Steric effects in the tetracyanoethylene catalysed methanolysis of some cyclohexane epoxides

Article abstract of DOI:10.1016/j.tet.2005.01.030

The presence of a hydroxyl group has been shown to direct the regiochemistry and stereochemistry of the TCNE methanolysis of cyclohexane hydroxy-epoxides. α-Pinene epoxide underwent cleavage to form the 8-methyl ether of trans-sobrerol.

Full text of DOI:10.1016/j.tet.2005.01.030

Tetrahedron 61 (2005) 4323–4327
Steric effects in the tetracyanoethylene catalysed methanolysis of
some cyclohexane epoxides
b
b
b
Cavit Uyanik,a, James R. Hanson, Peter B. Hitchcock and Meredith A. Lazar
*
aDepartment of Chemistry, Kocaeli University, Izmit 41300, Kocaeli, Turkey
bDepartment of Chemistry, University of Sussex, Brighton, Sussex BN1 9QJ, UK
Received 16 August 2004; revised 7 December 2004; accepted 7 January 2005
Available online 18 March 2005
Abstract—The presence of a hydroxyl group has been shown to direct the regiochemistry and stereochemistry of the TCNE methanolysis of
cyclohexane hydroxy-epoxides. a-Pinene epoxide underwent cleavage to form the 8-methyl ether of trans-sobrerol.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Reduction of 1 with sodium borohydride in methanol
followed by epoxidation of the alcohol 4 with m-chloro-
perbenzoic acid, gave cis-1,2-epoxy-1,5,5-trimethylcyclo-
hexan-3-ol 5. The cis relationship of the epoxide and
hydroxyl groups followed from the known6 directing effect
of an allylic hydroxyl group on the epoxidation of an
adjacent alkene.
Tetracyanoethylene (TCNE) is a mild p-acid catalyst which
has proved to be of value in the ring opening of epoxides.1,2
The stereochemistry of the reaction has been examined in
the steroid series where neighbouring group participation by
an adjacent cis hydroxyl group has been observed.3 Thus, a
5b-hydroxyl group has been shown to affect both the
regiochemistry and stereochemistry of the cleavage of an
adjacent 3b,4b-epoxide. Whereas the TCNE catalysed
methanolysis of 17b-acetoxy-3b,4b-epoxy-5b-androstane
gave the diaxial 3b-hydroxy-4a-methyl ether, methanolysis
of 5b-17b-dihydroxy-3b,4b-epoxy-5b-androstane gave the
diequatorial 3a-methoxy-4b,5b,17b-trihydroxy-5b-andros-
tane. In this paper, we describe the results of the TCNE
catalysed methanolysis of some cyclohexane and mono-
terpenoid epoxides.
Methanolysis of cis-1,2-epoxy-1,5,5-trimethylcyclohexan-
3-ol 5, catalysed by TCNE gave a single product, cis-2,3-
dihydroxy-trans-1-methoxy-1,5,5-trimethylcyclohexane 6.
The stereochemistry of the product was unambiguously
established by X-ray crystallography as shown in Figure 1.
The first compounds to be examined were the isomeric cis-
2,3-epoxy-1,5,5-trimethylcyclohexan-1-ol 34 and cis-1,2-
epoxy-1,5,5-trimethylcyclohexan-3-ol 5 in which the
methyl groups provide a conformational ‘lock’.
2. Results and discussion
The epoxides 3 and 5 were prepared from the readily
available isophorone 1. Treatment of isophorone epoxide
with hydrazine hydrate gave 1,5,5-trimethylcyclohex-2-en-
1-ol 2.5 This was epoxidized with m-chloroperbenzoic acid
to afford cis-2,3-epoxy-1,5,5-trimethylcyclohexan-1-ol 3.
Keywords: Cyclohexane;
Stereochemistry.
TCNE;
Methanoloysis;
Epoxide;
* Corresponding author. Tel.: C90 262 3249910; fax: C90 262 3313906;
e-mail: cuyanik@kou.edu.tr
Figure 1. X-ray structure of 6.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.030

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C. Uyanik et al. / Tetrahedron 61 (2005) 4323–4327
Methanolysis of the isomeric cis-2,3-epoxy-1,5,5-trimethyl-
cyclohexan-1-ol 3, catalysed by TCNE, gave cis-1,2-
dihydroxy-trans-3-methoxy-1,5,5-trimethylcyclohexane 7.
In the H NMR spectrum, the H-2 resonance (dH 3.19)
1
was a doublet (JZ9.2 Hz) whilst the H-3 resonance (dH
3.46) was a triplet (JZ9.2 Hz) of doublets (JZ4.1 Hz)
consistent with a diaxial relationship between H-2 and H-3.
The regiochemistry of the hydroxyl and methoxyl groups
was established by X-ray crystallography as shown in
Figure 2.
Whereas the methanolysis of the epoxide 5 proceeded in a
diaxial sense to give 6, that of epoxide 3 led to an eventual
diequatorial relationship between the hydroxyl and
methoxyl groups 7. In both cases, the hydroxyl group
arising from the epoxide is adjacent to the original hydroxyl
group. The overall diequatorial opening of cis-2,3-epoxy-
1,5,5-trimethylcyclohexan-1-ol 3 may arise via a diaxial
opening and conformational inversion of the ring to
maximize the number of equatorial substituents. This
contrasts with the formation of the diaxial 1,2-diol 9
which is obtained7 from 1,5,5-trimethylcyclohex-2-ene 8 on
treatment with hydrogen peroxide and formic acid, a
reaction which proceeds through the 1,2-epoxide. Hence
the hydroxyl group of a hydroxy-epoxide has determined
the regio- and stereochemistry of the methanolysis of the
epoxide catalysed by TCNE.
Figure 2. X-ray structure of 7.
The participation of the 8-hydroxyl group of 1,2-epoxy-8-
hydroxy-p-menthane in the acid catalysed hydrolysis of the
1,2-epoxide leading to the formation of 2-hydroxy-1,8-
cineole has been described previously.8 We have examined
the TCNE catalysed methanolysis of the mixed epoxides 10
of a -terpineol in the light of this transannular participation
of a hydroxyl group. Three major products were separated
1
by chromatography. The first was identified from its H
NMR spectrum as trans-2-hydroxy-1,8-cineole 11.8 The
second product, 12, contained a methoxyl group (dH 3.29)
and a further ether CHOR signal (dH 3.05) together with
three C-methyl group resonances (dH 1.14, 1.15 and 1.20).
The CHOR resonance was a narrow signal (w/2 c.4 Hz).
The stereochemistry of the compound was assigned on the
basis of this signal9 and from the nuclear Overhauser effect
enhancements arising from irradiation of the methyl group
signals at dH 1.14/1.15, 1.22 and 3.29. The assignments and
NOE. enhancements are summarized in Figure 4. The
structure of the third compound, 13, which was crystalline,
Figure 3. X-ray structure of 13.
Figure 4.

C. Uyanik et al. / Tetrahedron 61 (2005) 4323–4327
4325
Scheme 1.
3.17 (3H, s, OMe), 3.61(1H, br s, CHOH), 3.99 (1H, br s,
]CH)] (Schemes 1–3).
3. Conclusion
We have shown that the regiochemistry and stereochemistry
of the TCNE catalyzed methanolysis of some cyclohexane
epoxides have been directed by the presence of a hydroxyl
group. We have established the stereochemistry of the
products by X-ray crystallography. The structures of these
products indicate that when TCNE is used as a mild p-acid
catalyst for the cleavage of hydroxy-epoxides, the hydroxyl
group can participate in the reaction.
4. Experimental
4.1. General
Scheme 2. Reagents and conditions: (a) TCNE, MeOH, rt, 12 h.
Light petroleum refers to the fraction bp 60–80 8C. Silica for
chromatography was Merck 9385. Extracts were dried over
anhydrous sodium sulfate. IR spectra were determined as
nujol mulls. 1H NMR spectra were determined for solutions
in deuteriochloroform at 300 MHz. High-resolution mass
spectra were obtained on a Bruker Daltonics Apex III mass
spectrometer operating in the electrospray mode.
Scheme 3. Reagents and conditions: (a) TCNE, MeOH, rt, 2 h.
was established by X-ray crystallography as shown in
Figure 3. The isolation of these compounds can be
rationalized in terms of the diaxial opening of the epimeric
terpineol epoxides but with rather less participation of the
8-hydroxyl group in 1,8-cineole formation than is the case in
simple acid-catalysed hydrolysis.8
4.1.1. cis-1,2-Epoxy-1,5,5-trimethycyclohexan-3-ol (5). A
suspension of m-chloroperbenzoic acid (4 g, 23.2 mmol) in
chloroform (20 cm3) was added over 15 min to the alcohol 4
(1.5 g, 10.7 mmol) (prepared by the reduction of isophorone
1 with sodium borohydride in methanol) in chloroform
(20 cm3). The mixture was left at room temperature
overnight and then diluted with chloroform (50 cm3). The
solution was stirred with aqueous acidic iron (II) sulfate
(100 cm3) twice and then the chloroform layer was washed
thoroughly with aqueous sodium hydrogen carbonate, water
Treatment of a-pinene oxide 14 with TCNE in methanol
gave one major product. This compound, 15, had the H
1
NMR characteristics of the 8-monomethyl ether of trans-
sobrerol [dH 1.09 (6H, s, 2!Me), 1.76 (3H, br s, ]C.Me),

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C. Uyanik et al. / Tetrahedron 61 (2005) 4323–4327
and dried. The solvent was evaporated to give a residue
which was distilled at 70–80 8C (12 mm Hg) to give cis-1,2-
epoxy-1,5,5-trimethycyclohexan-3-ol 5 (1.03 g, 61%) as a
colourless oil; nmax (Nujol) 3421 cmK1; dH (300 MHz,
CDCl3) 3.91 (1H, m, 3-H), 3.10 (1H, d, JZ3.5 Hz, 2-H),
1.83–1.65 (4H, m, 2!CH2), 1.30 (3H, s, 1-Me), 1.11 and
0.80 (each 3H, s, 5-Me2); dC (75.4 MHz, CDCl3) 78.4, 61.7,
58.6, 46.8, 44.9, 29.9, 28.2, 27.5, 26.3; HRMS: MC, found
156.1158. C9H16O2 requires 156.1150.
br. s), 2.52–1.20 (7H, overlapping multiplets), 1.25 (3H, s,
Me), 1.17 (3H, s, Me), 1.08 (3H, s, Me).8
Further elution gave 1b,8-dihydroxy-2a-methoxy-p-
menthane 12 (228 mg, 21%) as a colourless oil; nmax
(Nujol) 3398 (br) cmK1; dH (300 MHz, CDCl3) 3.05 (1H, br.
s, w/2 4 Hz), 3.29 (3H, s, OMe), 1.94–1.09 (8H, overlapping
multiplets), 1.20 (3H, s, Me), 1.15 (3H, s, Me), 1.14 (3H, s,
Me); HRMS: MC, found 225.1461. C11H22O3Na requires
225.1457.
4.1.2. cis-2,3-Epoxy-1,5,5-trimethylcyclohexan-1-ol (3).
Under similar conditions 1,5,5-trimethylcyclohex-2-en-1-ol
2 (1.53 g, 10.9 mmol) (prepared by the reaction of
isophorone epoxide with hydrazine hydrate), gave cis-2,3-
epoxy-1,5,5-trimethylcyclohexan-1-ol 3 (1.13 g, 66%) as a
colourless oil; nmax (Nujol) 3443 cmK1; dH (300 MHz,
CDCl3) 3.33 (1H, q, JZ3.5 Hz, 3-H), 2.98 (1H, d, JZ
3.5 Hz, 2-H), 1.75–1.60 (4H, m, 2!CH2), 1.31 (3H, s,
1-Me), 1.14 and 0.83 (each 3H, s, 5-Me2); dC (75.4 MHz,
CDCl3) 72.7, 59.5, 57.6, 47.6, 41.4, 33.8, 30.6, 28.1, 27.4;
HRMS: MC, found 156.1158. C9H16O2 requires 156.1150.
Further elution gave 2a,8-dihydroxy-1b-methoxy-p-
menthane 13 (262 mg, 24%) as needles; mp 65–68 8C;
nmax (Nujol) 3367, 3335 (br) cmK1; dH (300 MHz, CDCl3)
3.44 (1H, s), 2.84 (3H, s, OMe), 2.20–0.74 (8H, overlapping
multiplets), 1.29 (3H, s, Me), 0.97 (3H, s, Me), 0.95 (3H, s,
Me); HRMS: MC, found 225.1460. C11H22O3Na requires
225.1456.
4.1.6. Reaction of 14. a-Pinene oxide 14 (500 mg,
3.24 mmol) in methanol (30 cm3) was treated with TCNE
(50 mg, 0.39 mmol) at room temperature for 2 h. The
solvent was evaporated in vacuo and the residue was
chromatographed on silica. Elution with 10% ethyl acetate/
light petroleum gave 8-methoxy-p-menth-6-en-2a-ol 15
(trans-sobrerol 8-methyl ether) (192 mg, 32%) as a colour-
less oil; nmax (Nujol) 3413, 1643 cmK1; dH (300 MHz,
CDCl3) 3.99 (1H, br.s), 3.61 (1H, s), 3.17 (3H, s, OMe),
2.05–1.50 (5H, overlapping multiplets), 1.76 (3H, s, Me),
1.09 (6H, s, Me2); HRMS: MC, found 391.2810.
(C11H20O2)2Na requires 391.2810.
4.1.3. cis-1,2-Dihydroxy-trans-3-methoxy-1,5,5-tri-
methylcyclohexane (7). cis-2,3-Epoxy-1,5,5-trimethyl-
cyclohexan-1-ol 3 (1.0 g, 6.4 mmol) in dry methanol
(20 cm3) was treated with tetracyanoethylene (200 mg,
1.5 mmol) at room temperature for 3 h. The solvent was
evaporated and the residue was chromatographed on silica.
Elution with 30% ethyl acetate: light petroleum gave cis-
1,2-dihydroxy-trans-3-methoxy-1,5,5-trimethylcyclo-
hexane 7 (600 mg, 50%) which was crystallized from ethyl
acetate as needles; mp 78–79 8C; (Found: C, 63.8; H, 10.7.
C10H20O3 requires C, 63.8; H, 10.7%); nmax (Nujol) 3453,
3350 cmK1; dH (300 MHz, CDCl3) 3.46 (1H, td, JZ9.2,
4.1 Hz, 3-H), 3.40 (3H, s, 3-OMe), 3.19 (1H, d, JZ9.2 Hz,
2-H), 1.85–1.64 (4H, m, 2!CH2), 1.25 (3H, s, 1-Me), 1.15
and 0.94 (each 3H, s, 5-Me2); dC (75.4 MHz, CDCl3) 78.9,
78.8, 72.7, 56.4, 48.3, 41.3, 33.9, 31.4, 28.8, 27.2.
4.2. X-ray analysis
4.2.1. cis-2,3-Dihydroxy-trans-1-methoxy-1,5,5-tri-
methylcyclohexane (6). C10H20O3, Mr 188.26, monoclinic,
˚
˚
P21/n (no. 14), aZ13.0204(6) A, bZ6.19.54(3) A,
˚
cZ26.6900(11) A, aZgZ908, bZ92.167(3)8, VZ
2151.45(17) A , ZZ8, DcalZ1.16 g cmK3, mZ0.08 mmK1
,
3
˚
4.1.4. cis-2,3-Dihydroxy-trans-1-methoxy-1,5,5-tri-
methylcyclohexane (6). Under similar conditions cis-1,2-
F(OOO)Z832. Data were collected on a crystal of size
0.30!0.05!0.02 mm3 on a KappaCCD diffractometer
operating for 4.54!q!25.58. Reflections of 21,352 were
collected for K15%h%15, K7%k%7, K31%l%31.
There were 3794 independent reflections with 2489
possessing IO2s(I). The structure was refined using
SHELXL-97 by full matrix least-squares on F2. The
goodness-of-fit on F2 was 1.027. The final R indices were
[IO2s(I)] R1Z0.06, wR2Z0.137 and the R indices (all
data) were R1Z0.101 and wR2Z0.156. The largest
epoxy-1,5,5-trimethylcyclohexan-3-ol
5
(900 mg,
5.7 mmol) gave, after chromatography on silica and elution
with 30% ethyl acetate: light petroleum, cis-2,3-dihydroxy-
trans-1-methoxy-1,5,5-trimethylcyclohexane 6 (540 mg,
49%) which was crystallized from ethyl acetate as needles,
mp 65–68 8C, nmax (Nujol) 3355 (br) cmK1; dH (300 MHz,
CDCl3) 4.17 (1H, dt, JZ9.2, 3.5 Hz, 3-H), 3.58 (1H, d, JZ
3.5 Hz, 2-H), 3.17 (3H, s, 1-OMe), 1.89–1.61 (4H, m, 2!
CH2), 1.22 (3H, s, 1-Me), 1.04 and 0.93 (each 3H, s, 5-Me2);
dC (75.4 MHz, CDCl3) 78.8, 78.6, 73.5, 51.4, 47.6, 44.2,
31.3, 30.9, 28.6, 27.2; HRMS: MC, found 188.1410.
C10H20O3 requires 188.1412.
K3
˚
difference peak and hole were 0.22 and K0.25 e A
.
4.2.2. cis-1,2-Dihydroxy-trans-3-methoxy-1,5,5-tri-
methylcyclohexane (7). C10H20O3, Mr 188.26, triclinic,
˚
˚
¯
PI (no. 2), aZ6.0870 (4) A, bZ8.2022(5) A, cZ
˚
4.1.5. Reaction of menthanes. The mixed 1,2-epoxy-8-
hydroxy-p-menthanes (50:50) (900 mg, 5.3 mmol) in
methanol (50 cm3) containing TCNE (100 mg, 0.78 mmol)
was left at room temperature overnight. The solvent was
evaporated in vacuo and the residue was chromatographed
on silica. Elution with a gradient of increasing amounts of
ethyl acetate in light petroleum gave trans-2-hydroxy-1,8-
cineole 11 (105 mg, 12%) as a colourless oil; nmax(Nujol)
3450 cmK1; dH (300 MHz, CDCl3) 3.72 (1H, m), 3,63 (1H,
10.9679(6) A, aZ93.845(4)8, bZ93.766(4)8, gZ
96.477(4)8, VZ541.39(6) A , ZZ2, DcalZ1.16 g cmK3
,
3
˚
mZ0.08 mmK1, F(OOO)Z208. Data were collected on a
crystal of size 0.2!0.1!0.1 mm3 on a KappaCCD
diffractometer operating for 4.64!q!25.088. 4993
Reflections were collected for K7%h%5, K9%k%9,
K13%l%13. There were 1900 independent reflections
with 1574 possessing IO2s(I). The structure was refined
using SHELXL-97 by full matrix least-squares on F2. The

C. Uyanik et al. / Tetrahedron 61 (2005) 4323–4327
4327
goodness-of-fit on F2 was 1.088. The final R indices were
[IO2s(I)] R1Z0.04, wR2Z0.098 and the R indices (all
data) were R1Z0.051 and wR2Z0.105. The largest
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 247473, 247474, 247475.
Copies of the data can be obtained free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK (fax: C44-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk).
K3
˚
difference peak and hole were 0.19 and K0.21 e A
.
4.2.3. 2a,8-Dihydroxy-1b-methoxy-p-menthane (13).
C11H22O3, Mr 202.29, orthorhombic, space group Pbca
˚
˚
(no. 61), aZ8.0065(2) A, bZ14.5231(4) A, cZ
3
˚
˚
19.9634(7) A, aZbZgZ908, VZ2321.33(12) A , ZZ8,
DcalZ1.16 mg cmK3, mZ0.08 mmK1, F(OOO)Z896. Data
were collected on a crystal of size 0.50!0.20!0.10 mm3
on a KappaCCD diffractometer operating for 3.92!q!
25.38. Reflections of 10,732 were collected for K9%h%19,
K15%k%14, K17%l%21. There were 1878 independent
reflections with 1556 possessing IO2s(I). The structure was
refined using SHELXL-97 by full matrix least-squares on
F2. The goodness-of-fit on F2 was 1.068. The final R indices
were [IO2s(I)] R1Z0.060, wR2Z0.151 and the R indices
(all data) were R1Z0.073 and wR2Z0.161. The largest
References and notes
1. Masaki, Y.; Miura, T.; Ochiai, M. Synlett 1993, 847.
2. Hanson, J. R.; Macias-Sanchez, A. J.; Uyanik, C. J. Chem. Res.
(S) 2001, 121. Hanson, J. R.; Macias-Sanchez, A. J.; Uyanik, C.
J. Chem. Res. (M) 2001, 401.
3. Hanson, J. R.; Hitchcock, P. B.; Uyanik, C. J. Chem. Res. (S)
1998, 330. Hanson, J. R.; Hitchcock, P. B.; Uyanik, C. J. Chem.
Res. (M) 1998, 1366.
K3
˚
difference peak and hole were 0.37 and K0.26 e A
.
4. Magnusson, G.; Thoren, S. J. Org. Chem. 1973, 38, 1380.
5. Arnaud, C. J. Chem. Educ. 1974, 51, 819.
6. Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958.
7. Klein, J.; Dunkelblum, E. Tetrahedron 1968, 24, 5701.
8. Carman, R. M.; Fletcher, M. T. Aust. J. Chem. 1984, 37, 1117.
9. Carman, R. M.; Fletcher, M. T. Aust. J. Chem. 1984, 37, 2129.
5. Crystallographic data
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the