorrected.
Elemental analyses of all new compounds were carried out in the Microanalytical Laboratory,
University of Vienna, and gave good agreement with the calculated values. The NMR spectra were
recorded with a Bruker AC 200 (200 MHz) spectrometer from CDCl3 solution; chemical shifts are
reported in ppm relative to internal TMS.
2-(2-Methyl-2-propenyl)cyclohexanone (14; C10H16O)
To a 10% solution of enamine 12/13 (120 mmol, 1.2 eq) in a 4:1 mixture of dry acetone/dry
acetonitrile, dried NaI (1.0 eq) was added under nitrogen. This suspension was treated dropwise with

Perhydro-3-isoquinolinones with Angular Methyl Group
1265
freshly distilled 3-chloro-2-methylpropene (1 eq) at room temperature and then re¯uxed for 24 h.
After concentration of the reaction mixture, the residue was taken up with H2O and re¯uxed for 2 h.
The product was isolated by extraction with diethyl ether. The combined organic layers were washed
with 1 N HCl, satd. NaHCO3 solution, and brine, dried over Na2SO4, and concentrated to give 14
after distillation in vacuo. Enamine 12 yielded 66% and compound 13 68% of pure 14 as a colorless
1
liquid. B.p.: 44±45ꢁC/1 mbar; H NMR (200 MHz, ꢀ, CDCl3): 1.15±2.57 (m, 11H), 1.68 (s, 3H,
CH3), 4.7 and 4.65 (2s, 2H, ˆ CH2) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 22.0 (q, CH3), 24.5 (t, C-
4), 27.7 (t, C-5), 33.0 (t, C-3), 37.1 (t, CH2), 41.7 t, C-6), 48.0 (d, C-2) 111.5 (t, ˆ CH2), 142.9 (s,
=C), 212.1 (s, C-1)ppm.
2-(2-Oxopropyl)cyclohexanone (15; C9H14O2)
A solution of 3.00 g 14 (19.7 mmol) in 40 cm3 dry CH2Cl2 under nitrogen was cooled to ꢀ70ꢁC and
gently treated with ozone generated by an ozonizer (Sander Labor Ozonisator) at a ¯ow of approx.
140Â103 cm3 Á hꢀ1 and in a concentration of approx. 20 g O3/m3 until the color of the mixture
changed to blue. The O3 ¯ow was stopped and the solution stirred at reaction temperature until the
color faded. The treatment with ozone was repeated until the blue color remained and TLC indicated
complete conversion (usually 20±30 min). The reaction mixture was warmed to room temperature,
dimethylsul®de (10 eq) in 10 cm3 of methanol was added, and the solution was stirred for 5 h.
Concentration and distillation in vacuo gave 2.58 g (85%) of pure 15 as a colorless liquid. B.p.: 63±
65ꢁC/0.5 mbar; 1H NMR (200 MHz, ꢀ, CDCl3): 1.22±2.38 (m, 9H), 2.15 (s, 3H, CH3), 2.84±3.02 (m,
2H) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 25.0 (d, C-4), 27.6 (d, C-5), 30.1 (q, CH3) 33.7 (d, C-3),
41.5 (d, C-6), 42.9 (d, CH2), 46.1 (d, C-2), 206.8 (s, C=O), 210.9 (s, C-1)ppm.
2H-3,3a,4,5,6,7-Hexahydro-2-indenone (11; C9H12O)
To remove oxygen, a mixture of 400 cm3 5% KOH and 10 cm3 EtOH was treated with N2. To this
9.90 g 15 (64.2 mmol) were added, and the solution was re¯uxed for 6 h. After cooling to room
temperature the mixture was neutralized with dilute H2SO4 and extracted with diethyl ether. The
combined organic layers were washed with water, dried over Na2SO4, concentrated, and distilled to
1
give 8.00 g (92%) of pure 11 as a colorless liquid B.p.: 38ꢁC/0.23 mbar; H NMR (200 MHz, ꢀ,
CDCl3): 0.96±2.78 (m, 11H), 5.80 (s, 1H, C±1) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 25.0, 26.8,
30.7, and 34.8 (4t, C-4, C-5, C-6 and C-7), 41.5 (d, C-3a), 42.1 (t, C-3), 126.4 (d, C-1), 184.6 (s, C-
7a) 208.6 (s, C-2) ppm.
cis-2H-1,3,3a,4,5,6,7,7a-Octahydro-7a-methyl-2-indenone (10a; C10H16O)
Dimethylcopperlithium was prepared by treating a suspension of dry CuI (1 eq) in dry diethyl ether
(1:20 dilution) with methyllithium solution (2 eq) at ꢀ15ꢁC under nitrogen. The mixture gave a
yellow precipitate with the ®rst equivalent of MeLi and turned homogenous after complete addition.
This solution (1.3 eq Me2CuLi) was cooled to ꢀ40ꢁC, 1.00 g 11 (7.34 mmol, 1 eq) was added
dropwise, the mixture was warmed to ꢀ25ꢁC, and stirred for 6 h. After hydrolysis with satd. NH4Cl
solution and extraction with diethyl ether, the combined organic layers were washed with water,
dried over Na2SO4, and concentrated. Kugelrohr distillation gave 1.01 g (91%) of pure 10a as
colorless oil B.p.: 45ꢁC/0.7 mbar; 1H NMR (200 MHz, ꢀ, CDCl3): 1.12 (s, 3H, CH3), 1.20±2.45 (m,
13 H) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 21.6 and 21.8 (2t, C-5 and C-6), 26.3 (t, C-4), 26.4 (q,
CH3), 33.9 (t, C-7), 37.8 (s, C-7a), 41.5 (d, C-3a), 42.4 (t, C-3), 51.4 (t, C-1), 219.6 (s, C-2) ppm.
(1ꢁ,3aꢁ,7aꢁ)-2H-1,3,3a,4,5,6,7,7a-Octahydro-1,7a-dimethyl-2-indenone (10b; C11H18O)
The initial addition of Me2CuLi was carried out according to the procedure for the conversion of 11
(2.00 g, 14.69 mmol) to 10a. After 6 h at ꢀ25ꢁC the reaction mixture was cooled to ꢀ40ꢁC again,

1266
P. Stanetty et al.
and HMPA (20 vol%) and MeI (3.5 eq) were added subsequently. The solution was warmed to
ꢀ25ꢁC and stirred for 6 h. General workup according to 10a gave 1.94 g (87%) of pure 10b as a
colorless oil after Kugelrohr distillation B.p.: 75ꢁC/0.7 mbar; 1H NMR (200 MHz, ꢀ, CDCl3): 0.83 (s,
3H, CH3), 0.90 (d, J ˆ 7 Hz, 3H, CH3), 1.10±2.50 (m, 12H) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 7.7
and 24.1 (2q, 2ÂCH3), 21.5 and 24.7 (t, C-5 and C-6), 29.3 (t, C-4), 33.8 (t, C-7) 40.2 (s and d, C-7a
and C-3a), 42.8 (t, C-3), 47.1 (d, C-1), 221.4 (s, C-2) ppm.
(1ꢁ,3aꢁ,7aꢁ)-2H-1,3,3a,4,5,6,7,7a-Octahydro-1,7a-dimethyl-2-indenone oxime (16b; C11H19NO)
Ketone 10b (3.06 g, 18.42 mmol) and hydroxylamine hydrochloride (3 eq) were dissolved in 30 cm3
of a 1:1 mixture of dry MeOH and pyridine and heated to 60ꢁC for 5 h. After evaporation of the
solvents in vacuo the residue was taken up with CH2Cl2 and 2 N HCl. The organic layer was washed
with water, dried over Na2SO4, and concentrated. Recrystallization from MeOH gave 3.27 g (97%)
of pure 16b as colorless crystals.
1
M.p.: 126±128ꢁC; H NMR (200 MHz, ꢀ, CDCl3): 0.80 (s, 3H, CH3), 0.99 (d, J ˆ 7 Hz, 3H,
CH3), 1.02±2.60 (m, 12H), 8.9 (bs, 1H, OH) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 10.8 and 23.2 (2q,
2ÂCH3), 21.7 and 24.5 (2t, C-5 and C-6), 28.8 (t, C-4), 31.9 and 33.0 (2t, C-3 and C-7), 41.0 and
41.6 (2d, C-1 and C-3a), 41.7 (s, C7a), 169.0 (s, C-2) ppm.
(1ꢁ,3aꢂ,7aꢂ)-2H-1,3,3a,4,5,6,7,7a-Octahydro-1,7a-dimethyl-2-indenone oxime (17b; C11H19NO)
Ketone 10b (1.94 g, 11.67 mmol) was added to a solution of hydroxylamine hydrochloride (3 eq) and
sodium acetate (5 eq) in 60 cm3 of a 1:1 mixture of MeOH and H2O and re¯uxed for 4 h. After
cooling to room temperature the precipitated crystals were collected by ®ltration to give pure 16b.
The remaining solution was concentrated and taken up with water and diethyl ether. The organic
layer was dried over Na2SO4 and evaporated. Separation from remaining 16b could be achieved by
repeated recrystallization from petroleum ether and MeOH. A total of 1.19 g (45%) of 16b and 0.35 g
(13%) of pure 17b were isolated as colorless crystals.
1
M.p.: 120±126ꢁC; H NMR (200 MHz, ꢀ, CDCl3): 0.99 (d, J ˆ 7 Hz, 3H, CH3), 1.10 (s, 3H,
CH3), 1.10±2.50 (m, 12H), 8.4 (bs, 1H, OH) ppm; 13C NMR (50 MHz, ꢀ, CDCl3): 8.7 and 22.0 (2q,
2ÂCH3), 20.1, 21.4, and 23.1 (3t, C-4, C-5, and C-6), 27.2 and 28.7 (2t, C-3 and C-7), 41.3 (s, C-7a),
41.4 and 41.6 (2d, C-1 and C-3a), 168.0 (s, C-2) ppm.
(1ꢁ,3aꢁ,7aꢁ)-3H-1,2,4a,5,6,7,8,8a-Octahydro-1,8a-dimethyl-3(4H)-isoquinolinone (9b; C11H19NO)
Method A: From oxime 16b
Oxime 16b (0.45 g, 2.48 mmol) was dissolved in 20 cm3 of dry pyridine, cooled to ꢀ10ꢁC, and
treated with 4-toluenesulfonyl chloride (1 eq). The mixture was slowly warmed to room temperature
and stirred until TLC indicated complete conversion (approx. 4 h), After hydrolysis with 2 N HCl and
extraction with CH2Cl2 the combined organic layers were washed with water, dried over Na2SO4,
and concentrated. Recrystallization from diisopropyl ether gave 0.43 g (96%) of pure 9b.
Method B: One-pot reaction from ketone 10b
Hydroxylamine (1 eq) in 5 cm3 of dry pyridine was added to a solution of 1.00 g ketone 10b
(6.02 mmol) in 15 cm3 of dry pyridine, and the mixture was heated to 60ꢁC for 2 h. After the reaction
was cooled to ꢀ10ꢁC, 4-toluenesulfonyl chloride (1 eq) was added, and the solution was slowly
warmed to room temperature. General workup according to Method A gave 1.02 g (77%) of pure 9b
as colorless crystals after recrystallization.

Perhydro-3-isoquinolinones with Angular Methyl Group
1267
1
M.p.: 139±140ꢁC; H NMR (200 MHz, ꢀ, CDCl3): 0.83 (s, 3H, CH3), 1.05 (d, J ˆ 7 Hz, 3H,
CH3), 1.10±1.83 (m, 9H), 2.00 (d, J ˆ 19 Hz, 1H, H-3a), 2.68 (dd, J1 ˆ 19 Hz, J2 ˆ 6 Hz, 1H, H-3b),
3.85 (q, J ˆ 7 Hz, 1H, H-1), 5.6 (bs, 1H, NH) ppm; 13C NMR(50 MHz, ꢀ, CDCl3): 15.7 and 21.9 (2q,
2ÂCH3), 21.3, 25.9, and 29.1 (3t, C-5, C-6, and C-7), 33.8 (s, C-8a), 35.0 and 35.2 (2t, C-4 and C-8),
41.2 (d, C-4a), 47.9 (d, C-1), 171.9 (s, C-3) ppm.
Crystal structure of 9b
ꢀ
ꢁ
Ê
Ê 3
A colorless crystal of 9b (C11H19NO, Fw ˆ 181.27, triclinic, space group P1, a ˆ 6.756(3) A,
ꢁ
ꢁ
Ê
Ê
b ˆ 7.745(4) A, c ˆ 11.075(6) A, ꢁ ˆ 94.65(3) , ꢂ ˆ 103.00(3) , ꢃ ˆ 111.68(3) , V ˆ 516.0(4) A ,
Z ˆ 2, d(calcd) ˆ 1.167 g/cm3, T ˆ 295 K) was used for data collection with Philips PW 1100 four-
circle diffractometer (MoKꢁ radiation, !-scans, ꢄ ˆ 2±18ꢁ, ꢀ5 ꢂ h ꢂ 5, 0 ꢂ k ꢂ 6, ꢀ9 ꢂ l ꢂ 9, 710
re¯ections collected, 699 independent, no correction for absorption). All available crystals gave
distinctly broadened X-ray re¯ections, and therefore data collection covered only a limited ꢄ-range.
The structure was solved with direct methods and was re®ned on F2 with anisotropic displacement
factors for non-hydrogen atoms. Hydrogen atoms were located from a difference Fourier map and
re®ned riding with the atoms to which they were bonded. Final re®nement gave R1 ˆ 0.096 and
wR2 ˆ 0.247 for all 699 re¯ections and 119 parameters. R1 ˆ 0.094 for the 646 data with Fo2 > 2ꢅ(Fo2).
Ê ꢀ3
Excursions in ®nal difference Fourier map; between ꢀ0.35 and 0.29 e Á A [15].
Crystal structure of 16b
A yellow rounded crystal (0.4Â0.4Â0.8 mm) of 17b C11H19NO, Fw ˆ 181.27, triclinic space group
ꢁ
ꢁ
ꢀ
Ê
Ê
Ê
P1, a ˆ 6.376(3) A, b ˆ 7.988(3) A, c ˆ 11.776(4) A, ꢁ ˆ 101.61(1) , ꢂ ˆ 101.13(1) ,
3
Ê 3
ꢁ
ꢃ ˆ 110.34(1) , V ˆ 527.8(3) A , Z ˆ 2, d(calcd) ˆ 1.141 g/cm , T ˆ 303 K) was used for data
collection with a Siemens/Bruker SMATR CCꢁD diffractometer (sealed Xꢁ-ray tube, MoKꢁ radiation,
Ê
ꢆ ˆ 0.71073 A, graphite monochromator, 0.3 !-scan frames, ꢄ ˆ 2±25 , ꢀ7 ꢂ h ꢂ 7, ꢀ9 ꢂ k ꢂ 9,
0 ꢂ l ꢂ 13, 2946 re¯ections collected, 1781 independent, correction for absorption by multi-scan
method and program SADABS, Rint ˆ 0.026). The structure was solved with direct methods and was
re®ned on F2 using anisotropic displacement factors for all non-hydrogen atoms. Hydrogen atoms
were located from a difference Fourier map and were re®ned in x, y, z, and Uiso without restraints.
Final re®nement gave R1 ˆ 0.044 and wR2 ˆ 0.106 for all 1781 re¯ections and 195 parameters.
R1 ˆ 0.040 for the 1600 data with Fo2 > 2ꢅ(Fo2). Excursions in ®nal difference Fourier map: between
Ê ꢀ3
ꢀ0.13 and 0.15 e Á A [15].
Crystal structure of 17b
A colorless rounded crystal (0.3Â0.5Â0.8 mm) of 16b (C11H19NO, Fw ˆ 181.27, monoclinic, space
Ê 3
ꢁ
Ê
Ê
Ê
group P21/c, a ˆ 11.847(2) A, b ˆ 6.325(1) A, c ˆ 14.485(3) A, ꢂ ˆ 93.87(1) , V ˆ 1082.9(3) A ,
Z ˆ 4, d(calcd) ˆ 1.112 g/cm3, T ˆ 295 K) was used for data collection with a Philips PW1100 four-
Ê
circle diffractometer (MoKꢁ radiation, ꢆ ˆ 0.71073 A, graphite monochromator, !ꢀ2ꢄ scans, ꢄ ˆ 2±
25ꢁ, 0 ꢂ h ꢂ 14, 0 ꢂ k ꢂ 7, ꢀ17 ꢂ l ꢂ 17, 1993 re¯ections collected, 1903 independent, no correction
for absorption, Rint ˆ 0.012). The structure was solved with direct methods (program SHELXS) and
re®ned on F2 (program SHELXL97) [14] using anisotropic displacement factors for all non-
hydrogen atoms. Hydrogen atoms were located from a difference Fourier map and were re®ned in
x,y,z, and Uiso without restraints. Final re®nement gave R1 ˆ 0.058 and wR2 ˆ 0.112 for all 1903
re¯ections and 195 parameters. R1 ˆ 0.041 for the 1439 data with Fo2 > 2ꢅ(Fo2). Excursions in ®nal
Ê ꢀ3
difference Fourier map: between ꢀ0.12 and 0.15 e Á A [15].
Acknowledgements
Financial support of this project by Novartis Crop Protection AG, Basel, Switzerland, is highly
appreciated.

1268
P. Stanetty et al.: Perhydro-3-isoquinolinones with Angular Methyl Group
References
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È
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[15] Crystallographic data (excluding structure factors) for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data Centre as supplementary publications
no. CCDC 115821 (17b), CCDC 115822 (16b), and CCDC 115823 (9b). Copies of the data can
be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(e-mail: deposit@ccdc.cam.ac.uk)
Received March 15, 1999. Accepted May 3, 1999