Stereochemistry of seven-membered heterocycles: XLIII. Steric structure of diastereoisomeric 8,8-dichloro(dibromo)-4-R-3,5-dioxabicyclo[5.1.0]octanes

Article abstract of DOI:10.1023/B:RUJO.0000003198.64663.ac

Dichloro- and dibromocyclopropanation of 2-substituted 1,3-dioxacyclohept- 5-enes according to Makosza resulted in formation of the corresponding 4-substituted 8,8-dichloro(dibromo)-3,5-dioxabicyclo-[5.1.0]octanes in good yields. Ultrasonic activation of

Full text of DOI:10.1023/B:RUJO.0000003198.64663.ac

Russian Journal of Organic Chemistry, Vol. 39, No. 7, 2003, pp. 1029 1033. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 7, 2003,
pp. 1092 1096.
Original Russian Text Copyright
2003 by Baryshnikov, Vafina, Fedorenko, Shtyrlin, Klimovitskii.
Stereochemistry of Seven-Membered Heterocycles:
XLIII.* Steric Structure of Diastereoisomeric
8,8-Dichloro(dibromo)-4-R-3,5-dioxabicyclo[5.1.0]octanes
R. N. Baryshnikov, R. M. Vafina, V. Yu. Fedorenko,
Yu. G. Shtyrlin, and E. N. Klimovitskii
Butlerov Research Chemical Institute, Kazan State University,
ul. Kremlevskaya 18, Kazan, 420008 Tatarstan, Russia
e-mail: Evgenii.Klimovitskii@ksu.ru
Received October 11, 2002
Abstract Dichloro- and dibromocyclopropanation of 2-substituted 1,3-dioxacyclohept-5-enes according to
Makosza resulted in formation of the corresponding 4-substituted 8,8-dichloro(dibromo)-3,5-dioxabicyclo-
[5.1.0]octanes in good yields. Ultrasonic activation of the process considerably shortened the reaction time.
According to the 13C NMR spectra, the chair twist equilibrium is essentially displaced toward the chair
conformer for the exo isomers and toward the twist conformer for the endo structures. Similar results were
obtained by AM1 semiempirical calculations which indicated that the CCl O interaction largely determines
the conformational equilibrium. The state of the diastereoisomer epimerization equilibrium depends on the
size of the substituent at the acetal carbon atom.
1,3-Dioxanes I are six-membered cyclic saturated
acetals which are classical models in stereochemical
studies. Up to now, a great deal of experimental and
theoretical data have been reported on equilibria of
their chair-like conformations. Comparative analysis
of conformational parameters of substituents in posi-
tions 2, 4 (6), and 5 of 1,3-dioxanes and cyclohexane
derivatives made it possible to elucidate the role of
heteroatoms and formulate basic concepts concerning
factors responsible for the state of chair(ax) chair(eq)
Scheme 1.
III, V, X = CCl2; IV, VI, X = CBr2; R = H (a), Ph (b), Me (c), Et (d), i-Pr (e), t-Bu (f).
____________
*
For communication XLII, see [1].
1070-4280/03/3907-1029$25.00 2003 MAIK Nauka/Interperiodica

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BARYSHNIKOV et al.
Table 1. 13C NMR chemical shifts ( C, ppm) of compounds III VI in CDCl3 at 25 C
Compound no.
C4
C2, C6
C1, C7
C8
Substituent on C4
a
IIIb
IIIc
IIId
IIIe
IIIf
IVb
IVc
IVd
IVe
IVf
IIIa Va
Vbc
Vcc
102.5
101.7
106.1
108.9
109.4
103.5
101.5
106.1
108.5
109.2
102.3
110.3
109.1
113.1
116.1
118.6
102.1
110.0
109.2
112.9
115.4
118.5
60.7
61.2
61.7
62.6
64.0
63.6
63.1
63.5
64.4
66.1
70.6
69.5
69.6
69.5
69.7
70.3
72.6
71.2
71.9
71.7
71.8
72.5
34.0
34.1
34.2
34.0
33.5
36.9
35.0
34.7
34.5
33.7
36.1
35.6
35.5
35.3
35.6
35.9
36.4
35.8
35.6
35.3
35.5
36.9
63.4
63.5
63.9
64.1
65.6
20.8
27.8, 9.3
33.0, 18.0
36.7, 25.4
a
36.4
b
21.3
b
b
b
27.7, 9.2
33.0, 18.3
b, 25.2
67.9
67.2
67.2
67.4
67.5
66.9
35.3
35.1
a
22.6
Vd
29.2, 9.5
34.1, 18.1
37.9, 25.9
Ve
Vfc
IVa VIa
VIbc
VIcc
VId
VIe
a
35.0
22.5
b
29.0, 9.5
33.9, 18.4
36.4, 26.0
b
VIfc
36.0
a
b
c
Signals from aromatic carbon atoms are not given.
Signals were not assigned.
Chemical shifts for isolated diastereoisomers.
equilibrium in saturated six-membered carbo- and
heterocycles [2 5]. It should be emphasized that the
most fruitful method for stereochemical study of the
above systems involves examination of the epimeriza-
tion process [3, 6]. It is commonly accepted that
epimerization equilibrium simulates conformational
equilibrium; therefore, conformational energies of
substituents can be determined [4].
Unlike 1,3-dioxanes, the chair and twist con-
formers of 2-substituted unsaturated seven-membered
acetals II having a planar carbocyclic fragment (cis-
butylene, o-xylylene, etc.) are characterized by similar
energies [7 10]. The state of conformational equilib-
rium in six- and seven-membered acetals was found
[4, 8] to be controlled by 1,3-repulsive interactions
involving substituents.
regarded as analogs of 5eq- and 5ax-substituted 1,3-di-
oxanes, in which the three-membered ring is a specific
substituent.
We have started systematic studies of hetero
analogs of bicyclo[5.1.0]octanes. The present com-
munication reports on the synthesis and steric struc-
ture of diastereoisomeric endo- (III, IV) and exo-
8,8-dichloro(dibromo)-4-R-3,5-dioxabicyclo[5.1.0]-
octanes (V, VI). In keeping with published data, the
dichlorocyclopropanation of 2-substituted 1,3-dioxa-
cyclohept-5-enes was performed according to Parham
[14, 18] (dichlorocarbene genaration from chloroform
by the action of potassium tert-butoxide [19]) or
Seyferth [11, 12, 20]. The yields of the target products
did not exceed 30%. The addition of dibromocarbene
to 1,3-dioxacyclohept-5-ene was also characterized by
a poor yield ( 10%) [18].
3,5-Dioxabicyclo[5.1.0]octanes III also possess
a planar carbocyclic fragment (C2C1C7C6). They can
exist in solution as chair conformers with exo- and
endo-oriented three-membered ring, as well as the
corresponding twist conformers [11 17] (Scheme 1).
The chair-like structures of these compounds may be
Our attempt to apply the Wagner procedure to
the same substrates (thermolysis of sodium trichloro-
acetate in benzene) was unsuccessful: no cyclopro-
panation product was formed at all. Replacement of
the aromatic solvent by CHCl3 in the presence of
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STEREOCHEMISTRY OF SEVEN-MEMBERED HETEROCYCLES: XLIII.
1031
benzyltriethylammonium chloride did not radically
change the result: the yield was as low as 10%. Struc-
turally related 5,6-disubstituted seven-membered
acetals underwent dichlorocyclopropanation according
to Makosza to give bicyclo[5.1.0]octanes in good
yields [16, 21]. Under analogous conditions, we
obtained dichloro- and dibromocyclopropanation
products [17] in 50 70% yield. When the reaction was
carried out under ultrasonic irradiation, the reaction
time was shortened from 40 to 4 h.
According to the 13C NMR spectra of the reaction
mixtures, in all cases (R H) a mixture of diastereo-
isomers was obtained at a ratio of 1:1. The adducts
can readily be purified by vacuum distillation.
An alternative version of the isolation of compounds
III VIb, Vc, and Vf is epimerization followed by
recrystallization. In such a way we succeeded in
isolating configurationally pure exo diastereoisomers.
The structure of products III VI was confirmed by
the 13C NMR spectra and elemental analyses. The
adducts were assigned to the endo or exo series on
the basis of the X-ray diffraction data for 2-phenyl-
substituted acetals Vb [10, 11] and VIb [17]. Com-
pounds Vb and VIb exist in crystal as chair con-
formers with exo-oriented cyclopropane rings. The 13C
NMR parameters of diastereoisomeric 8,8-dihalo-4-R-
3,5-dioxabicyclo[5.1.0]octanes are given in Table 1.
Table 2. Gibbs energies ( G0, kcal/mol) for the epi-
merization equilibrium of the endo and exo isomeric
adducts of dichloro- (A) and dibromocarbene (B) to 2-R-
1,3-dioxacyclohept-5-enes in carbon tetrachloride
R
A
B
Ph
Me
0.72
1.45
0.41
1.17
i-Pr
t-Bu
1.37
1.29
a
a
a
No endo isomer was detected by 13C NMR spectroscopy.
former predominates in the endo series. Compounds
IIIa VIa (R = H) should be assigned the chair struc-
ture, for the chemical shifts of C2/C6 ( 70.6 and
C
72.6 ppm) are similar to those of the 4-R derivatives.
1
Moreover, the H NMR spectra of acetal Vb and
8,8-dichloro formal Va in the temperature range from
20 to 80 C did not reveal conformational hetero-
geneity of these compounds.
In order to elucidate steric structure of bicyclic
acetals, we have resorted to AM1 semiempirical cal-
culations. This procedure was found to be appropriate
as applied to 2-substituted 1,3-dioxacyclohept-5-enes
[1, 22]. 8,8-Dichloro acetals IIIa and Va are the most
representative models for studying specific features of
steric structure. 4-Substituted derivatives, in principle,
could give rise to no more than two conformers due
to high conformational energy of substituents at the
acetal carbon atom in the chair(a) chair(e) equilib-
rium [8]. The calculated heats of formation of the
chair conformers with endo- and exo-oriented di-
chlorocyclopropane moieties and of the twist form
are 76.1, 78.8, and 77.6 kcal/mol, respectively.
Analysis of the AM1 geometric parameters of the con-
formers showed that the endo structure and flexible
conformation are unfavorable because of repulsion
between the endo-oriented chlorine and oxygen atoms.
The distance between the latter is shorter than the sum
of their van der Waals radii (3.15 and 3.12 , respec-
tively). In the chair-like endo isomer, repulsion
between the chlorine and two oxygen atoms leads to
increase of the OCC angles by 5.9 with respect to
the exo isomer (111.1 ). In the twist conformer, the
OCC angles are 109.7 and 114.0 .
It should be noted that 13C NMR spectroscopy
turned out to be very informative for analysis of the
steric structure of 1,3-dioxa-5,6-benzocycloheptenes
II [10]. The authors obtained frozen spectra of the
chair and twist conformers of a series of 2-substituted
acetals. Analysis of the 13C NMR spectra of the four
series of compounds (III VI) showed that in all cases
signals from carbon atoms of exo diastereoisomers
V and VI appear in a weaker field, the maximal
difference in the chemical shifts being observed for
the C4 and C2/C6 atoms (
= 9 ppm). Let us con-
C
sider the chemical shifts of C2/C6. These atoms are
located in the -position with respect to the substituent
on C4. The chemical shifts of C2/C6 in exo-dichlorides
V range from 69.5 to 70.3 ppm, and the corresponding
interval for dibromides VI is 71.2 72.5 ppm. In the
endo-isomer series, the chemical shifts of the same
carbon atoms are
respectively. The benzyl carbon signals of the chair
and twist conformers of II are located at 74.7 76.3
61.2 64.0 and 63.1 66.1 ppm,
C
C
and 67.6 70.4 ppm, respectively. Comparison of the
With the data on steric structure of diastereo-
isomers of the two series in hand, we performed their
epimerization in order to obtain information on the
effects of the 4-substituent and dihalocyclopropane
fragments on the configurational and conformational
composition of the compounds under study. It might
chemical shifts of C2/C6 in the series of compounds
III and V and IV and VI and of benzyl carbon atoms
in the spectra of phthalyl acetals II suggests that the
chair twist equilibrium for the exo-isomers is dis-
placed toward the chair form and that the twist con-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 7 2003

1032
BARYSHNIKOV et al.
Table 3. Melting (or boiling) points and elemental analyses of 4-R-substituted 8,8-dichloro- and 8,8-dibromo-3,5-dioxa-
bicyclo[5.1.0]octanes
Found, %
Calculated, %
mp, C, or bp,
C
R
Formula
(p, mm), nD
C
H
C
H
8,8-Dichloro-4-R-3,5-dioxabicyclo[5.1.0]octanes
Mea
Et
63 64
42.45
44.20
5.12
5.91
C7H10Cl2O2
C8H12Cl2O2
42.64
45.52
5.08
5.73
110 118 (5 10 ), n2D4 = 1.4907
1
89 91 (5 10 ), n2D0 = 1.4915
75 76, 90 91 (5 10 )
47.37
52.65
5.99
7.80
C9H14Cl2O2
C10H16Cl2O2
48.02
50.42
6.27
6.72
1
i-Pr
t-Bua
1
8,8-Dibromo-4-R-3,5-dioxabicyclo[5.1.0]octanes
Mea
Et
96 98
29.52
3.32
C7H10Br2O2
C8H12Br2O2
28.8
3.24
4.88
110 120 (6 10 ), n2D5 = 1.5338
1
b
141 145 (3 10 ), n2D4 = 1.5408
86 87
C9H14Br2O2
C10H16Br2O2
1
c
i-Pr
t-Bua
36.76
4.63
36.58
a
Pure exo diastereosomers.
Found, %: Br 53.20. Calculated, %: Br 53.27.
Found, %: Br 53.00. Calculated, %: Br 50.89.
b
c
be expected that, other conditions being equal, the
configurational equilibrium will be determined by
the size of the substituent on C4. In other words, the
pattern should be qualitatively similar to that observed
for acetals of the 1,3-dioxacyclohept-5-ene series and
seven-membered heterocycles II. Table 2 contains
the Gibss energies of the epimerization equilibria.
These data indicate that the fraction of the endo
diastereoisomer having a twist conformation of the
seven-membered ring decreases as the size of the
4-substituent increases. Thus we have an unam-
biguous proof for the existence of 1,3-interaction
between the 4-substituent and hydrogen atoms on C2
(C6) in the flexible form.
The data obtained by studying the epimerization
process do not allow us to determine the difference
in the conformational properties of dichloro- and di-
bromocyclopropane fragments, whereas the existence
of equilibria involving the chair and twist conformers
suggest conformational heterogeneity of the exo
isomers (except for the tert-butyl derivatives) with
considerable prevalence of the chair-like conformers.
were measured relative to the solvent signals.
A UZDN-A setup with an operating frequency of
22 kHz was used for ultrasonic activation. AM1 semi-
empirical calculations were performed with the aid
of MOPAC 6 software [23 25]; geometry optimiza-
tion was accomplished with a gradient norm of 0.1.
In all cases, second derivatives matrices were cal-
culated, and imaginary frequencies were absent.
4-Substituted 8,8-dichloro(dibromo)-3,5-dioxa-
bicyclo[5.1.0]octanes III VI (general procedure).
A 50% aqueous solution (14 g) of sodium hydroxide
was added dropwise over a period of 2 h to a solution
of 43.5 mmol of the corresponding 2-substituted
1,3-dioxacyclohept-5-ene and 0.3 g of benzyltriethyl-
ammonium chloride in 27.6 ml of CHCl3 (or 30.5 ml
of CHBr3) under vigorous stirring and cooling in
an ice bath. The mixture was stirred for 6 days at
room temperature, diluted with methylene chloride,
and washed with water. The organic layer was
separated and dried over Na2SO4. If the emulsion did
not divide into layers, the mixture was passed through
a glass filter. The products were purified by vacuum
distillation (0.1 mm) or recrystallization from hexane
ethanol (10:1) after epimerization. The yields were
50 70%. The physical constants and elemental
analyses of the products are given in Table 3. When
the reaction was carried out under ultrasonic activa-
tion (UZDN-A), the temperature was maintained at
EXPERIMENTAL
The 13C NMR spectra were recorded on Varian
Unity-300 (75.43 MHz) and Bruker WP-200 spec-
trometers (50.46 MHz) in CDCl3. The chemical shifts
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STEREOCHEMISTRY OF SEVEN-MEMBERED HETEROCYCLES: XLIII.
1033
25 C, the amounts of the reactants being the same.
The yields of the target products were no less than
50% in 4 6 h.
10. St.-Amour, R. and St.-Jacques, M., Can. J. Chem.,
1983, vol. 61, p. 109.
11. Clark, G.R., Fraser-Reid, B., and Palenik, G.,
J. Chem. Soc., Chem. Commun., 1970, p. 1641.
General procedure for epimerization. A catalytic
amount of p-toluenesulfonic acid was added to a 10%
solution of an isomer mixture in CCl4, and the mix-
ture was kept for a week at 25 2 C. The progress of
the reaction was monitored by the 13C NMR spectra
(the isomer ratio was determined from the peak intens-
ity ratio of the acetal and methylene carbon signals).
12. Clark, G.R. and Palenik, G., J. Chem. Soc., Perkin
Trans. 2, 1973, p. 194.
13. Taylor, K.G., Chaney, J., and Deck, J.C., J. Am.
Chem. Soc., 1976, vol. 98, p. 4163.
14. Gianni, M.H., Prezzavento, B., and Shea, K., J. Org.
Chem., 1985, vol. 50, p. 1554.
15. Pitea, D., Moro, G., and Favini, G., J. Chem. Soc.,
Perkin Trans. 2, 1987, p. 313.
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