The synthesis of 3-amino-3-methylbicyclo[3.3.1]nonanes: Endo-selectivity in the Ritter reaction of 1,3,5,7α-tetramethylbicyclo[3.3.1]nonan-3-ol

Article abstract of DOI:10.1039/a904394b

1,3,5,7α- and 1,3,5,7β-Tetramethylbicyclo[3.3.1]nonan-3-ols 3a and 3b were prepared from the corresponding ketones 2a and 2b. 7α-Methyl isomer 3a gave selectively endo-3α-N-formylaminobicyclononane 10 in the Ritter reaction with trimethylsilyl cyanide. 7β-Methyl epimer 3b suffered water elimination resulting in bicyclo[3.3.1]non-2-ene 12 under the same reaction conditions. The endo-amide structure was confirmed by X-ray analysis. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a904394b

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The synthesis of 3-amino-3-methylbicyclo[3.3.1]nonanes:
Endo-selectivity in the Ritter reaction of 1,3,5,7ꢀ-
tetramethylbicyclo[3.3.1]nonan-3-ol
Aigars Jirgensons, Valerjans Kauss, Anatolij F. Mishnev and Ivars Kalvinsh
Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga, LV-1006, Latvia
Received (in Cambridge, UK) 2nd June 1999, Accepted 20th September 1999
1
,3,5,7α- and 1,3,5,7β-Tetramethylbicyclo[3.3.1]nonan-3-ols 3a and 3b were prepared from the corresponding ketones
2
a and 2b. 7α-Methyl isomer 3a gave selectively endo-3α-N-formylaminobicyclononane 10 in the Ritter reaction with
trimethylsilyl cyanide. 7β-Methyl epimer 3b suffered water elimination resulting in bicyclo[3.3.1]non-2-ene 12 under
the same reaction conditions. The endo-amide structure was confirmed by X-ray analysis..
Introduction
The therapeutic value of N-methyl--aspartate (NMDA) recep-
tor antagonists for the treatment of central nervous system dis-
1
orders has been discussed for many years. The high-affinity
NMDA receptor antagonists provoke undesirable side effects at
therapeutic concentrations. However, Memantine 1 (1-amino-
Scheme 1 Reagents and conditions: i, Br , Fe, 83%; ii, NaOH, 79%.
2
served as a starting material for the preparation of both 1,5,7α-
and 1,5,7β-trimethylbicyclo[3.3.1]nonan-3-ones 2a and 2b.
Hydrogenation of unsaturated ketone 7 using a modified
5
literature procedure provided 1,5,7α-trimethylbicyclononan-3-
one 2a (Scheme 2). 3,5-Dimethyladamantan-1-ol was isolated
as a by-product in this reaction. With a sample of isomeric
ketone 2b in hand we were able to estimate that the hydrogen-
3
,5-dimethyladamantane) possessing moderate receptor affin-
ation was highly selective, i.e. less than 2% of 7β-methyl isomer
b was detected by GC analysis. 1,5,7β-Trimethylbicyclonon-
ity, acts as an uncompetitive NMDA receptor antagonist and
has been used for many years in the treatment of dementia.
2
1
anone 2b was obtained by the known procedure involving
Thus, clinical experience with Memantine 1 has shown that it is
possible to develop NMDA receptor antagonists which do not
activate receptors pathologically and retain their physiological
activity. During the investigations of N-methyl--aspartate
receptor ion channel blockers, Memantine 1 structural isomers,
compounds of increased lipophilicity with shapes similar to
6
Meerwein–Pondorf–Verley reduction of unsaturated ketone 7
and a subsequent acid catalyzed intramolecular proton trans-
7
fer in 7-methylene-1,5-dimethylbicyclo[3.3.1] nonan-3β-ol 8
(
Scheme 2).
2
Memantine 1, have been sought. Thus, it was necessary to
develop a synthetic route toward 1,3,5,7-tetramethylbicyclo-
[
3.3.1]nonan-3-amine 4 isomers (X = CH , Y = NH2 or vice
3
versa).
Up to now the successful introduction of a nitrogen func-
tionality at the tertiary C-3 carbon atom in bicyclo[3.3.1]non-
ane has not been reported. Moreover, nucleophilic additions to
the carbonyl group in this system have been found to be quite
difficult. Fortunately, recent studies of organocerium reagent
addition to bicyclo[3.3.1]nonan-3-one demonstrated the possi-
bility of developing the synthesis of the corresponding alcohols
3
from ketones 2. Our synthetic efforts were, therefore, focussed
on the Ritter reaction of tertiary alcohols 3. Herein we report
the first synthesis of 3-methyl-3-aminobicyclo[3.3.1]nonane
derivatives and evidence that the Ritter reaction proceeds endo-
selectively.
Scheme 2 Reagents and conditions: i, H
, PtO
, 34%; ii, “MeCeCl ”,
2 2
2
i
9
7% of both 3a and 3b; iii, Al(OPr ) , 57%; iv, 75% H SO , 73%.
3
2
4
Results and discussion
The next step involved the introduction of a methyl group at
7
-Methylene-1,5-dimethylbicyclononan-3-one
7
can be
the C-3 position of bicyclononane. Bicyclo[3.3.1]nonan-3-one
obtained in two steps by bromination of 1,3-dimethyl-
itself has been shown to be absolutely inert toward alkyl-
magnesium and -lithium reagents, while organolanthanoid
species were found to add to the carbonyl group more effi-
3
8
adamantane 5 and by subsequent Grob fragmentation of 1,3-
4
dibromo-5,7-dimethyladamantane 6 (Scheme 1). Ketone 7
J. Chem. Soc., Perkin Trans. 1, 1999, 3527–3530
This journal is © The Royal Society of Chemistry 1999
3527

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Table 1 Conversion of isomeric bicyclononanes 2 to tertiary alcohols 3
by organometallic reagents
Conversion to
a
alcohols (%)
Entry
Reaction conditions
3a
3b
1
2
3
MeMgI/Et O
MeLi/THF/cumene
MeMgI/CeCl /THF
50
70
100
9
40
100
2
3
a
The conversion was determined from alcohol/ketone ratio by GC.
9
ciently. 1,5,7-Trimethylbicyclononanones 2a and 2b displayed
low to moderate conversion in reactions with methylmagnesium
iodide and methyllithium, providing mixtures of the desired
alcohols and starting ketones. Using the reagent prepared from
methylmagnesium iodide and cerium trichloride, complete
reaction was observed with both substances to give alcohols 3a
and 3b in excellent yields (Table 1).
Fig. 1 Crystal structure of N-formyl-1,3,5,7β-tetramethylbicyclo-
[3.3.1]nonan-3α-amine 10.
To introduce the amino group both alcohols 3a and 3b were
used in the Ritter reaction with sulfuric acid and trimethylsilyl
10
cyanide as a hydrogen cyanide source (Scheme 3). Thus,
Fig. 2 Transannular hydride transfer in 13.
11–13
attack.
Such a reaction course was explained by torsional
strain caused by the 2,6-axial hydrogens, analogously to the
11,12
nucleophilic addition to cyclohexanones.
Alternatively,
Ichikawa suggested that the axial product resulted from the
ϩ
trans-antiparallel electrophilic addition of H and CH CN to
3
13
the olefinic bond.
It is known that 3α-methylbicyclo[3.3.1]nonanone undergoes
5
predominately exo attack of nucleophiles. It is reasonable to
assume that the capture of nitrile by the carbocation should
also occur predominately from the exo face. Obviously, the
selective endo product 10 formation cannot be explained by
steric discrimination as the bicyclononyl cation should adopt
the same conformation as the parent bicyclononanone. It is
possible that trans-antiparallel addition as suggested by
Ichikawa could be better rationalized as discrimination of the
carbocation faces due to the differing C–C and C–H hyper-
Scheme 3 Reagents and conditions: i, TMSCN, H SO , 34% of 9 and
2
4
14
ϩ
conjugation. The effect of hyperconjugation should thus over-
5
5% of 10; ii, H O , 71%.
3
ride the steric factors. It is evident, however, that a more
detailed investigation of the Ritter reaction stereochemistry
should be carried out.
1
7
,3β,5,7α-tetramethylbicyclo[3.3.1]nonan-3α-ol 3a gave 1,3,5,
β-tetramethylbicyclo[3.3.1]non-2-ene 9 and N-formyl-1,3,5,7-
7
β-Methylbicyclononanol 3b, unlike its epimer 3a, gave
,3,5,7β-tetramethylbicyclo[3.3.1]non-2-ene 12 as sole product
93% by GC of the reaction mixture) and no formamide was
tetramethylbicyclo[3.3.1]nonan-3-amine 10 (34% of 9 and 55%
of 10 by GC). The GC analysis of the reaction mixture indi-
cated that only one amide isomer was formed. The other peaks
registered with similar retention time were of negligible integral
1
(
isolated under the same Ritter reaction conditions (Scheme 4).
1
intensity (<1%). The H NMR spectrum of the reaction
product 10 was somewhat complicated due to the cis–trans
isomerism of the formyl group, as could be seen from the differ-
ent spin coupling constants of the formyl group protons. How-
ever, hydrolysis of formamide 10 undoubtedly gave one amine
1
13
isomer 11 according to GC analysis, and H and C NMR
spectra. As the correct stereochemical assignment of the
1
formamido group could not be determined from simple H
Scheme 4 Reagents and conditions: i, TMSCN, H SO , 66%.
NMR experiments due to the lack of any vicinal spin couplings,
crystals of N-formyl derivative 10 were prepared for a single
crystal X-ray analysis. This revealed two independent molecules
2
4
It has been shown that the 7β-methylbicyclononan-3-yl cation
13 undergoes rapid transannular hydride transfer and exists in
(
a and b) in the asymmetric unit cell (Fig. 1). These molecules
15
differ in the orientation of the formylamino group. The torsion
angles C5–C4–N3–C2 for the molecules a and b are Ϫ174.5(7)
and 59.2(8)Њ, respectively. The bicyclo[3.3.1]nonane framework
adopts a chair-boat conformation with the formamido group in
the axial position of the chair.
There is little information in the literature about the stereo-
chemistry of the Ritter reaction to explain the selective form-
ation of 10. Studies have been carried out only with 4-substi-
tuted cyclohexyl cations, showing the preference for axial nitrile
the double chair conformation (Fig. 2). As a result of this, the
endo face becomes inaccessible. The different reactivities of
alcohols 3a and 3b provide additional evidence that amide
formation from an obviously sterically unfavoured nitrile attack
from the endo side of the carbocation is much more rapid than
that from the exo side. This phenomenon requires an explan-
ation which can be provided only on the basis of more extended
studies. The results obtained for the Ritter reaction of both
bicyclononanols 3a and 3b show that the stereoselectivity of
3
528
J. Chem. Soc., Perkin Trans. 1, 1999, 3527–3530

View Article Online
amide formation does not follow the rules of nucleophilic
addition to the carbonyl group.
Catalyst was filtered off, water (20 ml) was added and the fil-
11
trate extracted with ether (30 ml). The organic phase was
washed with saturated aqueous NaHCO and dried (MgSO ).
3
4
After evaporation of ether the residue was purified by column
chromatography eluting with 4% ethyl acetate in petroleum
ether to give 2a (0.24 g, 34%) as an oil (Found: C, 79.78; H,
Experimental
Melting points were determined in capillary tubes on a Gallen-
kamp apparatus and are uncorrected. IR spectra were recorded
on a Perkin-Elmer 580B spectrometer. Mass spectra were regis-
tered on a Hewlett Packard HP 6890 Series GC system. Micro-
analyses were performed on a Carlo Erba Instrument EA1108.
1
1.15. C H O requires C, 79.94; H, 11.18%); m/z 180 (8%,
12 20
ϩ
ؒ
M ); δ (200 MHz, CDCl ) 0.80 (3H, d, J 7.4, 7-CH ), 1.05
H
3
3
(
6H, s, 1,5-CH ), 0.7–1.9 (8H, m, 2,4-H , 6,8,9-H ), 1.9–2.4
3
a
x
2
(
4
3H, m, 2,4-H , 7-H); δ (50 MHz, CDCl ) 24.75, 32.43, 33.82,
3.13, 44.8, 55.96; νmax(thin film)/cm 1709 (C᎐O).
eq
C
3
1
13
Ϫ1
H and C NMR spectra were determined on a Varian
Mercury 200BB spectrometer for solutions in CDCl with TMS
3
Further elution with 30% ethyl acetate in petroleum ether
gave 3,5-dimethyladamantan-1-ol (0.24 g) identical with an
authentic sample.
as internal standard. Chemical shifts are recorded as δ values in
ppm. J Values are given in Hz. Reaction mixture analyses were
made and the purity of all products were determined by GC
analysis [MN-OV-1 (Fused Silica), 25 m × 0.53 mm, d = 1.0 µ,
f
1
,5-Dimethyl-7-methylenebicyclo[3.3.1]nonan-3ꢁ-ol 8
Ϫ1
5
0–270 ЊC (10 ЊC min )]. Preparative chromatography was
The mixture of unsaturated ketone 7 (1g, 5.6 mmol) and alu-
minium triisopropoxide (2.64 g, 12.9 mmol) in toluene (20 ml)
was refluxed for 17 h. Aqueous NaOH (10 ml of a 10% solu-
tion) was added and the resulting two phase mixture was stirred
for 2 h at room temperature. The organic layer was separated,
the aqueous layer extracted with ether (2 × 20 ml), and the
carried out on Kieselgel 63–100 µm by the flash column
16
method. TLC analyses were performed on Kieselgel 60 F254
plates (Merck). Eluent: hexane–ethyl acetate, visualization
agent: iodine vapors. Ether refers to diethyl ether. Petroleum
ether refers to the fractions of bp 40–60 ЊC. Evaporation of
solvent indicates evaporation under reduced pressure using a
rotary evaporator. Tetrahydrofuran (THF) was distilled from
combined extracts were washed with brine and dried (MgSO ).
4
Evaporation of the solvent gave crude product which was puri-
fied by column chromatography eluting with 10% ethyl acetate
and then with 20% ethyl acetate in petroleum ether to give 8
sodium and benzophenone. Ether and acetonitrile (CH CN)
were distilled from calcium hydride. Petroleum ether, methanol
and ethyl acetate were distilled prior to use. Starting material
3
(
0.57 g, 57%), mp 94–96 ЊC (Found: C, 79.81; H, 11.17.
1
,3-dimethyladamantane 5 and all the reagents were purchased
ϩ
ؒ
C H O requires C, 79.94; H, 11.18%); m/z 180 (21%, M );
from Aldrich.
12 20
δ (200 MHz, CDCl ) 0.95 (6H, s, 1,5-CH ), 0.8–1.20 (4H, m,
H
3
3
1
,3-Dibromo-5,7-dimethyladamantane 6
6,8-Hax and 9-H ), 1.24 (1H, s, OH), 1.7–2.1 (4H, m, 2,4-Hax
2
and 6,8-H ), 2.16 (2H, d, J 14.2, 2,4-H ), 4.45–4.7 (3H, m,
eq
eq
Iron powder (1.5 g) was added to bromine (65 ml) cooled in an
ice bath. Neat 1,3-dimethyladamantane 5 (24.5 g, 150 mmol)
was added dropwise to the reaction mixture during 1 h. The
mixture was stirred for 1.5 h at room temperature then poured
onto ice (0.5 kg) and carbon tetrachloride (250 ml) was added.
Excess bromine was reduced with sodium metabisulfite. The
organic layer was separated and the aqueous phase was
extracted twice with chloroform (100 ml). The combined
᎐
᎐
CH and 3-H); δ (50 MHz, CDCl ) 31.48, 34.57, 46.56, 47.79,
2 C 3
4
8.34, 48.63, 108.49, 148.32.
1
,5,7ꢁ-Trimethylbicyclo[3.3.1]nonan-3-one 2b
Unsaturated alcohol 8 (0.45 g, 2.5 mmol) was stirred for 7 h in
75% H SO (13 ml) at room temperature. Water (30 ml) was
2
4
added and the mixture was extracted with hexane (50 ml and 25
organic layers were washed with brine, saturated NaHCO and
dried (CaCl ). Solvent evaporation gave a crude product which
ml). The organic layer was washed with saturated NaHCO (25
3
3
2
ml) and water (25ml), and dried (MgSO ). After evaporation of
4
was treated with methanol (50 ml). Crystals were collected by
filtration and washed with methanol to provide 6 (39.9 g; 83%),
mp 106–107 ЊC (Found: C, 44.88; H, 5.55. C H Br requires C,
solvent the residue was passed through a short silica gel column
eluting with 10% ethyl acetate in petroleum ether. Crystalline
product 2b (0.33g, 73%) was obtained, mp 48–50 ЊC (Found: C,
12
18
2
ϩ
4
4.75; H, 5.63%); m/z 241 (100%, [M Ϫ Br] ); δ (200 MHz,
80.02; H, 11.11. C H O requires C, 79.94; H, 11.18%); m/z 180
H
12 20
ϩ
ؒ
CDCl ) 0.92 (6H, s, 5,7-CH ), 1.23 (2H, s, 6-H ), 1.97 (8H, s,
(11%, M ); δ (200 MHz, CDCl ) 0.81 (3H, d, J 5.8, 7-CH ),
3
3
2
H
3
3
4
3
,8,9,10-H ), 2.69 (2H, s, 2-H ); δ (50 MHz, CDCl ) 28.86,
8.51, 47.95, 50.67, 53.17, 57.35.
0.7–1.0 (2H, m, 9-H ), 1.00 (6H, s, 1,5-CH ), 1.2–1.35 (1H, m,
2 3
2
2
C
3
7-H), 1.4–1.6 (4H, m, 6,8-H ), 2.01 (2H, d, J 15.4, 2,4-H ), 2.22
2
a
x
(
3
2H, dd, J 16.3 and 2.0, 2,4-H ); δ (50 MHz, CDCl ) 26.61,
0.96, 34.86, 47.27, 47.79, 47.71, 53.06; νmax(Nujol)/cm 1708
eq
C
3
1
7
1
,5-Dimethyl-7-methylenebicyclo[3.3.1]nonan-3-one 7
Ϫ1
(
C᎐O).
᎐
1
,3-Dibromo-5,7-dimethyladamantane 6 (21.6 g, 67 mmol) was
heated in a mixture of dioxane (200 ml) and 1 M NaOH (200
ml) in a steel autoclave at 180 ЊC for 20 h. Water (200 ml) was
added to the reaction mixture and the product was extracted
with ether (3 × 150ml). The combined extracts were washed
General procedure for synthesis of 1,3,5,7-tetramethylbicyclo-
[3.3.1]nonan-3ꢀ-ols 3a and 3b
CeCl ؒ7H O (4.0 mmol) was quickly powdered in a mortar and
3
2
with brine (100ml) and dried (CaCl ). Filtration and solvent
2
heated in vacuo (4 mmHg) while raising the temperature gradu-
ally to 140 ЊC, and then kept at this temperature for 2 h. After
cooling under an argon atmosphere, THF (17 ml) was added
and the suspension obtained was allowed to stir overnight at
room temperature. The suspension was cooled to 3 ЊC and
MeMgI (4.2 ml of a 0.95 M solution in ether, 4.0 mmol) was
added. After the mixture had been stirred for 1 h at 3 ЊC, a
solution of ketone 2a or 2b (2 mmol) in THF (5 ml) was added
evaporation gave an oily residue which was distilled at reduced
pressure (113–116 ЊC/12 mmHg) to provide 7 (9.4 g, 79%) as an
oil (Found: C, 81.04; H, 10.06. C H O requires C, 80.85; H,
1
2
18
ϩ
ؒ
1
1
0.18%); m/z 178 (10%, M ); δ (200 MHz, CDCl ) 1.06 (6H, s,
H
3
,5-CH ), 1.50 (2H, td, J 13.2 and 2.0, 9-H), 1.62 (2H, td, J 13.2
3
and 2.0, 9-H), 1.97 (2H, m, 6,8-H ), 1.98 (2H, m, 2,4-H ), 2.10
ax
ax
(
2H, dd, J 13.4 and 2.0, 6,8-H ), 2.20 (2H, dd, J 16.2 and 2.0,
eq
2
,4-H ), 4.74 (2H, t, J 1.4, ᎐CH ); δ (50 MHz, CDCl ) 30.26,
eq 2 C 3
dropwise. After 15 min, saturated aq. NH Cl was added. The
4
3
4.78, 47.24, 47.78, 53.05, 113.94, 142.79, 210.93.
aqueous layer was extracted with ether (2 × 20 ml) and the
combined extracts were washed with brine and dried over
1
,5,7ꢀ-Trimethylbicyclo[3.3.1]nonan-3-one 2a
MgSO . The solution was filtered and the solvent evaporated.
4
A solution of unsaturated ketone 7 (0.7 g, 3.9 mmol) in acetic
The residue was passed through a short silica gel column
eluting with ether to give essentially pure 3a or 3b.
acid (7 ml) was hydrogenated (1 atm) over PtO (70 mg) for 7 h.
2
J. Chem. Soc., Perkin Trans. 1, 1999, 3527–3530
3529

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1
,3ꢁ,5,7ꢀ-Tetramethylbicyclo[3.3.1]nonan-3ꢀ-ol 3a. Yield
as the excess of HCl were removed in vacuo. The residue was
9
7%; mp 87–89 ЊC (Found: C, 79.70; H, 12.26. C H O requires
C, 79.53; H, 12.32%); m/z 196 (0.1%, M ), 181 (4, [M Ϫ
CH ] ), 178 (5, [M Ϫ H O] ); δ (200 MHz, CDCl ) 0.52 (1H,
d, J 12.6, 9-H), 0.81 (3H, d, J 5.8, 7-CH ), 0.7–0.9 (1H, m, 9-H),
treated with CH CN and filtered to provide 12 as white crystals
13
24
3
ϩ
ؒ
(0.29 g, 71%), mp 284–285 ЊC (Found: C, 67.16; H, 11.39; N,
ϩ
ϩ
5.93. C H NؒHCl requires C, 67.36; H, 11.31; N, 6.04%); m/z
3
2
H
3
13 25
ϩ
ؒ
195 (11%, M ); δ (200 MHz, CDCl ) 0.67 (1H, d, J 13, 9-H),
3
H
3
0
2
3
.90 (6H, s, 1,5-CH ), 1.15 (3H, s, 3-CH ), 1.0–1.7 (10H, m,
0.96 (6H, s, 1,5-CH ), 1.03 (3H, d, J 6.5, 7-CH ), 1.54 (3H, s,
3 3
3
3
,4,6,8-H , 7-H and OH); δ (50 MHz, CDCl ) 22.03, 26.01,
3-CH ), 0.8–1.9 (8H, m, 2,4-H , 6,8-H , 7,9-H), 2.07 (2H, d,
3 ax 2
ϩ
2
C
3
0.36, 34.01, 35.21, 40.74, 44.61, 53.17, 72.33.
J 14.3, 2,4-H ), 8.2 (3H, br s, NH ); δ (50 MHz, CDCl )
eq 3 C 3
2
1.20, 26.18, 30.18, 32.15, 33.04, 42.43, 43.11, 49.48, 55.11.
1
,3ꢁ,5,7ꢁ-Tetramethylbicyclo[3.3.1]nonan-3ꢀ-ol 3b. Yield
9
7%; mp 72–74 ЊC (Found: C, 79.64; H, 12.30. C H O requires
Crystal structure determination for compound 10
25NO, M = 223.35, triclinic, a = 8.883(2), b = 12.104(2),
c = 13.479(3) Å, α = 88.19(3), β = 84.38(3), γ = 85.53(3)Њ, V =
13
24
ϩ
ؒ
C, 79.53; H, 12.32%); m/z 196 (0.1%, M ), 181 (14, [M Ϫ
CH ] ), 178 (4, [M Ϫ H O] ); δ (200 MHz, CDCl ) 0.80 (3H,
d, J 6.6, 7-CH ), 0.86 (6H, s, 1,5-CH ), 0.6–1.1 (4H, m, 9-H
and 6,8-H ), 1.06 (1H, s, OH), 1.24 (3H, s, 3-CH ), 1.3–1.6 (6H,
m, 2,4-H and 6,8-H ), 2.75 (1H, m, 7-H); δ (50 MHz, CDCl )
2
6
ϩ
ϩ
C H
14
3
2
H
3
3
3
2
3
Ϫ3
¯
437.5(5) Å , D = 1.032 g cm , space group P1, Z = 4,
Ϫ1
1
x
ax
3
µ(Mo-Kα) = 0.064 mm . Data were collected on a Syntex-P21
diffractometer using graphite monochromated Mo-Kα radi-
ation at room temperature. Reflections collected/unique 2122/
2
eq
C
3
3.68, 24.73, 30.36, 32.22, 33.48, 37.04, 47.77, 48.05, 51.30,
9.79.
1
980, R(int) = 0.034. The structure was solved by direct
18
methods (SHELXS86) and refined by the full-matrix least-
Ritter reaction of 1,3,5,7-tetramethylbicyclo[3.3.1]nonan-3ꢀ-ols
a and 3b
19
squares method (SHELXL93). Final R and Rw values were
.0847 and 0.1848 [1980 I > 2σ(I) reflections]. Full crystallo-
3
0
To the mixture of alcohol 3a or 3b (0.59 g, 3 mmol) and
TMSCN (0.80 ml, 6 mmol) was added acetic acid (0.5 ml) and
the mixture was cooled to 3 ЊC. Sulfuric acid (0.48 ml; 9 mmol)
was added dropwise (25 min). The reaction mixture was
allowed to warm to room temperature, stirred for 24 h and
poured into ice water (20 ml). The resulting mixture was neu-
tralized with 20% NaOH and extracted with ether (2 × 20 ml).
graphic details, excluding structure factor tables, have been
deposited at the Cambridge Crystallographic Data Centre
(
CCDC). CCDC referenece number 207/363. See http://
www.rsc.rsc.org/suppdata/p1/1999/3527/ for crystallographic
data in .cif format.
Acknowledgements
The combined extracts were dried (MgSO ) and the solvent
4
evaporated. The reaction products were separated by column
chromatography eluting with petroleum ether to give bicy-
clonene 9 or 12, then with 30% ethyl acetate in petroleum ether
to obtain amide 10.
We thank the analytical department of the Institute of Organic
Synthesis for obtaining IR, GC and MS analyses.
References
1
W. Danysz, C.G. Parsons, I. Bresink and G. Quack, Drug News
Perspect., 1995, 8, 261.
A. Jirgensons, V. Kauss, I. Kalvinsh, M. R. Gold, W. Danysz, C. G.
Parsons and G. Quack, Eur. J. Med. Chem., submitted.
1
,3,5,7ꢀ-Tetramethylbicyclo[3.3.1]non-2-ene 9.
A volatile
liquid (34%) (Found: C, 87.74; H, 12.35. C H requires C,
7.56; H, 12.44%); m/z 178 (6%, M ); δ (200 MHz, CDCl )
H 3
.87 (3H, d, J 6.8, 7-CH ), 0.92 and 0.94 (total 6H, both s, 1,5-
CH ), 1.57 (3H, br s, 3-CH ), 0.8–1.9 (9H, m, ring protons),
.15 (1H, br s, 2-H); δ (50 MHz, CDCl ) 22.30, 23.37, 26.19,
0.42, 30.63, 32.03, 32.84, 43.00, 44.23, 45.09, 45.64, 131.84,
33.39.
13
22
2
ϩ
ؒ
8
0
3
3 I. P. Lihotvorik, N. L. Dovgan and G. I. Danilenko, Zh. Org. Khim.,
1977, 13, 897.
4 A. R. Gagneux and R. Meier, Tetrahedron Lett., 1969, 1365.
5
6
7
3
3
5
3
1
C
3
K. Kimoto, T. Imagawa and M. Kawanisi, Bull. Chem. Soc. Jpn.,
972, 45, 3698.
1
R. S. Henry, F. G. Riddell, W. Parker and C. I. F. Watt, J. Chem.
Soc., Perkin Trans. 2, 1979, 1549.
N-Formyl-1,3ꢁ,5,7ꢀ-tetramethylbicyclo[3.3.1]nonan-3ꢀ-
amine 10. Yield 55%; mp 108–110 ЊC (Found: C, 75.31; H,
1.24; N, 6.23. C H NO requires C, 75.28; H, 11.28; N,
.27%); m/z 223 (2%, M ); δ (200 MHz, CDCl ) 0.93 and 0.94
total 6H, both s, 1,5-CH ), 0.57–2.2 (17H, m, ring protons and
,7-CH ), 5.2 and 5.6 (total 1H, both br s, NH), 8.03 and 8.33
3
total 1H, both d, J 2.6 and 12.8, CHO); δ (50 MHz, CDCl )
1.83, 25.10, 25.68, 30.47, 31.54, 33.69, 36.00, 40.42, 40.53,
4.69, 49.99, 52.29, 54.82, 160.66, 160.84.
T.A. Wnuk, J. A. Tonnis, M. J. Dolan, S. J. Padegimas and P.
Kovacic, J. Org. Chem., 1975, 40, 444.
1
6
(
3
(
8 L. A. Paquette, T. L. Underiner and J. C. Gallucci, J. Org. Chem.,
1992, 57, 86.
9
14
25
ϩ
ؒ
H
3
T. Momose, S. Takizawa and M. Kirihara, Synth. Commun., 1997,
7, 3213.
3
2
1
0 H. G. Chen, O.P. Goel, S. Kesten and J. Knobelsdorf, Tetrahedron
Lett., 1996, 37, 8129. It was claimed that TMSCN acts as a highly
nucleophilic nitrile component in the Ritter reaction. However it
was established by NMR experiment that TMSCN decomposes
rapidly after addition of a few drops of acetic acid to the TMSCN
C
3
2
4
1
,3,5,7ꢁ-Tetramethylbicyclo[3.3.1]non-2-ene 12. A volatile
solution in CDCl
component under the Ritter reaction conditions (H SO /AcOH).
This is confirmed by the similar reactivity of TMSCN and HCN in
the Ritter reaction of cyclohexyl derivatives (A. Jirgensons, V. Kauss
and I. Kalvinsh, unpublished results).
3
. This indicates that in fact HCN is the nitrile
liquid (66%) (Found: C, 87.69; H, 12.38. C H requires C,
7.56; H, 12.44%); m/z 178 (7%, M ); δ (200 MHz, CDCl )
H 3
.80 (3H, d, J 7.1, 7-CH ), 0.91 and 0.94 (total 6H, both s, 1,5-
CH ), 0.55–1.6 (7H, m, 6,8,9-H and 7-H), 1.63 (3H, br s,
-CH ), 1.63 and 1.80 (total 2H, both d, J 18, 4-H ), 5.03 (1H,
br s, 2-H); δ (50 MHz, CDCl ) 22.21, 22.82, 26.82, 29.51, 31.67,
2.06, 32.16, 34.17, 44.25, 46.48, 47.24, 130.21, 134.58.
2
4
13
22
ϩ
ؒ
8
0
3
3
2
11 J. C. Richer and R. Bisson, Can. J. Chem., 1969, 47, 2488.
12 A. Dobrev and M. Bon, Bull. Soc. Chim. Fr., 1993, 130, 160.
13 Y. Ichikawa, J. Chem. Soc., Perkin Trans. 1, 1992, 2135.
3
3
2
C
3
1
4 A. Rauk, T.S. Sorensen, C. Maerker, J. W. de M. Caneiro, S. Sieber
and P. v. R. Schleyer, J. Am. Chem. Soc., 1996, 118, 3761.
3
1
5 T. S. Sorensen and S. M. Whitworth, J. Am. Chem. Soc., 1990, 112,
1
,3ꢁ,5,7ꢀ-Tetramethylbicyclo[3.3.1]nonan-3ꢀ-amine
hydrochloride 11
8
135.
1
1
1
6 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
7 T. Laube and S. Hollenstein, J. Am. Chem. Soc., 1992, 114, 8812.
8 G. M. Sheldrick, 1985, SHELXS86, Program for the Solution of
Crystal Structures, University of Göttingen, Germany.
9 G. M. Sheldrick, 1993, SHELXL93, Program for the Refinement of
Crystal Structures, University of Göttingen, Germany.
Formamide 10 (0.39 g, 1.75 mmol) was refluxed in 20% aqueous
H SO (4.2 ml) for 6 h. The reaction mixture was poured onto
2
4
ice and neutralized with 20% NaOH. The product was
extracted with ether (2 × 25 ml), and the combined extracts
were dried over NaOH and filtered. To the filtrate was added
HCl (1.5 ml of a 2 M solution in ether) and the solvent as well
1
Paper 9/04394B
3
530
J. Chem. Soc., Perkin Trans. 1, 1999, 3527–3530