Unusual pathway of alkylation of 2-(4-bromobenzylidene)-p-menthan-3-one with ethyl bromoacetate

Article abstract of DOI:10.1007/s11172-007-0399-z

Reaction of enolate carbanion, generated from 2-(4-bromobenzylidene)-p- menthan-3-one, with ethyl bromoacetate proceeds selectively as the O-alkylation.

Full text of DOI:10.1007/s11172-007-0399-z

Russian Chemical Bulletin, International Edition, Vol. 56, No. 12, pp. 2506—2509, December, 2007
2506
Brief Communications
Unusual pathway of alkylation
of 2ꢀ(4ꢀbromobenzylidene)ꢀpꢀmenthanꢀ3ꢀone with ethyl bromoacetate

A. I. Krivoshei, S. V. Shishkina, V. V. Vashchenko, and O. V. Shishkin
Scientific Technological Institution "Institute for Single Crystals" , National Academy of Sciences of Ukraine,
60 prosp. Lenina, 61001 Kharkov, Ukraine.
Fax: +38 (057) 340 9343. Eꢀmail: krivoshey@isc.kharkov.com
Reaction of enolate carbanion, generated from 2ꢀ(4ꢀbromobenzylidene)ꢀpꢀmenthanꢀ3ꢀ
one, with ethyl bromoacetate proceeds selectively as the Оꢀalkylation.
Key words: Оꢀalkylation, arylindeneꢀpꢀmenthanꢀ3ꢀone core, enolates, enol ethers, Xꢀray
diffraction analysis.
(E,1R,4R)ꢀArylideneꢀpꢀmenthanꢀ3ꢀones 1 are widely
lowed by the mass spectrometry analysis of the fractions
allowed us to find out that only the main component of
the mixture has molecular weight corresponding to the
expected ester 4. Basic hydrolysis followed by acidificaꢀ
tion afforded the free acid in 40% yield, the composition
of which was confirmed by elemental analysis and mass
studied1—3 as the chiral components of liquid crystal (LC)
materials. The reaction of these compounds with ioꢀ
domethane in basic media according to the described
method4 preferably leads to the products of Сꢀalkylation
of the type 2 with high stereoselectivity (Scheme 1), which
also are of practical use as the chiral components of LC
materials.5
1
spectrometry data. In the Н NMR spectrum of the subꢀ
stance obtained, there are signals characteristic of pꢀmenꢀ
thane and 2ꢀarylidene fragments. However, signals of the
diаstereotopic protons in αꢀposition to the carboxylic
group resonate in rather downfield region (δ 4.19 and
4.07) than could have been expected for the proposed
structure 5. In the IR spectrum, absorption characteristic
of carboxylic acids is observed: a broad band at 3144 cm–1
(νOH), 1750 and 1709 cm–1 (free and associated νC=O).
However, there is no absorption band of the conjugated
carbonyl group of the pꢀmenthane fragment in the region
1700—1660 cm–1, at the same time, there are two weak
bands at 1628 and 1610 cm–1, which is more characterisꢀ
In order to prepare the analogs of compound 2, which
contain fragments suitable for further functionalization,
such as 4 or 5, we used ethyl bromoacetate, since it was
described as the Сꢀalkylation agent in most reactions with
enolate carbanions of various cyclohexanone derivatives
(see, for example, Refs 6—8).
The reaction of enolate carbanion 3, obtained by treatꢀ
ment of compound 1 (Ar = 4ꢀBrC6H4) with ButOK in
ButOH, with ethyl bromoacetate led to an oily mixture of
products, consisting of three main substances (HPLC
data). The microscale preparative HPLC separation folꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2420—2423, December, 2007.
1066ꢀ5285/07/5612ꢀ2506 © 2007 Springer Science+Business Media, Inc.

Menthane enol ether
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 12, December, 2007 2507
Scheme 1
Br(1)
C(10)
C(11)
tic of Оꢀalkyl ethers of the enol form of 2ꢀarylidenemenꢀ
thanones 8 (see Ref. 9). Thus, the spectroscopy data obꢀ
tained did not allow us to unambiguously ascribe the strucꢀ
ture of acid 5 to the compound under consideration.
The Xꢀray diffraction study of a monocrystal sample
showed that this reaction product has structure 7 isomeric
to the one of expected compound 5, to be exact, there is
an enol ether fragment in it (Fig. 1). Thus, Oꢀ rather than
Cꢀalkylation occurs in the reaction of enolate carbanion 3
(Ar = 4ꢀBrC6H4) with ethyl bromoacetate.
The cyclohexene ring in molecule 7 has the unsymꢀ
metrical halfꢀchair conformation. The deflections of C(4)
and С(5) atoms from the meanꢀsquare plane of the other
atoms of the ring are –0.30 and 0.45 Å, respectively. In
the cyclohexene ring, the С(2)—С(3) bond (1.522(3) Å)
is longer and the С(3)—С(4) bond (1.509(4) Å) is shorter
as compared with their average values10 (1.506 and 1.541
Å, respectively), which was also observed for the analog 8
studied earlier (see Ref. 9). The endocyclic double bond
is considerably twisted (torsion angle О(1)—С(1)—С(2)—
С(15) is 6.4(4)°) and is longer (1.350(3) Å) relatively to
the average value (1.326 Å). A conjugation between the
C(12)
C(9)
C(14)
C(8)
C(13)
C(6)
C(7)
C(5)
O(3)
C(19)
C(4)
C(3)
C(18)
C(1)
C(2)
O(2)
O(1)
C(17)
C(15)
C(16)
Fig. 1. Xꢀray data on the molecular structure of 2ꢀ[(5R,6E)ꢀ6ꢀ
(4ꢀbromobenzylidene)ꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexꢀ1ꢀ
enyloxy]acetic acid (7).

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 12, December, 2007
Krivoshei et al.
(5 mL) was added dropwise to it for 10—15 min. The reaction
mixture was stirred for 1.5 h, then, neutralized with dilute acetic
acid, and extracted with dichloromethane. The extract was conꢀ
centrated dry. Methanol (40 mL), water (15 mL), and potassiꢀ
um hydroxide (2.4 g, 43 mmol) were added to the residue. The
mixture was refluxed for 40 min with stirring, cooled, and neuꢀ
tralized with diluted acetic acid. The precipitate formed was
filtered off, washed with water, dried, and recrystallized from
methanol to obtain acid 7 (1.9 g, 40%) (Ar = 4ꢀBrC6H4) as
colorless crystals, m.p. 110—111 °C (from methanol). Found
(%): C, 60.16; H, 6.30. C19H23BrO3. Calculated (%): C, 60.17;
H, 6.11. IR, ν/cm–1: 3144 (OH), 2923, 2964, 2935 (CHaliph),
1750 (С=Оfree), 1709 (С=Оassoc), 1628 and 1610 (C=C and Ar).
MS, m/z (Irel (%)): 378 [M]+ (100), 363 (23), 335 (25), 319 (17),
endoꢀ and exocyclic double bonds is slightly disturbed
(torsion angle С(2)—С(1)—С(6)—С(7) is –162.8(2)°).
Bromophenyl substituent is in арꢀconformation relatively
to the С(1)—С(6) bond (torsion angle С(1)—С(6)—
С(7)—С(8) is 178.9(2)°) and is considerably turned relaꢀ
tively to the exocyclic double bond (torsion angle С(6)—
С(7)—С(8)—С(9) is 40.8(4)°).
In a crystal, compound 7 exists as the crystallosolvate
with methanol and forms endless chains along the crystalꢀ
lographic direction (010) due to the intermolecular hyꢀ
drogen bonds O(3)—H(3O)...O(1w) (H...O is 1.78 Å,
angle O—H...O is 173°) and O(1w)—H(1Ow)...O(2)´
(–x, 0.5 + y, –0.5 – z) (H...O is 1.90 Å, angle O—H...O
is 158°).
There is no reason for the change of the С(5) chiral
center configuration during the transformations described.
That is why we ascribed the same absolute configuration
to C(5) atom in compound 7 as in the starting ketone 1
(Ar = 4ꢀBrC6H4). Results on the research of the absolute
and relative configuration of compounds of the 1 series
are in details reported in paper.11
1
287 (17), 208 (25), 193 (24), 181 (20), 169 (22). H NMR, δ:
12.81 (s, 1 H, COOH); 7.53, 7.23 (both d, 2 H each, СН(Ar),
J = 8.4 Hz); 6.54 (s, 1 H, H(7)); 4.19, 4.07 (both d, 1 H each,
H(18), J = 5.5 Hz); 3.58—3.14 (m, 1 H, H(15)); 3.11—2.93 (m,
1 H, H(5)); 2.35—1.98 (m, 2 H, H(3)AH(3)B); 1.71—1.41 (m,
2 H, H(4)AH(4)B); 1.11 (d, 3 H, C(14)H3, J = 6.7 Hz); 1.00 (d,
3 Н, С(CH3)2, J = 5.3 Hz); 0.99 (d, 3 H, СMe2, J = 5.7 Hz).
Crystals of compound 7 are rhombic, C20H27O4Br, at 20 °C
a = 9.984(1), b = 10.303(1), c = 20.582(2) Å, V = 2117.0(5) Å3,
Mr = 411.33, Z = 4, space group P212121, dcalc = 1.291 g cm—3
,
In conclusion, the reaction of enolate carbanion of
2ꢀ(4ꢀbromobenzylidene)ꢀpꢀmenthanꢀ3ꢀone with ethyl
bromoacetate selectively proceeds as the Оꢀalkylation. We
failed in finding the literature examples of alkylation of
2ꢀarylidenecyclohexanones with haloacetic acid esters.
Rare scattered examples of the reaction directed at the
oxygen atom are described for the other cyclohexanone
derivatives.12,13 Study on the regioselectivity of alkylation
of enolizable α,βꢀunsaturated ketones with ethyl bromoꢀ
acetate, as well as a quest for the ways of selective Сꢀalkyꢀ
lation of compounds of the type 1 with ethyl bromoaceꢀ
tate are planned for our further research.
µ(MoꢀKα) = 1.961 mm–1, F(000) = 856. The unit cell parameꢀ
ters and the intensities of 8180 reflections (3664 independent
ones, Rint = 0.033) were measured on a Xcaliburꢀ3 diffractomeꢀ
ter (MoꢀKα radiation, ССD detector, graphite monochromaꢀ
tor, ωꢀscanning technique, 2θ
= 50°). The absorption was
max
calculated by semiempirical method based on the results of multiꢀ
scanning (Tmin = 0.508, Tmax = 0.908).
The structure was solved by direct method with the use of
the SHELX97 program package.15 Positions of the hydrogen
atoms were localized from the differential synthesis of electron
density and refined using a riding model with Uiso = nUeq
(n = 1.5 for the methyl and hydroxy groups and n = 1.2 for the
other hydrogen atoms). The structure was refined by the leasts
squares method with anisotropic fullꢀmatrix approximation F2
for nonꢀhydrogen atoms to wR2 = 0.051 based on 3642 reflecꢀ
tions (R1 = 0.029 based on 1861 reflections with F > 4σ(F),
S = 0.739). Coordinates of atoms and complete tables of bond
lengths and bond angles were deposited with the Cambridge
Structural Database (CCDC 642742).
Experimental
1
Н NMR spectra were recorded on a Varian Mercury VXꢀ200
spectrometer (200 MHz), DMSOꢀd6 was used as the solvent,
signals of residual protons of the deuterated solvent (δ 2.5014), as
the internal standard. Mass spectra were recorded on a Varian
1200L chromatoꢀmass spectrometer with direct exposure probe
(DEP), ionization by electron impact, and energy of ionization
70 eV. IR spectra were recorded on a Perkin—Elmer Spectrum
One Fourierꢀspectrometer. Elemental analysis was performed
on a Eurovector EAꢀ3000 instrument. The reaction course and
purity of the compounds obtained, as well as the microscale
separations were carried out on a Bischoff module liquid chroꢀ
matograph equipped with Prontosil 120ꢀ5ꢀC18H reversed phase
column, eluent, acetonitrile—water azeotropic mixture. Melting
points were determined on the Kofler heating table.
2ꢀ[(5R,6E)ꢀ6ꢀ(4ꢀBromobenzylidene)ꢀ2ꢀisopropylꢀ5ꢀmethylꢀ
cyclohexꢀ1ꢀenyloxy]acetic acid (7). Ketone 1 (Ar = 4ꢀBrC6H4,
4 g, 14.6 mmol) was dissolved in tertꢀbutanol (25 g) followed by
addition of potassium tertꢀbutoxide (3.2 g, 29 mmol) with stirꢀ
ring. The mixture obtained was kept for 15 min, cooled to 0 °C,
and a solution of ethyl bromoacetate (2.4 mL, 22 mmol) in THF
This work was financially supported by the National
Academy of Sciences of Ukraine.
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