Phase-transfer-catalysed Ring Opening of Cyclohexene Oxide by Phenylacetonitrile Carbanion in the Presence of Lithium Salts

Article abstract of DOI:10.1039/a606498a

Lithium cation assisted nucleophilic ring opening of cyclohexene oxide, by phenylacetonitrile carbanions, under phasetransfer conditions giving rise to a diastereoisomeric mixture of trans-7-hydroxynitriles 7 and 8 is reported.

Full text of DOI:10.1039/a606498a

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66 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 66–67†
Phase-transfer-catalysed Ring Opening of Cyclohexene
Oxide by Phenylacetonitrile Carbanion in the Presence of
Lithium Salts†
Rado Markovi´c,* Goran Dimitrijevi´c and Vesna Aleksi´c
Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 158, YU-11001
Belgrade, Yugoslavia
Lithium cation assisted nucleophilic ring opening of cyclohexene oxide, by phenylacetonitrile carbanions, under phase-
transfer conditions giving rise to a diastereoisomeric mixture of trans-g-hydroxynitriles 7 and 8 is reported.
Intramolecular cyclizations of epoxynitriles 1 and inter-
molecular ring openings of epoxides by alkanonitrile carban-
ions (Scheme 1, routes A and B), constitute an important
method for the synthesis of highly reactive and versatile
g-hydroxynitriles 2–4 (Scheme 1).1,2
anhydrous K2CO3, Na2CO3, KHCO3, KOH, NaOH and
KOBut, still strong enough to generate a significant equili-
brium concentration of carbanions, phase-transfer catalysts
and crown ethers were found to be particularly useful and
effective for (1) alkylation of phenylacetonitrile,7 (2) acyla-
tion of phenylalkanenitrile,7 (3) nucleophilic addition of
sodium arylalkenenitrile carbanions to substituted
o-propenylanisoles8 and (4) the preparation of ethynyl-sub-
stituted phenylacetonitriles from vinylidene chloride and
phenylacetonitrile derivatives.9 There has been as yet no
report of the phase-transfer-catalysed ring opening of
epoxides of that type. The only related reaction recently
described by Abenhaim et al.10 is the ring opening of a fatty
epoxide by diethyl acetamidomalonate in basic medium by
phase-transfer catalysts.
H
α
H
H
(A)
O
Base
(iii)
CN
[CH2]n
CN
[CH2]n
HO
6
1
n = 0, 1-3
Base
(i)
Based on a concept employing weaker bases in a solid–
liquid and liquid–liquid two phase system,11 we report now
phase-transfer-catalysed ring opening of cyclohexene oxide
under diverse reaction conditions, by in situ generated potas-
sium phenylacetonitrile (Scheme 2) affording the dia-
H
H
H
α
CN
γ
–
(ii)
• •
O
γ
HO
CN and/or
[CH2]n
[CH2]n
CN
HO
stereoisomeric
trans-2-hydroxycyclohexyl(phenyl)aceto-
[CH2]n
nitriles 7 and 8 in good yields (45–76%). Followed by the
hydrolysis to trans-2-hydroxycyclohexyl(phenyl)acetic acids 9
and 10, and cyclization to 11 and 12, the complete reaction
sequence constitutes a competitive method for the trans-
formation of epoxides into the corresponding g-lactones.
As shown in Table 1, we focused our attention on the
reaction of 1 with phenylacetonitrile under various condi-
tions in the presence of LiCl or LiClO4 as an appropriate
promoter for the epoxide opening, using benzyltriethyl-
2
3
α
O
H
HO
H
H
O
(B)
–
Base
(i)
• •
(ii)
R
CN
R
CN
R
CN
4
OH
α
H
Base
(iii)
5
Scheme 1
Many studies indicate that, owing to the high pKa values of
nitriles3 [CH3CN, pKDMSO = 31.3; PhCH(CH3)CN, pKDMSO
= 23.0; PhCH2CN, pKDMSO = 21.9] the efficient ionization of
an a-hydrogen, as an initial step [Scheme 1, step i in (A) or
(B)], can be effected only under strongly basic conditions.2–4
Accordingly, the oxirane opening by the resulting nucleo-
phile (step ii) was usually accomplished using KNH2 in liquid
NH3–glyme mixture,1 NaNH2 in PhH,2 BuLi in THF–hexane,
or lithium diisopropylamide in THF. In competition with
path i, the strong base is capable of (a) elimination of the
a-hydrogen, giving rise to unsaturated alcohols 5 and 6 (path
iii) and (b) nucleophilic attack on the nitrile group as well.
However, phenylacetonitriles, being of more strongly acidic
nature than acetonitrile, do react satisfactorily with weaker
bases.5–7 In the search for the use of appropriate bases, e.g.,
*To receive any correspondence (e-mail: Markovic@hf01.chem.
bg.ac.yu).
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Scheme 2

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J. CHEM. RESEARCH (S), 1997 67
ammonium chloride (TEBA) or tetrabutylammonium
fluoride (TBAF) as a phase-transfer catalyst, and solid
KOBut or KOH (or concentrated aqueous KOH) as a base.
The proposed mechanism, illustrated in Scheme 3,
involves as a first step initial formation of the conjugate base
of phenylacetonitrile by heterogenous deprotonation with
the solid KOH [eqn. (1)].
Table 1 The ring opening of 1,2-epoxycyclohexane by
phenylacetonitrile carbanion in the presence of PTC, promoted
by Li-cation participationa
and the lack of unfavourable nucleophile–solvent inter-
actions.11 It is interesting to note that, in an attempt to
explore the effect of PTC catalysts, we observed the highest
yield of 6 with TBFA as a catalyst and LiClO4 as a metal salt
promoter (76.0%, Table 1, entry 3). This is attributed to the
enhanced nucleophilicty of the organic carbanion,13 as an Fꢀ
ion, which is capable of forming strong hydrogen bonds,
probably assists in proton abstraction via the hydrogen-
bonded complex 14.
The protonation of an alkoxide ion liberates the ion-pair
Qǹ OHꢀ [eqn. (4)]. The favourable ion-exchange equili-
brium forcing the migrations of OHꢀ ions out of the organic
phase regenerates the catalyst11 [eqn. (5)].
Base
(11 mmol)
Li salt
(11 mmol)
PTC
(1 mmol)
Yield
(%)d
Entry
1
2
3
4
5
6
KOHb
LiCl
TEBA
TBFA
TBFA
TEBA
TEBA
TBFA
45.0
51.5
76.0
ꢁ5.0
61.8
74.2
KOH (50% aq.)
LiCl
KOHb
LiClO4
none
LiCl
KOHb
KOBut c
KOBut
LiClO4
aConditions: reaction temp. 60–70 °C.; reaction time 8–10 h;
cyclohexene oxide: 10 mmol. bPulverized KOH. cThe reaction
was carried out under solvent-free conditions, i.e., the organic
phase consisted of neat organic substrates, to ensure as
thorough mixing of the reacting species as possible to eliminate
unfavourable solute-solvent interactions, but the isolation of the
product was rather difficult dYields refer to the amount of the
mixture of diastereoisomer trans-2-hydroxycyclohexyl(phenyl)-
acetic acids 9 and 10.
In conclusion, we have demonstrated that nucleophilic ring
opening of epoxides, assisted by a Lewis-acidic Liǹ cation,
may be successfully used, under PTC conditions, in organic
syntheses.
Experimental
Typical Procedure for Phase-transfer-catalysed Ring Opening of
Cyclohexene Oxide in the Presence of Li salt.sTo a suspension of
TBAF (0.31 g, 1 mmol), pulverised KOH (0.51 g, 11 mmol) and
LiClO4 (1.17 g, 11 mmol) in dry benzene (4 ml) a solution of
phenylacetonitrile (1.17 g, 10 mmol) in benzene (2 ml) was added.
After stirring for 1 h at 60 °C, cyclohexane oxide (0.98 g, 10 mmol)
was added dropwise during 0.5 h, and the reaction mixture was
then well stirred for an additional 8 h, cooled to room temperature
and allowed to stand with stirring for 2 h. Dilution with water,
extraction with benzene (15 ml) and removal of benzene in vacuo
afforded a crude, pale yellow oil, which was without further purifi-
cation saponified by the standard procedure to yield, after acidi-
fication, 1.78 g (76%) the mixture of diastereoisomeric trans-2-
hydroxycyclohexylphenylacetic acids 9 and 10. The crude product
was crystallized from benzene–light petroleum (bp 40–70 °C) to
give colourless crystals: mp 159–161 °C (lit.,2 mp 160 °C; vmax/cmꢀ1
(KBr) 3259 (OH), 3061 (Aryl CH), 1678 (CtO), 768, 698 (mono-
sub. Ar); dH (200 MHz) (CDCl3) 1.06–1.75 (m, 6 H, cyclohexyl H-3;
-4, -5) 1.90 (m, 2 H, cyclohexyl H-6), 2.98 (d, 1 H, J 3.7 Hz,
HCCOH), 3.82 [d, 1 H, J 6.5 Hz, HC(Ph)CO2H], 4.65 (br s, 1 H,
OH), 7.30 (m, 5 Harom), 12.07 (br s, 1 H, CO2H); m/z 234 (3%, Mǹ),
216 (63), 172 (84), 136 (93), 118 (88), 91 (100), 77 (24), 44 (8)
(Found: C, 71.59; H, 7.72. Calc. for C14H18O3: C, 71.8; H, 7.7%).
Extraction of Nuꢀ from the KOH surface as an ion pair
with the lipophilic catalyst cation Qǹ into the organic phase is
the next step [eqn. (2)] (the reaction was slower in larger
quantity of PhH as a solvent). Phenylacetonitrile carbanion,
being a strong nucleophile, opens up the oxirane ring in the
Received, 20th September 1996; Accepted, 25th October 1996
Paper E/6/06498A
Scheme 3
organic phase [eqn. (3)] in a step which deserves some com-
ments. The stereochemistry of the ring opening appears to be
trans-diaxial, as would be expected for a mechanism involving
nucleophilic attack of a carbanion from the periplanar direc-
tion. Secondly, it is facilitated by the prior addition of a Li salt
which coordinates with the oxygen, and by polarizing the
CsO bond as depicted in structure 13, makes the oxirane
ring more prone to the nucleophilic attack.
Electrophilic assistance of this type, based on the coordi-
nating capacity of the metallic cations, has been presumed to
play an important role in many cases.4,10,12 A drastic decrease
in the yield of 6 (to ꢁ5%) with nearly complete recovery of
the starting epoxide, when the reaction is carried out in the
absence of any lithium salt (Table 1, entry 4), illustrates the
importance of Liǹ participation in alkali-carbanion-mediated
epoxide-cleavage reactions. Furthermore, the enhanced
nucleophilicity of PhCHCNꢀ is anticipated under the PTC
conditions, because of the high degree of ionic dissociation
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