Reaction of methyl 1-bromocycloalkanecarboxylates with zinc and benzoin

Article abstract of DOI:10.1007/s11172-014-0615-6

The Reformatsky reagents derived from methyl 1-bromocyclohexane-or 1-bromocyclopentanecarboxylate and zinc add to benzoin to afford the corresponding 4-hydroxy-3,4-diphenyl-2-oxaspiro[4.5]decan-1-one and 4-hydroxy-3,4-diphenyl-2-oxaspiro[4.4]nonan-1-one.

Full text of DOI:10.1007/s11172-014-0615-6

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Russian Chemical Bulletin, International Edition, Vol. 63, No. 6, pp. 1438—1440, June, 2014
Brief Communications
Reaction of methyl 1ꢀbromocycloalkanecarboxylates with zinc and benzoin*
N. F. Kirillov,a P. A. Slepukhin, E. A. Nikiforova, A. N. Vasyanin, and S. N. Shurov
b
a
a
a
aPerm State University,
1
5 ul. Bukireva, 614990 Perm, Russian Federation.
Eꢀmail: kirillov@psu.ru
b
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
2 ul. S. Kovalevskoi, 620990 Ekaterinburg, Russian Federation
2
The Reformatsky reagents derived from methyl 1ꢀbromocyclohexaneꢀ or 1ꢀbromocycloꢀ
pentanecarboxylate and zinc add to benzoin to afford the corresponding 4ꢀhydroxyꢀ3,4ꢀdiꢀ
phenylꢀ2ꢀoxaspiro[4.5]decanꢀ1ꢀone and 4ꢀhydroxyꢀ3,4ꢀdiphenylꢀ2ꢀoxaspiro[4.4]nonanꢀ1ꢀone.
Key words: Reformatsky reaction, spiro compounds, lactones, tetrahydrofuranones.
Reformatsky reagents add to the carbonyl group to
phenylꢀ2ꢀoxaspiro[4.4]nonanꢀ1ꢀone (5b) were obtained
(Scheme 1).
form bromozinc alkoxide. If the latter contains an approꢀ
priately arranged functional group, it can undergo cyclizaꢀ
tion to give heterocyclic compounds.1 With the goal of
synthesizing such spiroheterocyclic compounds, we studꢀ
ied the reaction of Reformatsky reagents 1a,b, which were
derived from methyl 1ꢀbromocyclohexaneꢀ or 1ꢀbromoꢀ
cyclopentanecarboxylate and zinc, with benzoin (2). In
a diethyl ether—benzene—HMPA mixture (10 : 10 : 2),
hydroxy ketone 2 reacted with two molecules of Reforꢀ
matsky reagent 1a,b to form intermediates 3a,b. The latter
undergo cyclization accompanied by elimination of broꢀ
mozinc methoxide to give intermediates 4a,b. On quenchꢀ
ing of the reaction mixture, 4ꢀhydroxyꢀ3,4ꢀdiphenylꢀ2ꢀ
oxaspiro[4.5]decanꢀ1ꢀone (5a) and 4ꢀhydroxyꢀ3,4ꢀdiꢀ
The structures of compounds 5a,b were confirmed by
,2
1
13
elemental analysis and by H and C NMR and IR
spectroscopy. The IR spectra show absorption bands of
the carbonyl group of ꢀlactones and the hydroxy group at
–
1
1750—1755 and 3450—3455 cm , respectively. In the
1
H NMR spectrum, methine protons give signals at
 6.25—6.35.
Generally, ꢀhydroxy esters containing a hydrogen
atom at the ꢀcarbon atom easily eliminate a water moleꢀ
3
cule to yield ,ꢀunsaturated esters. The formation of the
double bond conjugated to the benzene ring occurs even
more easily. However, compounds 5a,b proved to be rathꢀ
er stable and do not decompose not only in the course of
the isolation but even when treated with acetic anhydride
or upon heating with pꢀtoluenesulfonic acid. In order to
explain the above results, we calculated the geometric and
*
Dedicated to Academician of the Russian Academy of Sciences
O. N. Chupakhin on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1438—1440, June, 2014.
066ꢀ5285/14/6306ꢀ1438 © 2014 Springer Science+Business Media, Inc.
1

4
ꢀHydroxyꢀ2ꢀoxaspiro[4.n]alkanꢀ1ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1439
Scheme 1
1
, 3—5: n = 2 (a), 1 (b)
energy characteristics of the molecules by the ab initio
method at the B3LYP/6ꢀ31G(d) level. Due to the presꢀ
ence of two chiral centers, compound 5a can exists as four
stereoisomers. Each pair of them has the 3R*,4S* and
symmetric space group of the monoclinic system (Fig. 1).
The bond lengths and bond angles are typical of this class
of compounds. The cyclohexane ring adopts a chair conꢀ
formation. The heterocyclic moiety has an envelope conꢀ
formation with the C(4) atom as the flap. The phenyl
substituents at the heterocycle are in trans positions, and
the hydroxy group is in the (pseudo)axial position. In
the crystal, the molecules are linked via intermolecular
O—H...O hydrogen bonds [1 – x, 1 – y, –z] between the
hydroxy group and the carbonyl oxygen atom to form
dimers. Due to this interaction, the carbonyl groups of
adjacent molecules are closely spaced with the C...O disꢀ
tance of 3.1 Å, which attests to the possible — interacꢀ
tion between these molecules. There are no other specific
intermolecular contacts in the crystal packing.
4
3
S*,4S* relative configurations of the chiral centers and
are diastereomers.
Etot = –1039.1389 a.u.
Etot = –1039.1441 a.u.
According to the results of calculations, the diastereoꢀ
mer with the 3S*,4S* configuration is somewhat more
stable (by 13.7 kJ mol ), as shown by the comparison of
Experimental
–
1
the total energies (Е ). In this isomer, the hydrogen atom
tot
The IR spectra of compounds 5a,b in Nujol mulls were meaꢀ
at the C(3) atom and the hydroxy group at the C(4) atom
sured on a Spectrum Two Fourierꢀtransform infrared spectroꢀ
are in trans positions. The calculated dihedral angle

(H—C(3)—C(4)—O) is –167.3, which could facilitate
C(15)
C(16)
the dehydration of compound 5a. However, the hydroxy
group at the C(4) atom is shielded by both the orthoꢀ
hydrogen atoms of the nearest phenyl substituent and the
methylene hydrogen atoms of the cyclohexane moiety,
which interferes with the approach of a dehydrating agent
and elimination of the oxygenꢀcontaining leaving group.
In this case, the benzene ring cannot stabilize the electron
deficiency that arises at the carbon atom C(4), because
the rotation of the benzene ring necessary for the efficient
overlap of electron clouds is hindered by the substituents
at both the C(3) atom and the C(5) atom of the tetraꢀ
hydrofuran ring.
C(14)
C(13)
C(17)
C(10)
C(12)
C(4)
C(9)
C(8)
C(11)
C(5)
C(21) C(1)
C(6)
O(3)
O(1)
C(20)
C(3)
C(7)
C(18)
C(2)
O(2)
C(19)
In order to determine the exact structures of the synꢀ
thesized compounds, compound 5a was studied by Xꢀray
diffraction. It was found that 5a crystallizes in the centroꢀ
Fig. 1. Molecular structure of compound 5a with thermal ellipꢀ
soids drawn at 50% probability level.

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Kirillov et al.
meter (Perkin—Elmer). The H (300 MHz) and 13C (75 MHz)
1
sulfate, the solvents were distilled off, and the products were
recrystallized from ethyl acetate.
NMR spectra were recorded in CDCl on a Mercury Plusꢀ300
3
spectrometer using SiMe4 as the internal standard. Quantum
chemical calculations were carried out on a PGUꢀTesla multiꢀ
processor computer complex with hybrid architecture based on
4ꢀHydroxyꢀ3,4ꢀdiphenylꢀ2ꢀoxaspiro[4.5]decanꢀ1ꢀone (5a).
Yield 65%, m.p. 191—192 C. IR, /cm : 3455 (OH); 1750
–
1
1
(C=O). H NMR, : 0.74—2.25 (m, 10 H, (CH ) ); 4.69 (s, 1 H,
2
5
13
2
0 dualꢀprocessor nodes with Intel Xeon 5670 CPU and Nvidia
OH); 6.35 (s, 1 H, CHO); 7.22—7.64 (m, 10 H, Ar). C NMR,
: 20.76, 21.33, 24.67, 25.07, 31.07 (C(6)—C(10)); 51.69 (C(5));
81.26 (C(4)); 84.29 (C(3)); 126.94, 127.27, 128.16, 128.37,
128.46, 128.73, 132.98, 137.07 (Carom); 178.08 (C(1)). Found (%):
C, 78.03; H, 6.95. C H O . Calculated (%): C, 78.23; H, 6.88.
4
Tesla S2050 processors using the Firefly program package. The
Xꢀray diffraction data set for compound 5a was collected at 295(2) К
on a Xcalibur S automated singleꢀcrystal Xꢀray diffractometer
(
(
(
Oxford diffraction) using monochromatized MoꢀK radiation
0.71073 Å, graphite monochromator). Absorption was ignored
 = 0.086 mm ). Colorless crystals belong to the monoclinic
21
22
3
4ꢀHydroxyꢀ3,4ꢀdiphenylꢀ2ꢀoxaspiro[4.4]nonanꢀ1ꢀone (5b).
–
1
–1
Yield 68%, m.p. 198—199 C. IR, /cm : 3450 (OH); 1755
1
system; the unit cell parameters a = 10.7285(9) Å, b = 6.4360(6) Å,
(C=O). H NMF, : 0.90—2.05 (m, 8 H, (CH ) ); 4.94 (s, 1 H,
2
4
3
13
c = 23.864(3) Å;  = 90.671(8), V = 1647.6(3) Å , Z = 4, space
OH); 6.25 (s, 1 H, CHO); 7.20—7.70 (m, 10 H, Ar). C NMR,
: 24.93, 25.13, 27.69, 34.45 (C(6)—C(9)); 60.23 (C(5)); 82.62
(C(4)); 83.45 (C(3)); 127.03, 127.06, 128.38, 128.49, 128.60,
128.89, 132.94, 137.38 (Carom); 178.53 (C(1)). Found (%):
C, 77.81; H, 6.57. C H O . Calculated (%): C, 77.90; H, 6.54.
group P2 /c; a total of 3975 unique reflections were measured
1
(
Rint = 0.0678), of which 1475 reflections were with I > 2(I).
The structure solution and refinement were performed using the
5
SHELXTL program package; the final R factor was R = 0.0481
1
20 20
3
(
based on reflections with I > 2(I)). The crystallographic data
were deposited in the Cambridge Crystallographic Data Centre
CCDC 993240) and can be obtained, free of charge, on appliꢀ
The present work was financially supported by the Minꢀ
istry of Education and Science of the Russian Federation
(Project No. 3.3925.2011) and the Russian Foundation
for Basic Research (Project No. 13ꢀ03ꢀ96010).
(
cation to http://www.ccdc.cam.ac.uk/data_request/cif.
Methyl 1ꢀbromocyclohexaneꢀ and 1ꢀbromocyclopentaneꢀ
carboxylates were prepared by the successive treatment of the
corresponding cycloalkanecarboxylic acid with thionyl chloride,
6
References
bromine, and methanol. Commercial cyclopentaneꢀ and cycloꢀ
hexanecarboxylic acids and benzoin were used. Before the synꢀ
thesis, benzoin was recrystallized from ethanol. For drying, diꢀ
ethyl ether and benzene were distilled over sodium metal, and
HMPA was vacuum distilled over calcium oxide.
Synthesis of compounds 5a,b (general procedure). A solution
of methyl 1ꢀbromocyclohexaneꢀ or 1ꢀbromocyclopentanecarbꢀ
oxylate (0.025 mol) in anhydrous benzene (10 mL) was added
dropwise to a mixture of zinc chips (3 g), benzoin (0.01 mol),
a catalytic amount of mercury dichloride, anhydrous diethyl ether
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2. W. R. Ocampo, W. R. Dolbier, Tetrahedron, 2004, 9325.
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1972, p. 176.
(
10 mL), anhydrous benzene (10 mL), and HMPA (2 mL). Then
the reaction mixture was refluxed for 2 h, cooled, decanted, and
hydrolyzed with 5% hydrochloric acid. The organic layer was
separated, and the aqueous layer was twice extracted with diꢀ
ethyl ether. The organic phase was dried with anhydrous sodium
Received November 25, 2013;
in revised form March 21, 2014