Synthesis of 16-aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-diones by reformatsky reaction

Article abstract of DOI:10.1134/S1070428015040089

Abstract Methyl 1-bromocyclohexanecarboxylate reacted with zinc and aromatic aldehydes in two steps to afford 16-aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-diones; methyl 1-[aryl(hydroxy)methyl]cyclohexanecarboxylates were also formed as by-products.

Full text of DOI:10.1134/S1070428015040089

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 4, pp. 513–517. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © N.F. Kirillov, E.A. Nikiforova, A.N. Vasyanin, M.V. Dmitriev, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51,
No. 4, pp. 530–534.
Synthesis of 16-Aryl-15-oxadispiro[5.1.5.3]hexadecane-
7,14-diones by Reformatsky Reaction
N. F. Kirillov, E. A. Nikiforova, A. N. Vasyanin, and M. V. Dmitriev
Perm State National Research University, ul. Bukireva 15, Perm, 614990 Russia
e-mail: kirillov@psu.ru
Received December 26, 2014
Abstract—Methyl 1-bromocyclohexanecarboxylate reacted with zinc and aromatic aldehydes in two steps to
afford 16-aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-diones; methyl 1-[aryl(hydroxy)methyl]cyclohexanecar-
boxylates were also formed as by-products.
DOI: 10.1134/S1070428015040089
2,4-Dioxotetrahydropyran fragment is a structural
unit of some biologically active natural compounds
[1]. Substituted spirotetrahydropyran-2,4-diones were
found to exhibit analgesic activity [2, 3]. Dispiropyran-
2,4-diones were synthesized previously by reaction of
bromo oxo esters with zinc and aromatic aldehydes
[4–7]. The reaction of methyl 1-bromocyclohexane-
carboxylate (1) with zinc and nitrobenzaldehydes in
two steps afforded 16-nitrophenyl-15-oxadispiro-
[5.1.5.3]hexadecane-7,14-diones [8] instead of the ex-
pected normal reaction products, hydroxy esters. In
order to obtain new substituted dispiro pyran-2,4-di-
ones, compound 1 was brought into reaction with zinc
and aromatic aldehydes under analogous conditions; as
a result, we isolated 16-aryl-15-oxadispiro[5.1.5.3]-
hexadecane-7,14-diones 7a–7i (Scheme 1).
Two schemes of formation of compounds 7a–7i are
possible. According to the first scheme, bromo ester 1
reacts with zinc to give Reformatsky reagent 2 whose
homocoupling in the absence of other electrophiles
yields new Reformatsky reagent 3. Analogous self-
condensation of Reformatsky reagents has been report-
ed in [9], and its probability is higher for sterically
hindered substrates. After addition of aromatic alde-
hyde 4a–4i, intermediate 3 adds to the carbonyl group
of 4 with formation of intermediate 5a–5i which
undergoes spontaneous cyclization to bromozinc hemi-
ketal 6a–6i, and hydrolysis of the latter yields final
Scheme 1.
ZnBr
COOMe
Br
ZnBr
Zn
2
BrZnO
MeO
COOMe
COOMe
1
2
3
Ar
O
BrZnO
Ar
OMe
OZnBr
COOMe
ArCHO
4a–4i
H+/H2O
–MeOZnBr
–Zn(OH)Br
–MeOH
BrZnO
MeO
O
O
Ar
O
O
5a–5i
6a–6i
7a–7i
4–7, Ar = Ph (a), 4-BrC6H4 (b), 4-ClC6H4 (c), 2,4-Cl2C6H3 (d), 4-FC6H4 (e), 3-BrC6H4 (f), 2-O2NC6H4 (g),
3-O2NC6H4 (h), 4-O2NC6H4 (i).
513

KIRILLOV et al.
514
16-aryl-15-oxadispiro[5.1.5.3]hexadecane-7,14-dione
7a–7i (Scheme 1).
by heating a mixture of bromo ester 1 and zinc in
boiling benzene; samples were withdrawn after heating
for 0.5, 1, 2, 3, and 4 h. The samples were subjected to
hydrolysis and extraction, the solvent was distilled off
from the extract, and the residue was analyzed by
GC/MS to determine the ratio of compound 9 and
methyl cyclohexanecarboxylate (10) formed by hy-
drolysis of Reformatsky reagent 2; the results are given
below. It is seen that heating for 3 h is sufficient to
ensure the maximum yield of 3.
An alternative reaction path involves reaction of
Reformatsky reagent 2 with aromatic aldehyde 4 with
formation of intermediate 8 which undergoes attack by
the second molecule 2. The subsequent transforma-
tions of intermediate 5 thus formed are the same as in
the first scheme (Scheme 2).
Scheme 2.
Ar
4
Reaction time, h
Fraction of 9, %
Fraction of 10, %
0.5
1
2
3
4
2
OZnBr
05.6 31.0 61.3 77.9 79.2
94.4 69.0 38.7 22.1 20.8
COOMe
8
2
Reformatsky reagent 2 present in the reaction mix-
ture reacted with aromatic aldehydes to give methyl
1-[aryl(hydroxy)methyl]cyclohexanecarboxylates 11a–
11d (Scheme 4).
5
6
7
Analogous mechanism was proposed in [10] for the
reaction of Reformatsky reagent derived from ethyl
bromoacetate with carbonyl compounds. This reaction
afforded δ-hydroxy-β-ketoesters as a result of addition
of the Reformatsky reagent to the carbonyl group and
subsequent attack by the second Reformatsky reagent
molecule on the primary adduct, followed by hydrol-
ysis. The reaction was called by the authors “double
Reformatsky reaction.” The formation of pyrandiones
via cyclization of products resulting from double
attack by organomagnesium compounds was observed
in the reaction of ethyl α-bromoisobutyrate with mag-
nesium and aromatic aldehydes [11].
Scheme 4.
Ar
4
2
OZnBr
COOMe
8
Ar
H+/H2O
OH
COOMe
11a–11d
–Zn(OH)Br
To determine whether the reaction follows one or
another scheme, methyl 1-bromocyclohexanecarbox-
ylate (1) was treated with zinc without addition of
aromatic aldehyde. After hydrolysis, we isolated
methyl 1-(cyclohexylcarbonyl)cyclohexanecarboxylate
(9) (Scheme 3).
Compound 11b was also isolated when the reaction
was carried out with simultaneous addition of the
initial reactants. Regardless of the ratio of 4-bromo-
benzaldehyde (4b) and methyl 1-bromocyclohexane-
carboxylate, no tetrahydropyrandione 7b was isolated,
which also indicated that the reaction followed
Scheme 1.
Scheme 3.
O
H+/H2O
The structure of the newly synthesized compounds
was confirmed by their elemental analyses and IR and
1H NMR spectra, and the structure of compound 7h
was unambiguously determined by X-ray analysis (see
figure). Compound 7h crystallized in a centrosym-
metric space group belonging to monoclinic crystal
system. All bond lengths and bond angles in molecule
7h are consistent with the corresponding reference
values. The cyclohexane fragments appear in a chair
conformation, and the pyran ring adopts a distorted
boat conformation. The C9C10C7O3 fragment is essen-
tially twisted (deviations of atoms from the mean-
3
–Zn(OH)Br
–MeOH
COOMe
9
Compound 9 was synthesized previously by reac-
tion of Reformatsky reagent 2 with cyclohexanecar-
bonyl chloride [4]. Therefore, we concluded that the
described reaction follows the first path through inter-
mediates 3, 5, and 6.
The reaction conditions were optimized by carrying
out the reaction in the absence of aldehyde component,
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SYNTHESIS OF 16-ARYL-15-OXADISPIRO[5.1.5.3]HEXADECANE-7,14-DIONES
515
square plane range from +0.09 to –0.09 Å). The C11
C19
C18
and C8 atoms deviate from the plane formed by the
other four ring atoms by 0.73 and 0.35 Å, respectively.
The m-nitrophenyl substituent is oriented pseudo-
equatorially. Molecules 7h in crystal are linked to each
other through van der Waals interactions.
C20
C21
C9
C17
Compounds 7a, 7b, 7g–7i, 9a, and 9b showed anal-
gesic activity comparable or exceeding the activity of
the reference analgesic metamizole sodium.
O1
C8
O2
O3
C10
EXPERIMENTAL
C7
The IR spectra were recorded from samples dis-
persed in mineral oil on a Perkin Elmer Spectrum Two
spectrometer with Fourier transform. The H NMR
C11
C3
1
C16
C4
spectra were measured on a Varian Mercury Plus-300
spectrometer (300 MHz) from solutions in CDCl3 (7b,
7f, 11a, 11b) or DMSO-d6 (11c, 11d) using tetra-
methylsilane as internal reference. Gas chromato-
graphic–mass spectrometric analysis was performed on
an Agilent Technologies 7890B instrument [HP-5MS
capillary column, 30 m×0.25 mm, film thickness
0.25 μm; injector temperature 250°C, oven tempera-
ture programming from 200°C (7 min) at a rate of
25 deg/min to 300°C (4 min); carrier gas helium, flow
rate 1 mL/min, split ratio 100:1; a.m.u. range 16–350].
C12
C15
C2
O5
C5
C6
C1
C13
C14
N1
O4
Structure of the molecule of 16-(3-nitrophenyl)-15-oxadi-
spiro[5.1.5.3]hexadecane-7,14-dione (7h) according to the
X-ray diffraction data. Non-hydrogen atoms are shown as
thermal vibration ellipsoids with a probability of 50%.
The X-ray diffraction data for compound 7h were
obtained at 293(2) K on an Xcalibur R automatic
diffractometer with a CCD detector according to stan-
dard procedure (MoKα radiation, ω-scanning with
a step of 1°) [12] from a 0.6×0.6×0.5-mm fragment of
a yellow prismatic single crystal. A correction for
absorption was applied empirically according to
SCALE3 ABSPACK algorithm [12]. Monoclinic crys-
tal system, space group P21/c; C21H25NO5; unit cell
parameters: a = 12.5406(19), b = 12.206(2), c =
12.515(2) Å; β = 95.731(14)°; V = 1906.1(5) Å3; Z = 4.
Total of 10264 reflection intensities were measured,
including 4412 independent reflections and 3531 re-
flections with I > 2σ(I) (completeness 99.9% for
θ < 26.00°). The structure was solved directly and was
refined against F2 by the full-matrix least-squares
procedure in anisotropic approximation for all non-hy-
drogen atoms. The positions of hydrogen atoms were
refined according to the riding model in isotropic
approximation with dependent thermal parameters. All
calculations were performed using SHELX97 software
suite [13]. Final divergence factors R1 = 0.0503, wR2 =
0.1310 [for reflections with I > 2σ(I)] and R1 = 0.0628,
wR2 = 0.1399 (for all reflections); goodness of fit
1.038; maximum and minimum residual electron den-
sity peaks 0.254 and –0.241 ē Å–3. The set of
X-ray diffraction data for compound 7h was deposited
to the Cambridge Crystallographic Data Centre
(entry no. CCDC 1 057 390) and is available at
www.ccdc.cam.ac.uk/data_request/cif.
Compounds 7a–7i and 11a–11d (general proce-
dure). A mixture of 2.5 g of zinc, 5.53 g (25 mmol) of
bromo ester 1, a catalytic amount (5 mg) of HgCl2, and
40 mL of benzene was heated for 3 h under reflux. The
mixture was cooled, 10 mmol of aldehyde 4a–4i was
added, and the mixture was heated for 2 h under reflux.
After cooling, the mixture was treated with 5% aque-
ous acetic acid, the organic phase was separated and
dried over Na2SO4, and the solvent was distilled off.
The crystalline product (7a–7i) was recrystallized from
ethyl acetate. Treatment of the residue with methanol
led to crystallization of compound 11a–11d which was
recrystallized from methanol.
16-Phenyl-15-oxadispiro[5.1.5.3]hexadecane-
7,14-dione (7a). Yield 1.57 g (48%), mp 167–168°C.
16-(4-Bromophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (7b). Yield 2.11 g (52%), mp 215–
216°C. IR spectrum, ν, cm–1: 1742, 1710 (C=O).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 4 2015

KIRILLOV et al.
516
1H NMR spectrum, δ, ppm: 0.73–2.20 m [20H,
(CH2)5], 5.16 s (1H, 16-H), 7.21 d (2H, Harom, J =
8.4 Hz), 7.52 d (2H, Harom, J = 8.4 Hz). Found, %:
C 62.10; H 6.28; Br 19.94. C21H25BrO3. Calculated, %:
C 62.23; H 6.22; Br 19.71.
mp 77–78°C. IR spectrum, ν, cm–1: 3532 (OH), 1705
(C=O). 1H NMR spectrum, δ, ppm: 0.95–2.25 m [10H,
(CH2)5], 3.55 s (3H, OMe), 4.55 s (1H, CH), 5.52 s (1H,
OH), 7.18 d (2H, Harom, J = 7.8 Hz), 7.33 d (2H, Harom
,
J = 7.8 Hz). Found, %: C 63.85; H 6.62; Cl 12.41.
C15H19ClO3. Calculated, %: C 63.71; H 6.77; Cl 12.54.
16-(4-Chlorophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (7c). Yield 1.62 g (45%), mp 210–
211°C; published data [4]: (mp 211–212°C.
16-(2,4-Dichlorophenyl)-15-oxadispiro[5.1.5.3]-
hexadecane-7,14-dione (7d). Yield 1.03 g (26%),
mp 219–220°C; published data [4]: mp 220–221°C.
16-(4-Fluorophenyl)-15-oxadispiro[5.1.5.3]-
hexadecane-7,14-dione (7e). Yield 2.00 g (58%),
mp 176–177°C.
16-(3-Bromophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (7f). Yield 2.47 g (61%), mp 145–
146°C. IR spectrum, ν, cm–1: 1741, 1710 (C=O).
1H NMR spectrum, δ, ppm: 0.80–2.24 m [20H,
(CH2)5], 5.18 s (1H, 16-H), 7.28 d (1H, Harom, J =
7.4 Hz), 7.29 t (1H, Harom, J = 7.4 Hz), 7.53 d (1H,
Methyl 1-[(2,4-dichlorophenyl)(hydroxy)meth-
yl]cyclohexanecarboxylate (11d). Yield 0.35 g (11%),
mp 100–101°C. IR spectrum, ν, cm–1: 3548 (OH),
1
1711 (C=O). H NMR spectrum, δ, ppm: 0.95–2.42 m
[10H, (CH2)5], 3.60 s (3H, OMe), 5.04 s (1H, CH),
5.72 s (1H, OH), 7.41 d (1H, Harom, J = 7.8 Hz), 7.45 d
(1H, Harom, J = 7.8 Hz), 7.50 s (1H, Harom). Found, %:
C 56.88; H 5.85; Cl 22.17. C15H18Cl2O3. Calculated,
%: C 56.80; H 5.72; Cl 22.35.
Reaction of methyl 1-bromocyclohexanecarbox-
ylate with zinc. A mixture of 5.0 g of zinc, 11.06 g
(50 mmol) of ester 1, and 5 mg of HgCl2 in 80 mL of
benzene was heated for 4 h under reflux, and 10-mL
samples were withdrawn after 0.5, 1, 2, 3, and 4 h.
Each sample was cooled and hydrolyzed with 5% ace-
tic acid. The organic phase was separated, and the
aqueous phase was extracted with three portions of
ethyl acetate. The extracts were combined with the
organic phase and dried over anhydrous sodium sul-
fate, the solvent was distilled off, and the residue was
analyzed by GC/MS. The residual reaction mixture
was treated in a similar way, and vacuum distillation
gave methyl 1-(cyclohexylcarbonyl)cyclohexanecar-
boxylate, bp 160–168 (10 mm), mp 48–50°C (from
hexane).
H
arom, J = 7.4 Hz), 7.54 s (1H, Harom). Found, %:
C 62.38; H 6.16; Br 19.54. C21H25BrO3. Calculated, %:
C 62.23; H 6.22; Br 19.71.
16-(2-Nitrophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (7g). Yield 1.60 g (43%), mp 197–
198°C; published data [8]: mp 198–199°C.
16-(3-Nitrophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (7h). Yield 2.08 g (56%), mp 188–
189°C.
16-(4-Nitrophenyl)-15-oxadispiro[5.1.5.3]hexa-
decane-7,14-dione (7i). Yield 1.93 g (52%), mp 194–
196°C; published data [8]: mp 195–196°C.
Methyl 1-[hydroxy(phenyl)methyl]cyclohexane-
carboxylate (11a). Yield 0.30 g (12%), mp 69–70°C.
IR spectrum, ν, cm–1: 3525 (OH), 1698 (C=O).
1H NMR spectrum, δ, ppm: 1.05–2.20 m [10H,
(CH2)5], 2.93 s (1H, OH), 3.65 s (3H, OMe), 4.61 s
(1H, CH), 7.16–7.33 m (5H, Harom). Found, %: C 72.67;
H 8.18. C15H20O3. Calculated, %: C 72.55; H 8.12.
Methyl 1-[(4-bromophenyl)(hydroxy)methyl]-
cyclohexanecarboxylate (11b). Yield 0.52 g (16%),
mp 93–94°C. IR spectrum, ν, cm–1: 3489 (OH), 1721
(C=O). 1H NMR spectrum, δ, ppm: 1.05–2.23 m [10H,
(CH2)5], 2.95 s (1H, OH), 3.66 s (3H, OMe), 4.58 s
(1H, CH), 7.07 d (2H, Harom, J = 7.2 Hz), 7.42 d (2H,
Harom, J = 7.2 Hz). Found, %: C 55.29; H 5.96;
Br 24.25. C15H19BrO3. Calculated, %: C 55.06; H 5.85;
Br 24.42.
Reaction of methyl 1-bromocyclohexanecarbox-
ylate with zinc and 4-bromobenzaldehyde. A mix-
ture of 2.5 g of zinc, 5.53 g (12 mmol) of ester 1,
10 mmol of 4-bromobenzaldehyde (4b), and 5 mg of
HgCl2 in 40 mL of benzene was heated for 3 h under
reflux. The mixture was treated with 5% acetic acid,
the organic phase was separated and dried over
Na2SO4, the solvent was distilled off, and the residue
was treated with methanol to isolate 1.77 g (54%) of
compound 11b.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 13-03-96010).
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SYNTHESIS OF 16-ARYL-15-OXADISPIRO[5.1.5.3]HEXADECANE-7,14-DIONES
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