DIVERGENT PATHWAYS OF REACTION BETWEEN CYCLOHEXANONE ENAMINES AND α,β-UNSATURATED ACID CHLORIDES

Article abstract of DOI:10.1135/cccc19951343

The reaction of cyclohexanone enamines with α,β-unsaturated acid chlorides and 2- and 3-chloropropanoyl chlorides under various conditions has been investigated. α,α'-Annulation of enamines Ia-Ie occurs on treatment with chlorides IIa-IId or 3-chloropropanoyl chloride to give bicyclo<3.3.1>nonane-2,9-dione derivatives III.The formation of isomeric bicyclononadiones IIIe and IIIh and chromanones VIIIa and VIIIb in the reaction of enamines derived from substituted cyclohexanones suggests that the cyclization might proceed also by another pathway than vis <3.3> sigmatropic rearrangement.Based on the reaction course and product distribution in these reactions, a parallel reaction pathway involving a C-acylation-Michael addition has been suggested.

Full text of DOI:10.1135/cccc19951343

Reaction of Cyclohexanone Enamines
1343
DIVERGENT PATHWAYS OF REACTION BETWEEN CYCLOHEXANONE
ENAMINES AND α,β-UNSATURATED ACID CHLORIDES
Eugenius BUTKUS and Birute BIELINYTE-WILLIAMS
Department of Organic Chemistry,
Vilnius University, 2734 Vilnius, Lithuania
Received January 23, 1995
Accepted June 5, 1995
The reaction of cyclohexanone enamines with α,β-unsaturated acid chlorides and 2- and
3-chloropropanoyl chlorides under various conditions has been investigated. α,α′-Annulation of
enamines Ia–Ie occurs on treatment with chlorides IIa–IId or 3-chloropropanoyl chloride to give
bicyclo[3.3.1]nonane-2,9-dione derivatives III. The formation of isomeric bicyclononanediones IIIe
and IIIh and chromanones VIIIa and VIIIb in the reaction of enamines derived from substituted
cyclohexanones suggests that the cyclization might proceed also by another pathway than via [3,3]
sigmatropic rearrangement. Based on the reaction course and product distribution in these reactions,
a parallel reaction pathway involving a C-acylation–Michael addition has been suggested.
The reaction of cycloalkanone enamines with α,β-unsaturated electrophiles is one of
the most versatile methods of carbocyclization1. Products of this process are bicyclic
and adamantane ring structures2. The dependence of the reaction course on the structure
of initial reagents and on the reaction conditions is generally recognized3. The proposed
cyclization mechanism involves N-acylation of the enamine, followed by a [3,3] sigma-
tropic rearrangement leading to a ketene intermediate, and subsequent cyclization4. An
alternative explanation for the ring closure leading to bridged or fused bicyclic struc-
tures has been suggested that assumes a C-acylation of the enamine or a direct interac-
tion between the β-position of the enamine and the β-position of the α,β-unsaturated
acid chloride5. The evidence for each of the reaction pathways was obtained by struc-
ture elucidation of the reaction products or by isolation of reaction intermediates. The
sensitivity of the reaction to substituents in both the enamines and the reactants, as well
as to the reaction conditions, and discrepancies in the reaction pathways prompted us to
study the reaction of cyclic ketone enamines with unsaturated acid chlorides and related
electrophiles in order to rationalize the reaction course.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1344
Butkus, Bielinyte-Williams:
RESULTS AND DISCUSSION
Reaction of Cyclohexanone Enamines with α,β-Unsaturated Acid Chlorides
The reaction of cyclohexanone enamines with α,β-unsaturated acid chlorides is a facile
route to the bicyclo[3.3.1]nonane-2,9-dione system6. Recently7 we have shown that the
reaction of enamine Ia with alkyl 3-chloroformyl acrylates IIa and IIb gives 4,9-dioxo-
bicyclo[3.3.1]nonane-2-carboxylates IIIa and IIIb (Scheme 1). Proton and 13C NMR
spectra indicated that the products were obtained in diastereomerically pure form. Simi-
lar results were obtained using compound IId as the annulation reagent to give IIIk. In
addition, the reaction of enamine Ia with (1R,2S,5R)-(–)-menthyl-IIc afforded the
corresponding diastereoisomerically pure (–)-menthyl derivative IIIc. The positions and
number of signals of keto and ester carbonyl groups (δ 209.1, 207.0 and 172.3) in its
13C NMR spectrum confirm that a single diastereoisomer was formed.
We studied the effect of the reaction temperature, solvent, concentration of enamine,
and duration of addition of the chloride on the yield of diones IIIa and IIIb (Table I).
The yield of the bicyclic product increased when the reaction was carried out in an inert
atmosphere. As optimum conditions we found: equimolar ratio of the reagents, a non-
polar solvent, slow addition of the acid chloride and a low enamine concentration.
TABLE I
Reaction of cyclohexanone enamine Ia with methyl 3-chloroformylacrylate IIa
Temperature
Yield of IIIa
Entry Enamine equiv. Addition time, h Solvent
Timea, h
°C
%
1
1
0.4
5
C6H6
C6H6
C6H6
C6H6
C6H6
CCl4
80
20
8
12
32
63
20
28
2
2b
3c
4d
5e
6
1
20
1
1
20
6
1
1
20
6
1
1
20
6
9
1
0 to –5
20
20
20
6
7
2.2
1
1
C6H6
C6H5CH3
Et2O
21
30
56
31
8
1
20
9
1
1
20
6
10
1
1
CHCl3
20
6
a
b
Acid chloride addition time is included. Reaction was performed with ethyl 3-chloroformylacry-
c
d
e
late. Entries 3–8 were carried out under inert atmosphere. Pyrrolidine enamine. Piperidine en-
amine.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Reaction of Cyclohexanone Enamines
1345
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1346
Butkus, Bielinyte-Williams:
The effect of the enamine moiety on the yield of the diketo ester IIIa followed the same
trend as in the reaction of Ia with acryloyl chloride IIe, i.e., the yield of IIIa decreased
in the order morpholine > piperidine > pyrrolidine enamines4.
The annulation reagents IIa–IId introduce functional groups into the final bicyclo-
nonane skeleton in one operation. Using the conditions developed for the synthesis of
IIIa–IIIc, we examined the reactions of enamines derived from substituted cyclohexa-
nones. Reaction of 2-methylcyclohexanone enamine Id with chloride IIa was expected
to produce a single structure, IIId, because the transition state for the intermediate sig-
matropic rearrangement of the less reactive enamine with more substituted double
bond, I′, would be impeded by the methyl group from both the axial and equatorial side
of the enamine. However, the reaction gave a mixture of two compounds that could not
1
be separated. The H NMR spectrum of the reaction product showed two singlets at δ
3.63 and 3.59 due to methyl protons of the ester group, overlapping singlets of methyl
protons at δ 1.05–1.08 and no signals in the region of olefinic and carboxylic protons.
The 13C NMR spectrum showed four signals of keto carbonyl and two of ester carbonyl
groups. According to the spectral and analytical data we suggest the structures IIId and
IIIi for the components of the mixture (Scheme 1).
It has been reported that the reaction of the same enamine Id with acryloyl chloride
IIe leads to 1-methyl-2,9-dione6 IIIe. In order to get more evidence for the structural
assignment and the cyclization path, this reaction was reexamined. To our surprise, it
did not give a single isomer under various conditions employed, i.e. addition of the acid
chloride to a boiling solution of the enamine or addition at room temperature. Both the
1H NMR and 13C NMR spectra indicated that this reaction gave rise to a mixture of
bicyclic diketones. Gated 13C NMR spectrum showed two doublets at δ 72.4 and 63.5
that could be assigned to the tertiary carbon atoms C-1 and C-5 in IIIe and IIIh, respec-
tively, and consequently the mixture consisted of two structural isomers, IIIe and IIIh.
The same conclusion was drawn from the results of hydrolysis of the reaction product.
Hydrolysis of the bicyclic dione IIIe should give acid IVb, however, a mixture of
isomeric acids was isolated (Scheme 2). It was reported that Michael addition of ethyl
acrylate to enamine Id in dioxane gave a mixture of 2,2- and 2,6-substituted cyclohexa-
none derivatives IV and V, respectively, the ratio of the product V to stereoisomers IVa
and IVb being approximately one to one8. As shown by GLC and spectral data, the
latter mixture was identical with that obtained by hydrolysis of bicyclic diones. Con-
trary to the reported results6, no pure cis-acid, melting at 72–73 °C, was obtained.
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Reaction of Cyclohexanone Enamines
1347
The series of annulation reactions with enamines derived from substituted cyclohexa-
nones Ib, Ic, Ie, VI and VIIa gave mixtures of compounds from which an appreciable
amount of the bicyclic dione was isolated in the case of the 2-benzylcyclohexanone
enamine9 Ie. Attempted cyclization of the enamine of tetrahydronaphthalen-2-one VIIa
was unsuccessful both with acryloyl chloride IIe and chloride IIa. The only product
obtained from a vast amount of tar was the unsaturated diketone VIIb that quickly
decomposed on air. Enamines of (–)-menthone VI were very reactive and tetrahydro-
chromanone derivative VIIIb was obtained in a low yield.
Notably, the formation of isomeric bicyclic diones IIIe and IIIh and tetrahydrochro-
manones in the reaction of enamines with α,β-unsaturated acid chlorides suggests that
divergent reaction mechanisms might operate in the reaction. The main reasons for this
assumption are the transition state structure and the stereoelectronic requirements for
[3,3] sigmatropic rearrangement that leads to a single structural isomer of bicyclono-
nanedione. Secondly, the tetrahydrochromanone must arise by C-acylation of the en-
amine followed by cyclization of the enol tautomer.
Reactions of Enamines with Chloropropanoyl Chlorides
We next turned our attention to the reaction of enamines with annulation reagents that
could react in other way than through a [3,3] sigmatropic rearrangement. It seemed
likely that 3-chloropropanoyl chloride could be such a reagent. Reaction of this
chloride with enamine Ia was carried out under conditions developed10b for acid
chlorides II and afforded bicyclononane-2,9-dione10 IIIj. Its spectra were identical with
those of the reaction product formed from enamine Ia and acryloyl chloride. Best yields
were obtained with 1 equivalent of N-ethylmorpholine in boiling benzene. With
triethylamine as external base, the yield of the bicyclic product decreased and addi-
tional uncharacterized products were formed. Triethylamine probably was too strong a
base. Reaction of 3-chloropropanoyl chloride with N-ethylmorpholine under the cycli-
zation conditions produced almost quantitatively the salt Cl–(R+–CH2CH2COR+)Cl–,
where R = N-ethylmorpholine. Attempts to obtain the cyclization product by reaction of
the enamine with this salt failed.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1348
Butkus, Bielinyte-Williams:
Regeneration of the enamine before the last cyclization step might lead to isomer
with the most substituted double bond since it seems to be stabilized by conjugation
with the adjacent carbonyl group. This should be true for pyrrolidine but not for the
morpholine enamine11. Therefore, the results suggest that the enamine reacts with
3-chloropropanoyl chloride by a C-acylation–C-alkylation pathway without formation
of double bond or intermediate IX (Scheme 3). If this suggestion is not true and the
reaction involves formation of the double bond at any step of this transformation, the
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Reaction of Cyclohexanone Enamines
1349
reaction with 2-chloropropanoyl chloride should lead to the bicyclic dione as well. In
order to test this hypothesis we carried out the reaction of enamine Ia with 2-chloropro-
panoyl chloride. Since with this chloride the elimination of hydrogen chloride requires
more vigorous conditions, triethylamine in boiling benzene was used as additional base.
As predicted, no bicyclic dione was found in the reaction mixture and we obtained the
acylated enamine X (Scheme 3) as the reaction product. Reaction of 2-chloropropanoyl
chloride with triethylamine under the cyclization conditions produced the salt
CH3CH(N+R3Cl–)CON+R3Cl– (R = C2H5) quantitatively and again formation of a
double bond was not observed. These results are in agreement with the proposed reac-
tion pathway. The only role of the additional base is to bind hydrogen chloride and to
facilitate the regeneration of free enamine. Since the reaction with 3-chloropropanoyl
chloride seems to proceed through a different pathway than with acryloyl chloride, the
product of the reaction with the enamine Id should be the isomeric bicyclononanedione
IIIh. However, the reaction of enamine Id and 3-chloropropanoyl chloride afforded a
mixture of bicyclic compounds and 1H NMR spectrum showed the same peaks as found
for the reaction product from enamine Id with acryloyl chloride. These data indicate
that the cyclization with 3-chloropropanoyl chloride was not regioselective. The reac-
tion involved both isomers of the enamine and, in accord with the acyl–alkyl pathway,
the attack on the more substituted enamine double bond should also give bicyclic dione
(as already mentioned, this is impossible if the reaction proceeds through a [3,3] sigma-
tropic rearrangement because of steric hindrance by the methyl group).
Mechanistic Considerations
The mechanistic implications of the obtained results are interesting. The formation of
mixtures of bicyclic diones, tetrahydrochromanones and unsaturated diketones, together
with the results obtained with 3-chloropropanoyl chloride, suggest that, in addition to
the [3,3] sigmatropic route, another reaction pathway should exist in cyclization reac-
tions of enamines with α,β-unsaturated acid chlorides, leading to bicyclononanediones.
This might be a C-acylation–Michael addition pathway. The regio- and stereoselectivity of
unsubstituted enamine annulations with 3-chloroformylacrylates IIa and IIb can be rea-
sonably explained by the [3,3] sigmatropic rearrangement mechanism proposed by
Hickmott4,12. Although the preferred transition state conformation for a [3,3] sigma-
tropic rearrangement is normally the chair form, an examination of molecular models
shows that a boat transition state appears to be sterically equivalent. The involvement
of a boat transition state is supported by formation of diastereoisomerically pure keto
esters IIIa, IIIb with exo-configuration of the ester group at C-2. These findings were
also substantiated by MM2 molecular mechanics calculations, indicating that the lowest
energy form of III is the chair–boat conformation with exo-configuration of the ester
group13. Finally, the X-ray analysis (Fig. 1) fully proves the chair–boat conformation of
IIIa as presented in Scheme 1, with bond lengths and angles given in Table II.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1350
Butkus, Bielinyte-Williams:
Another possible reaction pathway that would explain formation of mixtures of bicyclic
isomers, tetrahydrochromanones and unsaturated diketones might be a C-acylation fol-
lowed by Michael addition. C-Acylation may occur by direct attack of the acid chloride
at the nucleophilic carbon atom of the enamine double bond or it may be the result of
a further reaction after the attack on nitrogen. Direct attack by the acid chloride at the
double bond should produce a stable iminium salt and the cyclization should fail. Two
paths of the second alternative could be anticipated from the study of a similar reaction
of acylated tertiary amines with nucleophiles14. The cyclization might occur if the en-
amine is regenerated with the less substituted double bond and this should be true for
the morpholine enamine. The subsequent Michael addition might occur from either side
of the double bond of the attached fragment. The topological rule for the stereochemistry
of Michael addition reactions to enamines predicts that E-isomers of enamines (i.e.
enamines with the less substituted double bond) should give syn-products in reaction
with electrophilic olefins15. Thus, a bicyclic dione with the endo-ester group is ex-
pected to predominate in this reaction.
In conclusion, the general course of the reaction can be outlined as paths A or B in
Scheme 3. The products obtained depend on the ratio A/B2 (B1). As it appears from the
experimental data, the reactions proceed by both mechanisms and mixtures of products
are obtained. Bicyclic diones IIIa–IIIf with the substituent closer to the newly formed
carbonyl group are produced by [3,3] rearrangement while the isomeric diones IIIh–IIIk,
chromanones VIII and unsaturated diketones are formed by an initial C-acylation path-
way. The ratios of products from 2(6)-substituted enamines indicate that the relative
O(2)
O(4)
C(9)
C(11)
C(10)
C(1)
C(8)
C(2)
C(6)
C(5)
C(3)
O(3)
C(4)
C(7)
O(1)
FIG. 1
Molecular structure of IIIa
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Reaction of Cyclohexanone Enamines
1351
amount of bicyclononanediones IIIa–IIIf, arising through the [3,3] sigmatropic shift
increases with increasing substituent size. This could be attributed to higher reactivity
of the ketene intermediates compared with that of electrophilic double bond of the
acylated enamine intermediate which is more sensitive to steric requirements. Reaction
of 3-chloroformylacrylates IIa and IIb with unsubstituted cyclic enamines appears to
proceed through the A pathway since only a single isomer with the exo-ester group was
obtained, but the path B cannot be completely excluded either. When this reaction was
applied to enamines of substituted ketones, both mechanisms operated and product
mixtures were obtained.
TABLE II
Bond lengths (Å) and angles (°) in IIIa
Atoms
Bond length
Atoms
Angle
C(1)−C(2)
C(1)−C(9)
C(2)−C(3)
C(4)−C(5)
C(5)−C(6)
C(6)−C(7)
C(9)−O(2)
C(10)−O(4)
C(1)−C(8)
C(2)−O(1)
C(3)−C(4)
C(4)−C(10)
C(5)−C(9)
C(7)−C(8)
C(10)−O(3)
O(3)−C(11)
1.548(5)
1.501(4)
1.543(4)
1.514(5)
1.542(5)
1.515(5)
1.211(4)
1.196(4)
1.540(5)
1.516(5)
1.504(5)
1.210(4)
1.502(4)
1.508(5)
1.330(4)
1.436(4)
C(2)−C(1)−C(8)
C(8)−C(1)−C(9)
C(1)−C(2)−C(3)
C(2)−C(3)−C(4)
C(3)−C(2)−C(10)
C(4)−C(5)−C(6)
C(6)−C(5)−C(9)
C(6)−C(7)−C(8)
C(1)−C(9)−C(5)
C(5)−C(9)−O(2)
C(2)−C(10)−O(4)
C(10)−O(3)−C(11)
C(2)−C(1)−C(9)
C(1)−C(2)−C(10)
O(1)−C(4)−C(3)
C(3)−C(4)−C(5)
C(5)−C(4)−O(1)
C(5)−C(6)−C(7)
C(1)−C(8)−C(7)
C(1)−C(9)−O(2)
C(4)−C(10)−O(3)
O(3)−C(10)−O(4)
113.2(3)
106.8(3)
113.5(3)
112.9(3)
110.0(3)
109.9(3)
107.9(3)
112.5(3)
112.0(3)
123.5(3)
125.9(3)
116.1(3)
110.4(3)
110.8(3)
122.9(3)
116.2(3)
120.8(3)
110.9(3)
113.0(3)
124.4(3)
110.9(3)
123.2(3)
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1352
Butkus, Bielinyte-Williams:
EXPERIMENTAL
All purchased reagents were purified immediately before use. The solvents were dried by conven-
tional methods and distilled. The reactions were performed in dried glassware in an atmosphere of
nitrogen. The IR spectra were measured as liquid films in Nujol (unless stated otherwise) on a Spe-
cord M80 spectrophotometer. Proton and carbon-13 NMR spectra were recorded in deuteriochloro-
form (unless stated otherwise) on a BS 487 C Tesla spectrometer (80 MHz for protons and 20 MHz
for 13C). Chemical shifts are given in ppm (δ-scale) relative to tetramethylsilane as internal standard.
GLC analyses were performed on a Chrom 5 instrument. Thin-layer chromatography was carried out
on Silufol aluminium sheets coated with silica gel, column chromatography on silica gel L 40/100
(Lachema, Czech Republic). Melting points were determined on a Kofler block; the boiling and melting
points are uncorrected.
Materials
Methyl 3-chloroformylacrylate (IIa), b.p. 67–69 °C/1.9 kPa, m.p. 16 °C (reported16 b.p. 69.6 °C/14 mm Hg)
and ethyl 3-chloroformylacrylate (IIb), b.p. 77–78 °C/1.6 kPa (reported17 b.p. 90–92 °C/19 mm Hg)
were prepared according to a published procedure17.
(1R,2S,5R)-(–)-Menthyl 3-chloroformylacrylate (IIc) was synthesized by adding dry (–)-menthol
(4.3 g, 0.03 mol) to cooled (10 °C) freshly distilled fumaroyl dichloride in a two-necked flask
equipped so that dry nitrogen could be introduced and reduced pressure could be applied during the
reaction. The mixture was gently shaken until the menthol dissolved, and then heated at 70 °C for 30 min
until the vigorous evolution of gas ceased. Then the heating bath was removed and hydrogen chloride
was completely blown out by introducing dry nitrogen under reduced pressure for 15 min. The pro-
duct IIc was obtained in 60% yield and was used without further purification.
Benzyl 3-chloroformyl-3-butenoate (IId) was prepared from 3-methylenebutanedioyl dichloride ac-
cording to the method described above for IIc, m.p. 82 °C. For C12H12O4 (220.2) calculated: 65.45% C,
5.49% H; found: 65.43% C, 5.79% H. 1H NMR spectrum (CCl4): 10.3 s, 1 H (OH); 7.15 s, 5 H
(arom. H); 6.33 and 5.68 m, 2 H (=CH); 4.98 s, 2 H (CH2Ph); 3.23 s, 2 H (CH2CO).
2-Benzylcyclohexanone was prepared as described18, b.p. 136–137 °C/0.3 kPa (ref.18 states b.p.
137–138 °C/2 mmHg). 4-Oxocyclohexyl benzoate was obtained from 1,4-cyclohexanediol by a described
method19; m.p. 62 °C (reported19 m.p. 62 °C). Methyl 4-oxocyclohexylcarboxylate was synthesized accord-
ing to a published procedure20; b.p. 127 °C/1.6 kPa, nD20 1.4658 (reported20 b.p. 104–105 °C/2 mmHg,
n2D0 1.4589). 3,4-Dihydro-2(1H)-naphthalenone (VIIa) was prepared from 2-naphthol as described21;
b.p. 131 °C/1.5 kPa.
Enamines were prepared from cyclic ketones (0.1 mol) and secondary amines (0.12 mol) in the
presence of catalytic amount of p-toluenesulfonic acid (0.02 g) in dry benzene (250 ml) by a des-
cribed procedure22. The following enamines were obtained:
N-(2(6)-Methylcyclohexen-1-yl)morpholine (Id) (mixture of isomers), b.p. 128–130 °C/1.7 kPa,
n2D0 1.543 (reported22 b.p. 125–127 °C/12 mmHg, n2D0 1.545). H NMR spectrum: 4.60 m, 1 H (CH=);
1
3.63 t, 4 H; 2.70 t, 4 H; 2.4–1.3 m, 7 H; 1.0–0.85 m, 3 H (CH3). N-(2(6)-Benzylcyclohexen-1-yl)mor-
pholine (Ie) (mixture of isomers), b.p. 163 °C/0.3 kPa. 1H NMR spectrum: 7.0 s, 5 H (arom. H); 4.5–4.6 m,
1 H (CH=); 3.4 t, 4 H; 3.1–2.45 m, 2 H (CH2Ph); 2.3 t, 4 H; 2.0–1.9 m, 7 H. 1-(N-morpholino)cyclo-
hexen-1-yl benzoate (Ic), viscous liquid, decomposing upon distillation. 1H NMR spectrum: 7.9 and 7.35 m,
5 H (arom. H); 5.25 m, 1 H (CHO); 4.45 m, 1 H (CH=); 3.6 t, 4 H; 2.8 t, 4 H; 2.6–1.8 m, 6 H (3 × CH2).
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Reaction of Cyclohexanone Enamines
1353
General Procedure for Reaction of Enamines with Alkyl 3-Chloroformylacrylates
A solution of IIa or IIb in benzene (10 ml) was added dropwise at 20 °C during 5–6 h to a stirred
solution of freshly distilled enamine (0.06 mol) in benzene (400 ml). The reaction mixture was
stirred at room temperature for an additional hour under exclusion of moisture and then filtered. The
crystalline precipitate was washed with dry hexane and dissolved in ice-cold water (200 ml). The
aqueous solution was allowed to stand overnight and then extracted with methylene chloride. The
combined organic extracts were dried over magnesium sulfate, filtered and concentrated at reduced
pressure. The crude bicyclic products were purified by recrystallization from anhydrous solvents or
chromatographed on a silica gel column in benzene–acetone (9 : 1).
Methyl (IIIa) and ethyl (IIIb) 4,9-dioxobicyclo[3.3.1]nonane-2-carboxylates were obtained as des-
cribed7.
(–)-Menthyl 4,9-dioxobicyclo[3.3.1]nonane-2-carboxylate (IIIc); yield 53%, m.p. 71 °C (ether).
1
For C20H30O4 (334.4) calculated: 71.83% C, 9.04% H; found: 71.80% C, 9.04% H. H NMR spectrum
(CCl4): 4.5 m, 1 H (CHCO); 3.05–2.3 m, 5 H; 2.3–1.0 m, 14 H (methylene envelope); 1.0–0.5 m, 9 H
(3 × CH3). 13C NMR spectrum: 209.1 and 207.1 (ketone C=O), 172.3 (ester C=O), 75.6 (C-11), 63.1
(C-5), 47.9 (C-1), 46.6 (C-2), 42.0, 40.7, 40.3 (C-3, C-12, C-16), 35.5, 35.3, 33.9, 31.1 (C-6, C-15,
C-14), 25.9, 23.0, 21.7, 20.5, 18.6, 15.9.
Methyl 1- and 5-methyl-4,9-dioxobicyclo[3.3.1]nonane-2-carboxylates (IIId and IIIi); yield 56%,
pale yellow oil. For C12H16O4 (224.2) calculated: 64.28% C, 7.19% H; found: 63.71% C, 6.84% H.
1H NMR spectrum: 3.7–3.55 m and 3.63 s and 3.59 s, 3.6 H (OMe and CHαCO); 3.4–2.5 m, 4.7 H
(CHαCO and COCHCHCOOR); 2.4–1.3 m, 4.6 H; 1.05–0.8 m, 3 H (CH3). 13C NMR spectrum:
209.6, 208.4, 207.1, 204.5 (all ketone CO), 173.3, 173.1 (both ester CO), 71.1, 69.3 (αCCO), 62.7,
62.5, 52.3, 47.3, 46.7, 43.5, 42.7, 41.7, 41.6, 40.5, 33.2, 30.9, 28.0, 25.1, 24.4, 20.4.
Benzyl 4,9-Dioxobicyclo[3.3.1]nonan-3-ylacetate (IIIk)
Freshly prepared compound IId (4.5 g, 0.019 mol) was diluted with dry benzene (10 ml) and the
solution was added during 45 min to a stirred solution of Ia (3.3 g, 0.019 mol) in dry benzene (135 ml)
at room temperature. The resulting solution was stirred overnight. Benzene was decanted and the oily
residue was hydrolyzed with ice-cold water (30 ml) for 3 h. The aqueous solution was extracted with
diisopropyl ether (2 × 50 ml) and the combined extracts were dried over magnesium sulfate. Removal
of the solvent afforded 2.8 g of pale yellow viscous oil. A part of this mixture (300 mg) was chro-
matographed on a silica gel column (tetrachloromethane–acetone 4.5 : 1) to give 100 mg (16%) of
the title product as a colourless oil. For C18H18O4 (298.3) calculated: 71.99% C, 6.71% H; found:
1
71.98% C, 6.88% H. H NMR spectrum: 7.25 s, 5 H (ArH); 5.05 s, 2 H (CHαCOOBn); 3.3 m, 1 H
(CHαCO); 2.9–2.1 m, 4 H (H adjacent to CO); 2.1–1.25 m, 6 H.
General Procedure for Reaction of Enamines with Acryloyl Chloride
Freshly distilled acryloyl chloride (IIe; 21.1 g, 0.3 mol) in dry benzene (10 ml) was added to a solution
of the enamine (0.3 mol) in dry benzene (150 ml) at room temperature. After heating at reflux for 6 h,
the mixture was cooled and the precipitate was filtered, washed with dry hexane and stirred with
ice-cold water (50 ml). The aqueous phase was extracted several times with ether and the combined
extracts were dried over magnesium sulfate. After removal of the solvent, the residue was purified by
column chromatography. The following compounds were obtained:
Bicyclo[3.3.1]nonane-2,9-dione (IIIj), yield 70%, m.p. 118 °C (reported5 m.p. 117 °C). For
C9H12O2 (152.1) calculated: 71.02% C, 7.94% H; found: 70.99% C, 7.87% H. IR spectrum (CCl4):
two bands in the region 1 700–1 730 cm–1 (C=O). 1H NMR spectrum: 3.10 m, 1 H; 2.75–1.45 m,
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Butkus, Bielinyte-Williams:
11 H (methylene envelope). 13C NMR spectrum: 211.9 (C-2), 210.2 (C-9), 64.1 (C-1), 44.3 (C-5),
39.1 (C-3), 35.65, 34.95, 22.18, 18.6.
1(5)-Methylbicyclo[3.3.1]nonane-2,9-dione (IIIe and IIIh), yield 71%, waxy solid, m.p. 36–37 °C
(reported m.p. 37 °C). For C10H14O2 (166.2) calculated: 72.26% C, 8.49% H; found: 72.10% C,
1
8.51% H. IR spectrum (CCl4): two bands in the region 1 710–1 735 cm–1 (C=O). H NMR spectrum:
3.1 m, 1 H (CHCO); 3.0–1.50 m, 10 H (methylene envelope); 0.9 m, 3 H (CH3). 13C NMR spectrum:
211.3, 210.2, 72.41 (d, C-1), 70.59 (C-1), 63.5 (d, C-5), 44.1, 43.9, 43.7, 42.5, 41.3, 39.4, 38.9, 33.6,
28.4, 25.1, 23.4, 20.7, 19.2, 18.2.
Benzylbicyclo[3.3.1]nonane-2,9-dione (IIIf), yield 40%, m.p. 58 °C. For C16H18O2 (242.3) calcu-
1
lated: 79.31% C, 7.49% H; found: 79.20% C, 7.41% H. H NMR spectrum: 7.0 s, 5 H (arom. H);
3.1–2.2 m, 5 H (CH2Ph and HαCO); 2.2–1.45 m, 8 H (methylene envelope). 13C NMR spectrum:
212.1, 209.3, 130.8, 127.7, 126.0, 44.8 (C-1), 43.0 (C-3), 41.2 (C-4), 37.5 (C-10), 37.0 (C-8), 21.1
(C-6), 18.42 (C-7).
8-Benzyl-5,6,7,8-tetrahydrochromanone-4 (VIIIa), yield 12%, yellow oil, decomposing on distilla-
tion. For C16H18O2 (242.3) calculated: 79.31% C, 7.49% H; found: 78.99% C, 7.39% H. 13C NMR
spectrum: 213.2 (C=O), 171.6 (O–C=C), 140.2, 128.9, 128.1, 125.7, 125.9, 66.6, 52.7, 50.2.
8-Isopropyl-5-methyl-5,6,7,8-tetrahydrochromanone-4 (VIIIb), pale yellow liquid, decomposing
when exposed to air and moisture; yield 18%. For C13H20O2 (208.3) calculated: 74.99% C, 9.68% H;
1
found: 74.80% C, 8.55% H. n2D0 1.455. H NMR spectrum: 3.75 m, 2 H (OCH2); 3.15–1.25 m, 8 H
(alicyclic H); 1.03–0.75 m, 9 H (3 × CH3).
1-Acryloyl-1,2,3,4-tetrahydronaphthalen-2-one (VIIb), pale yellow quickly decomposing oil; yield 10%.
1H NMR spectrum (CD2Cl2): 7.3–7.0 m, 6 H (ArH and =CH); 5.2 m, 1 H (COCH=); 5.1 s, 1 H
(COCHCO); 2.8 t, 2 H (CH2CO); 2.3 t, 2 H (CH2).
General Procedure for Reaction of Enamines with 3- and 2-Chloropropanoyl Chlorides
A solution of the acyl chloride (3.81 g, 0.03 mol) in dry benzene (10 ml) was added dropwise to a
boiling and stirred solution of the enamine (0.03 ml) and the tertiary amine (0.06 mol) in dry benzene
(150 ml). The reaction mixture was refluxed for 6 h. After cooling, the precipitate was filtered,
washed with hexane and hydrolyzed with ice-cold water overnight. The aqueous solution was extracted
several times with ether and the combined extracts were dried over magnesium sulfate. The solvent
was evaporated and the remaining oil was purified by column chromatography.
Bicyclo[3.3.1]nonane-2,9-dione (IIIj), waxy solid (yield 69%), m.p. 118 °C. Analytical and spec-
tral data corresponded in all respects with those of the sample obtained from Ia and acryloyl
chloride.
1(5)-Methylbicyclo[3.3.1]nonane-2,9-dione (IIIe and IIIh), waxy solid (yield 61%), m.p. 35–37 °C.
Analytical and spectral data corresponded in all respects with those of the sample obtained from Id
and chloride IIe.
[2-(N-Morpholinyl)cyclohex-1-en-3-yl]-2-chlorobutan-1-one (X, R1 = H), yellow oil, qickly de-
1
composing on air. H NMR spectrum: 5.0 q, 1 H (CHCl); 3.27 t, 4 H; 2.7 t, 4 H; 2.5 m, 2 H; 2.35 m,
9 H (3 × CH2 and CH3).
Acid Hydrolysis of Mixture of IIIe and IIIh
To a mixture of IIIe and IIIh (2 mmol), dissolved in a minimum amount of methanol (5 ml), was
added 1 M HCl and the mixture was refluxed for 8 h. After cooling, the mixture was several times
extracted with ether. The solvent was evaporated and the residue was chromatographed on a silica gel
column in ether–acetone (1 : 1) to give a mixture of IVa, IVb and V (about 1 : 1) as a colourless oil,
yield 72%. Analytical GLC and spectral data corresponded to those of the sample obtained from Id
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Reaction of Cyclohexanone Enamines
1355
and ethyl acrylate. Several recrystallizations from ether afforded an acid, melting at 95 °C (for 3-(1-
methyl-2-oxocyclohexyl)propanoic acid reported23 m.p. 49–50 °C, for cis-3-(3-methyl-2-oxocyclo-
1
hexyl)propanoic acid reported8 m.p. 72 °C). IR spectrum: 1 704, 1 720 cm–1. H NMR spectrum: 10.8 s,
1 H; 2.4–1.2 m, 12 H (methylene envelope); 0.95 d, 3 H (CH3).
3-(3-Methyl- and 1-methyl-2-oxocyclohexyl)propanoic acids (IVa and IVb). Ethyl acrylate (2.3 g,
0.022 mol) was added to a stirred solution of Id (3.0 g, 0.017 mol) in dioxane (7 ml). The solution
was heated at reflux for 3 h and a buffered acetic acid hydrolysis mixture (25 ml of acetic acid, 25 ml
of water and 12.5 g of sodium acetate) was added. The mixture was refluxed for an additional hour,
poured into water, and extracted three times with ether. The combined ethereal extracts were concen-
trated, the residue was mixed with 20% KOH (10 ml) and the mixture was refluxed for 8 h. The
aqueous solution was neutralized with HCl, the resulting mixture was extracted with ether and the
combined ethereal extracts were dried over magnesium sulfate. Removal of the solvent gave 2.0 g
(76%) of a colourless oil. For C10H16O3 (184.2) calculated: 65.20% C, 8.75% H; found: 65.64% C,
1
8.71% H. H NMR spectrum: 10.95 s, 1 H (OH); 2.5–1.05 m, 12 H (methylene envelope); 1.05–0.85 m,
3 H (CH3).
Tertiary Amine Salts with 2- and 3-Chloropropanoyl Chlorides
To a refluxing solution of the tertiary amine (0.06 mol) in dry benzene (150 ml) was added dropwise
2- or 3-chloropropanoyl chloride (3.81 g, 0.03 mol) and the mixture was refluxed for 1 h. The white
precipitate was filtered and washed with hexane.
N-Ethyl-N-(3-propanoyl-N-ethylmorpholinium chloride) morpholinium chloride; yield 99%, colourless
1
crystals, decomposing > 200 °C. H NMR spectrum: 3.83–3.89 m, 10 H (methylenes adjacent to O);
2.85–3.3 m, 14 H (methylenes at N and of ethyl group); 1.25 t, 6 H (CH3).
N-Triethyl-N-(2-propanoyl-N-triethylammonium chloride) ammonium chloride, yield 98%, decom-
1
posing >200 °C. H NMR spectrum: 4.2 m, 1 H (CH); 3.8 m, 6 H (methylenes at CO); 2.9 q, 6 H
(CH2); 1.2 m, 21 H (7 × CH3).
X-Ray Crystallography of IIIa
Colourless needle, 0.1 × 0.1 × 0.6 mm, C11H14O4, m.w. = 210.2. Monoclinic (space group P2/n);
a = 6.461(1) Å, b = 8.913(1) Å, c = 17.367(3) Å, α = γ = 90°, β = 92.40(1)°; V = 999.2(3) Å3, Z = 4,
Dcalc = 1.40 g/cm3, T = 24 °C, radiation MoKα (λ = 0.71069 Å), µ = 1.0 cm–1, F(000) = 448, R = 0.047,
Rw = 0.047, S = 1.24, 137 parameters. The intensity data were taken as θ/2θ scans on a Nicolet
R3mE four circle diffractometer for 2 931 unique reflections in the range 4° < 2θ < 60°, of which
961 with I > 3σ(I) were used for the structure solution and refinement. The data were corrected for
Lorentz and polarization effects. No absorption or extinction corrections were needed. The structure
was solved by direct methods and non-hydrogen atoms were refined by block-cascade least-squares
with anisotropic thermal parameters, using statistic weighing. The crystallographic calculations were
done with the SHELXTL program package by Sheldrick Siemens Analytical X-Ray Instruments, Ma-
dison, Wi, U.S.A. The calculated hydrogen positions were used for the structure refinement after all
hydrogens had been located on different maps, and a common isotropic thermal parameter was
refined for all hydrogens, U = 0.046(3) Å2.
We thank Dr R. Larsen, Montana State University, U.S.A., for the X-ray structure determination of IIIa.
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