Isopulegol as a model compound: Metalation and substitution of an allylic position in the presence of an unprotected hydroxy function

Article abstract of DOI:10.1002/(SICI)1099-0690(199902)1999:2<459::AID-EJOC459>3.0.CO;2-F

When treated with butyllithium and potassium tert-butoxide for 2 h at 0 °C in hexanes, the unsaturated monoterpenic alcohol isopulegol is simultaneously deprotonated at the hydroxy function and the allylic methyl group. The metaloxy allylmetal species thu

Full text of DOI:10.1002/(SICI)1099-0690(199902)1999:2<459::AID-EJOC459>3.0.CO;2-F

FULL PAPER
Isopulegol as a Model Compound: Metalation and Substitution of an Allylic
Position in the Presence of an Unprotected Hydroxy Function
Manfred Schlosser*[a] and Martina Kotthaus[a]
Keywords: Electrophilic substitution / Metalations / Monoterpene / Protective groups / Superbase
When treated with butyllithium and potassium tert-butoxide
for 2 h at 0 °C in hexanes, the unsaturated monoterpenic
alcohol isopulegol is simultaneously deprotonated at the
hydroxy function and the allylic methyl group. The metaloxy
allylmetal species thus generated can be silylated, alkylated,
carboxylated and oxidized to afford the expected products in
good to excellent yields. Thus, a specific protection of
hydroxy groups is not required, alcohols being instanta-
neously converted by superbases into alcoholates.
The levorotatory enantiomer of isopulegol [(1R,2S,5R)-
2-isopropenyl-5-methylcyclohexanol] is a relatively inexpen-
sive chiral building block. Simple and efficacious structural
elaboration should be possible by proton abstraction from
the allylic methyl group and subsequent reaction with an
electrophile. We wanted to establish the feasibility of such
a sequence in order to demonstrate the superiority of su-
perbasic mixed-metal reagents[1Ϫ4] in the critical hydrogen/
metal exchange (“metalation”) step. Several examples of
successful metalation of hydroxy-(or, more correctly, metal-
oxy-)substituted alkenes with butyllithium in the presence
of potassium tert-butoxide have been reported.[1,4Ϫ8] In
contrast, tetramethylethylenediamine-(TMEDA-)activated
butyllithium, which was found suitable for the metalation
of hydrocarbon-type monoterpenes,[9,10] performs poorly at
best with functionalized substrates.
Smooth metalation took indeed place when isopulegol
was treated with butyllithium (2.0 equiv.) and potassium
tert-butoxide (1.0 equiv.) for 2 h in hexanes at 0°C. Sub-
sequent addition of methyl iodide to the suspension af-
forded the trapping product, 5-methyl-2-(1-methylenepro-
pyl)cyclohexanol (1) in 84% yield.
Scheme 1. Hydrogen/metal exchange at the allylic methyl group
of lithium(potassium) isopulegolate and subsequent trapping with
methyl iodide
When the slurry containing the metalated isopulegol de-
rivative was poured on dry ice, the β,γ-unsaturated lactone
2 was obtained (43%). In basic medium it underwent iso-
merization to the conjugated enelactone 3 (93%). Intercep-
tion with excess chlorotrimethylsilane gave the trimethyl-
Scheme 2. (a) LiC4H9 (2.0 equiv., 1  in hexane) ϩ KOC(CH3)3
(1.0 equiv.) 2 h, 0°C; (b) crushed dry-ice (excess), then pH ϭ 3; (c)
KOC(CH3)3 (catalytic amount) in tetrahydrofuran; (d) ClSi(CH3)3
(5.0 equiv.); (e) H5C6ϪIϭO (2 equiv.) ϩ BF3·Et2O (1.0 equiv.); (f)
CrO3 ϩ pyridine; (g) FB(OCH3)2 (1.5 equiv.), then H2O2 ϩ aq.
NaOH; (h) MnO2 (11 equiv.) in CH2Cl2; (i) Ag2CO3 on kieselguhr
(j) BrCH2CHϭC(CH3)2 (1.5 equiv.); (k) ClSi(C2H5)3 ϩ pyridine,
next LiC4H9 ϩ KOC(CH3)3, then FB(OCH3)2 ϩ H2O2, finally
(H9C4)4NϩFϪ·(H2O)3.
[a]
´
Institut de Chimie organique de lЈUniversite, Section de Chimie
(BCh),
CH-1015 Lausanne, Switzerland
Eur. J. Org. Chem. 1999, 459Ϫ462
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0202Ϫ0459 $ 17.50ϩ.50/0
459

M. Schlosser, M. Kotthaus
FULL PAPER
J ϭ 6.5 Hz, 5 H). Ϫ 13C NMR: δ ϭ 152.5, 109.1, 71.0, 53.5, 42.6,
34.4, 31.3, 30.5, 26.2, 22.1, 12.1. Ϫ MS; m/z (%): 168 (2) [Mϩ], 121
(46), 81 (100). Ϫ C11H20O (168.28): calcd. C 78.51, H 11.98; found
C 78.83, H 12.02. Ϫ Another reaction was performed under iden-
tical conditions, except that potassium tert-butoxide was replaced
by N,N,NЈ,NЈ-tetramethylethylenediamine. The yield of 1 dropped
to 3%.
silyloxy-substituted silane 4 (67%), which was hydrolyzed to
the hydroxylated silane 5 (66%). When either product (4 or
5) was allowed to react with iodosobenzene, the tetrahydro-
furan 6 was formed (80%) which could be further oxidized
with chromium trioxide to give the methylenelactone 7[11]
(60%). The latter compound is also accessible through the
diol 8 (82%), prepared by consecutive treatment of the or-
ganometallic intermediate with fluorodimethoxyborane and
hydrogen peroxide. The aldehyde 9,[12] prepared (43%) by
dehydrogenation of the diol 8 with manganese dioxide, can
be converted via the lactol isomer 10 into the lactone 7
(64%) by oxidation with silver carbonate.[12,13]
Condensation of the allylpotassium species with prenyl
bromide (3-methyl-2-butenyl bromide) afforded the dienol
11 (71%) which, after protection of the hydroxy by the tri-
ethylsilyloxy group, was metalated and subsequently trans-
formed into the dienediol 12 (35% overall) by applying
again the bornylation/oxidation sequence. The last two re-
actions may be jokingly qualified as “anticipating natural
product synthesis”. Although neither the alcohol 11 nor the
diol 12 have been described so far, they may well be found
one day as naturally occurring sesquiterpenes.
(7R,9R,10S)-7-Methyl-4-methylene-3,4,4a,5,6,7,8,8a-2H-1-benzo-
pyran-2-one (2): The isopulegol-derived organometallic reaction
mixture was poured on an excess of freshly crushed dry ice. At
25°C, a 1  solution of hydrogen chloride (20 mmol) in diethyl
ether (20 mL) was added. The mixture was stirred for 15 min and
filtered. When hexanes (10 mL) were added to the concentrated
filtrate (5Ϫ10 mL), crystallization set in. The product (2) was iso-
lated as colorless platelets; m.p. 68Ϫ69°C; [α]2D0 ϭ Ϫ7.4 (C2H5OH;
c ϭ 1.0); yield 0.78 g (43%). Ϫ IR (KBr): ν˜ ϭ 1735 (s, ν[CϭO])
1
1650 (m, ν[CϭC]). Ϫ H NMR: δ ϭ 4.90 (d, J ϭ 16.1, 2 H), 3.92
(dt, J ϭ 10.5, 4.4 Hz, 1 H), 3.39 (d, J ϭ 18.8 Hz, 1 H), 3.30 (d,
J ϭ 18.8 Hz, 1 H), 2.1 (m, 3 H), 1.77 (symm. m, 1 H), 1.50 (symm.
m, 1 H), 1.2 (m, 2 H), 1.0 (dm, J ϭ 6.6 Hz, 4 H). Ϫ 13C NMR:
δ ϭ 170.3, 140.2, 109.2, 80.8, 43.0, 40.1, 38.8, 33.2, 30.6, 27.0, 21.6.
Ϫ MS (CI); m/z (%): 198 (100) [Mϩ ϩ NH4], 181 (91) [Mϩ ϩ 1],
180 (14) [Mϩ], 121 (17). Ϫ C11H16O2 (180.25): calcd. C 73.30, H
8.95; found C 73.16, H 8.90.
In conclusion, allylmetal species (presumably[14] contain-
ing potassium as the major, lithium as the minor π-
bound[15,16] metal component) can be generated by depro-
tonation of olefins with superbasic reagents (such as the
LIC-KOR mixture) with extreme ease, even when unprotec-
ted hydroxy groups, are present. A variety of chain-length-
(7R,9R,10S)-4,7-Dimethyl-4a,5,6,7,8,8a-2H-1-benzopyran-2-one
(3): Lactone 2 (0.90 g, 5.0 mmol) was dissolved in tetrahydrofuran
(10 mL) which contained a small amount of potassium tert-butox-
ide (approx. 0.1 g, 1 mmol). After 6 h at 25°C, a 1  solution
of hydrogen chloride (5 mmol) in diethyl ether was added. Upon
distillation a colorless liquid was collected which eventually solidi-
ened or functionalized derivatives can be prepared by sim- fied; b.p. 96Ϫ98°C/5 Torr; m.p. 41Ϫ42°C; [α]2D0 ϭ Ϫ88.2 (C2H5OH,
c ϭ 1.0); yield 0.84 g (93%). Ϫ IR (KBr): ν˜ ϭ 1735 (s, γ[CϭO]. Ϫ
1H NMR: δ ϭ 5.78 (symm. m, 1 H), 3.97 (dt, J ϭ 11.3, 4.0 Hz, 1
H), 2.1 (m, 3 H), 1.90 (t, J ϭ 1.6 Hz, 3 H), 1.78 (symm. m, 1 H),
1.54 (symm. m, 1 H), 1.29 (q, J ϭ 11.8 Hz, 1 H), 1.12 (dq, J ϭ
12.8, 3.3 Hz, 1 H), 1.0 (dm, J ϭ 6.5 Hz, 4 H). Ϫ 13C NMR: δ ϭ
165.0, 160.9, 116.8, 80.4, 41.7, 39.4, 33.8, 30.8, 25.8, 21.6, 19.4. Ϫ
MS; m/z (%): 181 (99) [Mϩ ϩ 1], 180 (46) [Mϩ], 95 (100). Ϫ
C11H16O2 (180.25): calcd. C 73.30, H 8.95; found C 73.06, H 8.78.
Ϫ Lactone 3 was obtained directly (although only in 33% yield)
when gaseous carbon dioxide was bubbled into the stirred reaction
mixture prepared by metalation of (Ϫ)-isopulegol or when a 1 
solution of hydrogen chloride (35 mmol) in diethyl ether was added
to the mixture after the latter had been poured on freshly crushed
ice and the product was immediately isolated by distillation.
ple electrophilic manipulation.
Experimental Section
General: 1H-, 13C- and 19F-NMR spectra were recorded of samples
dissolved in deuteriochloroform at 400, 101 and 376 MHz, respec-
tively. Chemical shifts (δ) are given relative to the signals of tetra-
methylsilane, used as an internal standard. For working routine and
abbreviations, see recent articles from this laboratory.[17,18] The key
starting material (Ϫ)-isopulegol was purchased from Fluka. De-
spite a discrepancy in optical rotation numbers {[α]2D0 ϭ Ϫ20.0,
[α]54620 ϭ Ϫ23.6 (ref.[19]: [α]54620 ϭ Ϫ25.9; all neat)}, the compound
was found to be enantiomerically pure (> 98% e.e.) by 19F-NMR
spectroscopy of the Mosher ester and gas chromatography on a
chiral capillary column (30 m, CyclodexϪB, 35Ǟ80°C applying a
heating rate of 1°C/min).
(1R,2S,5R)-5-M ethyl-2-[1-methylene-2-(trimethylsilyl)ethyl]-
cyclohexyloxy]trimethylsilane (4): The organometallic reaction mix-
ture, obtained as described above (see preparation of the homolog
1), was treated with chlorotrimethylsilane (3.8 mL, 3.3 g, 30 mmol).
After 1 h of vigorous stirring at 25°C, the product (4) was absorbed
on silica gel (10 mL) and eluted with hexanes from a column filled
(1R,2S,5R)-5-Methyl-2-(1-methylenepropyl)cyclohexanol (1): (Ϫ)-
Isopulegol (1.7 mL, 1.5 g, 10 mmol) and potassium tert-butoxide
(1.1 g, 10 mmol) were added to a solution of butyllithium (20
mmol) in hexanes (20 mL). The suspension was kept at 0°C and
vigorously stirred for 2 h. After methyl iodide (0.62 mL, 1.4 g, 10
mmol) had been added, stirring was continued for 1 h at 0°C. The
mixture was poured into water (50 mL) and extracted with diethyl
ether (3 ϫ 20 mL). The combined organic layers were washed with
water (20 mL) and brine (20 mL), dried and evaporated. Upon
distillation of the residue, the product (1) was collected as a color-
20
with more silica gel (0.1 L); nD ϭ 1.4556, yield 2.0 g (67%). Ϫ
1H NMR: δ ϭ 4.61 (d, J ϭ 4.8 Hz, 2 H), 3.46 (ddd, J ϭ 10.5, 9.2,
4.5 Hz, 1 H), 1.84 (symm. m, 1 H), 1.6 (m, 5 H), 1.46 (symm. m,
1 H), 1.25 (qd, J ϭ 13.4, 3.4 Hz, 1 H), 1.04 (dt, J ϭ 12.0, 10.8 Hz,
1 H), 0.9 (dm, J ϭ 6.7 Hz, 4 H), 0.08 (s, 9 H), 0.02 (s, 9 H). Ϫ 13C
NMR: δ ϭ 151.3, 105.7, 76.5, 52.5, 45.6, 34.7, 31.7, 31.3, 29.6,
22.2, 0.4 (3 C), Ϫ1.3 (3 C). Ϫ C16H34OSi2 (298.62): calcd. C 64.36,
H 11.48; found C 64.44, H 11.13.
20
less oil; b.p. 98Ϫ100°C/12 Torr; nD ϭ 1.4236; [α]2D0 ϭ Ϫ43.5
(C2H5OH, c ϭ 1.0), yield 1.4 g (84%). Ϫ H NMR: δ ϭ 4.85 (s, 2
1
H), 3.47 (dt, J ϭ 10.4, 4.2 Hz, 1 H), 2.0 (m, 3 H), 1.82 (ddd, J ϭ (1R,2S,5R)-5-Methyl-2-[1-methylene-2-(trimethylsilyl)ethyl]-1-
12.5, 9.6, 3.4 Hz, 1 H), 1.6 (m, 2 H), 1.45 (symm. m, 1 H), 1.23
(dq, J ϭ 12.4, 3.5 Hz, 1 H), 1.03 (t, J ϭ 7.4 Hz, 3 H), 0.9 (dm,
cyclohexanol (5): Silane 4 (1.5 g, 5.0 mmol) was dissolved in a 1:3
(v/v) mixture (20 mL) of 2  hydrochloric acid and tetrahydrofu-
460
Eur. J. Org. Chem. 1999, 459Ϫ462

Metalation and Substitution of an Allylic Position in the Presence of an Unprotected Hydroxy Function
FULL PAPER
ran. After waiting 30 min at 25°C, the solution was absorbed on
silica gel (10 mL) while being concentrated in a rotatory evaporator.
Elution with a 1:1 (v/v) mixture of diethyl ether and hexanes from
a column filled with more silica gel (50 mL) gave the product (5)
as a colorless oil; nD20 ϭ 1.3564; [α]D20 ϭ Ϫ61.2 (C2H5OH; c ϭ 1.0);
hexanes as the eluent. The aldehyde 9 was obtained as a colorless
20
oil; nD ϭ 1.439; [α]D20 ϭ Ϫ35.3 (acetone, c ϭ 1.5) (ref.[25]
:
[α]2D0 ϭ Ϫ37, chloroform, c ϭ 4.6); yield 0.29 g (43%). Ϫ 1H NMR:
δ ϭ 9.58 (s, 1 H), 6.36 (s, 1 H), 6,12 (s, 1 H), 3.55 (dt, J ϭ 10.4,
4.3 Hz, 1 H), 2.44 (ddd, J ϭ 13.1, 7.0, 3.4 Hz, 1 H), 2.04 (symm.
m, 1 H), 1.7 (m, 3 H), 1.54 (symm. m, 1 H), 1.36 (dq, J ϭ 13.1,
3.4 Hz, 1 H), 1.04 (symm. m, 1 H), 0.96 (dm, J ϭ 6.5 Hz, 4 H). Ϫ
C10H16O2 (168.23): calcd. C 71.39, H 9.59; found C 71.08, H 9.87.
1
yield 0.75 g (66%). Ϫ H NMR: δ ϭ 4.77 (d, J ϭ 11.8 Hz, 2 H),
3.54 (dt, J ϭ 10.2, 4.0 Hz, 1 H), 2.0 (m, 2 H), 1.7 (m, 4 H), 1.5 (m,
3 H), 1.17 (dq, J ϭ 12.8, 3.1 Hz, 1 H), 0.9 (dm, J ϭ 6.4 Hz, 4 H),
0.05 (s, 9 H). Ϫ 13C NMR: δ ϭ 149.3, 107.7, 73.1, 55.4, 42.4, 34.6,
31.4, 30.7, 25.8, 22.2, Ϫ0.5 (3 C). Ϫ MS (CI): 227 (9) [Mϩ ϩ 1],
211 (12), 121 (49), 73 (100). Ϫ C13H26OSi (226.43): calcd. C 68.96,
H 11.57; found C 69.13, H 11.59.
(1R,2S,5R)-5-Methyl-2-(5-methyl-1-methylene-4-hexenyl)cyclo-
hexanol (11): 3-Methyl-2-butenyl bromide (prenyl bromide; 1.5 g,
10 mmol) were added to the suspension resulting from the metal-
ation of (Ϫ)-isopulegol (10 mmol). After 15 min of stirring at 25°C,
dienol 11 was isolated by distillation as a colorless oil; b.p. 137Ϫ139
(6R,8R,9S)-6-Methyl-3-methylene-2,3,3a,4,5,6,7,7a-octahydroben-
zofuran (6): This product was prepared by oxidation of silane 5 (1.3
g, 4.4 mmol), dissolved in 1,4-dioxane (2.0 mL), with iodosoben-
zene[20] (2.0 g, 8.8 mmol) in the presence of boron trifluorideϪdie-
thyl ether (0.60 mL, 0.53 g, 4.4 mmol), as described,[21] and isolated
by column chromatography on silica gel using hexanes as the elu-
20
g/5 Torr; nD ϭ 1.3301; [α]2D0 ϭ Ϫ38.4 (C2H5OH; c ϭ 1.0); yield
1
1.6 g (71%). Ϫ H NMR: δ ϭ 5.11 (symm. m, 1 H), 4.92 (s, 2 H),
3.51 (dt, J ϭ 10.6, 4.2 Hz, 1 H), 2.1 (m, 2 H), 2.0 (m, 3 H), 1.91
(s, 1 H), 1.85 (ddd, J ϭ 13.2, 10.0, 3.4 Hz, 1 H), 1.7 (m, 1 H), 1.68
(s, 3 H), 1.6 (m, 1 H), 1.61 (s, 3 H), 1.49 (m, 1 H), 1.27 (dq, J ϭ
13.2, 3.5 Hz, 1 H), 0.95 (dm, J ϭ 6.6 Hz, 6 H). Ϫ 13C NMR: δ ϭ
150.7, 131.9, 123.9, 110.6, 71.1, 53.5, 42.5, 34.5, 33.6, 31.4, 30.6,
26.4, 25.6, 22.2, 17.7. Ϫ MS; m/z (%): 240 (43) [Mϩ ϩ NH4], 223
(10) [Mϩ ϩ 1], 109 (29), 81 (100). Ϫ C15H26O (222.37): calcd. C
81.02, H 11.78; found C 80.83, H 11.67.
20
1
ent; nD ϭ 1.3924, yield 0.54 g (80%). Ϫ H NMR: δ ϭ 4.84 (q,
J ϭ 2.6 Hz, 1 H), 4.80 (q, J ϭ 2.6 Hz, 1 H), 4.50 (symm. m, 1 H),
4.27 (dq, J ϭ 13.4, 2.4 Hz, 1 H), 3.12 (td, J ϭ 10.8, 3.9 Hz, 1 H),
2.21 (ddt, J ϭ 11.5, 3.8, 1.3 Hz, 1 H), 2.12 (q, J ϭ 12.9, 5.1 Hz, 1
H), 1.84 (symm. m, 1 H), 1.75 (symm. m, 1 H), 1.50 (symm. m, 1
H), 1.2 (m, 2 H), 1.0 (dm, J ϭ 6.8 Hz, 4 H). Ϫ C10H16O (152.24):
calcd. C 78.90, H 10.59; found C 78.93, H 10.54.
(Z)-6-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-2-methyl-2,6-
heptadien-1-ol (12): A solution of the dienol 11 (5.6 g, 25 mmol)
and chlorotriethylsilane (5.0 mL, 4.5 g, 30 mmol) in pyridine (25
mL) was heated 2 h to 50°C before being concentrated to dryness.
The residue was mixed with some kieselguhr and eluted with hex-
anes from a column filled with neutral alumina. After removal of
the solvent, (1S,2R,4R)-4-methyl-1-(5-methyl-1-methylene-4-hex-
enyl)-2-(triethylsilyloxy)cyclohexane was collected as a colorless oil;
(6R,8R,9S)-6-Methyl-3-methylene-3a,4,5,6,7,7a-hexahydrobenzo-
furan-2-one (7): Benzofuran 6 (0.30 g, 2.0 mmol) was oxidized with
chromium trioxide (5.5 g, 55 mmol) in the presence of pyridine (5.5
mL, 5.4 g, 68 mmol) in refluxing dichloromethane (15 mL) during
2 h, as described.[11] The product (7) was isolated by extraction and
purified by chromatography on silica gel using a 1:2 mixture of
diethyl ether and hexanes as the eluent; m.p. 35Ϫ36°C (ref.[22]: m.p.
37Ϫ39°C); [α]D20 ϭ ϩ51.3 (CHCl3, c ϭ 1.78), (ref.[22]: [α]2D0 ϭ ϩ54.4,
same conditions); yield 0.20 g (60%). Ϫ 1H NMR: δ ϭ 6.04 (d, J ϭ
3.1 Hz, 1 H), 5.36 (d, J ϭ 3.1 Hz, 1 H), 3.71 (ddd, J ϭ 11.5, 10.9,
3.6 Hz, 1 H), 2.34 (tq, J ϭ 11.5, 3.1 Hz, 1 H), 2.24 (symm. m, 1
H), 2.07 (dq, J ϭ 13.0, 3.1 Hz, 1 H), 1.80 (symm. m, 1 H), 1.2 (m,
4 H), 1.01 (d, J ϭ 6.6 Hz, 3 H). Ϫ 13C NMR: Ref.[12] Ϫ Analy-
sis: Ref.[12]
20
nD ϭ 1.3919; [α]2D0 ϭ Ϫ26.9 (ethanol, c ϭ 1.0); yield 8.4 g (99%)
1
crude; 7.2 g (86%) pure. Ϫ H NMR: δ ϭ 5.11 (m, symm., 1 H),
4.76 (s, 2 H), 3.48 (dt, J ϭ 9.9, 4.3 Hz, 1 H), 2.1 (m, 2 H), 2.0 (m,
2 H), 1.9 (m, 1 H), 1.81 (ddd, J ϭ 12.8, 9.8, 3.7 Hz, 1 H), 1.66 (s,
3 H), 1.6 (m, 2 H), 1.59 (s, 3 H), 1.42 (symm. m, 1 H), 1.25 (dq,
J ϭ 12.6, 3.5 Hz, 1 H), 0.90 (t, J ϭ 8.0 Hz, 9 H), 0.9 (m, 2 H),
0.89 (d, J ϭ 6.2 Hz, 3 H), 0.52 (q, J ϭ 8.4 Hz, 6 H). Ϫ 13C NMR:
δ ϭ 152.8, 131.1, 124.6, 108.1, 74.8, 52.3, 45.5, 36.4, 34.6, 31.7,
26.3, 25.7, 22.3, 17.7, 7.0, 5.2. Ϫ MS (CI); m/z (%): 336 (12) [Mϩ],
307 (97), 204 (100), 115 (33). Ϫ C21H40OSi (336.63): calcd. C 74.93,
H 11.98; found C 75.20, H 12.32. Ϫ At Ϫ75°C, precooled tetra-
hydrofuran (20 mL) was added to butyllithium (10 mmol) from
which the commercial solvent (hexanes) had been stripped off be-
fore. The triethyl silyl ether (3.3 g, 10 mmol) just described,
N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (2.1 mL, 1.7 g, 10
mmol) and potassium tert-butoxide were added again at Ϫ75°C.
After 6 h at Ϫ50°C, the mixture was treated with fluorodimeth-
oxyboraneϪdiethyl ether[23] (2.0 mL, 11 mmol), 30% aqueous hy-
drogen peroxide (2.0 mL) and 3  aqueous sodium hydroxide (8.0
mL). It was vigorously stirred for 2 h at 25°C, before the yield of
(Z)-6-[(1S,2R,4R)-4-methyl-2-(triethylsilyloxy)cyclohexyl]-2-methyl-
2,6-heptadien-1-ol was determined by gas chromatography (2 m 5%
SEϪ30, 200°C; 2 m, 8% CϪ20 M, 120°C [after 5 min 30°C/
min]Ǟ220°C [15 min]; tetradecane as an internal standard): 48%
along with 16% of starting material. The product was absorbed on
silica gel (10 g) and eluted from a column filled with more silica
2-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-2-propen-1-ol
(8):
The isopulegol-derived organometallic intermediate was consecu-
tively treated with fluorodimethoxyboraneϪdiethyl ether[23] (5.6
mL, 5.0 g, 30 mmol) and, after 15 min at Ϫ75°C, with 30% aque-
ous hydrogen peroxide (3.0 mL, 1.0 g, 29 mmol). After vigorous
stirring at 25°C for 1 h, the reaction mixture was poured into a 3
 aqueous solution (20 mL) of sodium hydroxide and extracted
with diethyl ether (3 ϫ 15 mL). The combined organic phases were
washed with brine (2 ϫ 10 mL), dried and concentrated. Upon
recrystallization of the residue from diethyl ether, diol 8 was ob-
tained as colorless needles; m.p. 101Ϫ102°C (ref.[24]: m.p. 101°C);
1
[α]2D0 ϭ Ϫ40.1 (C2H5OH; c ϭ 1.0); yield 1.4 g (82%). Ϫ H NMR:
δ ϭ 5.16 (s, 1 H), 5.02 (s, 1 H), 4.08 (q, J ϭ 11.1 Hz, 2 H), 3.52
(dt, J ϭ 10.6, 4.2 Hz, 1 H), 2.48 (br. s, 2 H), 1.99 (symm. m, 1 H),
1.92 (ddd, J ϭ 13.0, 10.4, 3.4 Hz, 1 H), 1.7 (m, 2 H), 1.50 (symm.
m, 1 H), 1.3 (m, 1 H), 0.9 (dm, J ϭ 6.3 Hz, 5 H). Ϫ 13C NMR:
Ref.[12] Ϫ Analysis: Ref.[24]
2-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]-2-propenal (9): The (0.1 L) with a 1:5 (v/v) mixture of diethyl ether and hexanes; nD20 ϭ
1
allylic alcohol 8 (0.68 g, 4.0 mmol) and freshly precipitated manga-
nese dioxide (3.5 g, 40 mmol) were suspended in hexane (10 mL).
After 24 h of vigorous stirring at 25°C, the mixture was absorbed
on silica gel (15 mL) and eluted from a column filled with more of
the support (75 mL) using a 1:1 (v/v) mixture of diethyl ether and
1.4825; yield 1.3 g (36%). Ϫ H NMR: δ ϭ 5.29 (t, J ϭ 6.9 Hz, 1
H), 4.76 (d, J ϭ 7.4 Hz, 2 H), 4.11 (d, J ϭ 2.4 Hz, 2 H), 3.49 (dt,
J ϭ 10.1, 4.4 Hz, 1 H), 2.17 (sept, J ϭ 7.0 Hz, 2 H), 2.1 (m, 2 H),
1.8 (m, 2 H), 1.78 (s, 3 H), 1.6 (m, 2 H), 1.41 (symm. m, 1 H), 1.24
(m, 2 H), 0.9 (m, 14 H), 0.54 (q, J ϭ 7.6 Hz, 6 H). Ϫ 13C NMR:
Eur. J. Org. Chem. 1999, 459Ϫ462
461

M. Schlosser, M. Kotthaus
FULL PAPER
[6]
[7]
E. Moret, M. Schlosser, Tetrahedron Lett. 1984, 25, 1449Ϫ1452.
E. Moret, L. Franzini, M. Schlosser, Chem. Ber. 1997, 130,
335Ϫ339.
Metalations of methyl-substituted phenols: A. S. Kende, F. H.
Ebetino, T. Ohta, Tetrahedron Lett. 1985, 26, 3063Ϫ3066; R. B.
Bates, T. J. Siahaan, J. Org. Chem. 1986, 51, 1432Ϫ1434; R. B.
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Soc. 1972, 94, 4298Ϫ4306.
M. Adrianome, B. Delmond, Tetrahedron Lett. 1985, 26,
6341Ϫ6342.
δ ϭ 152.5, 134.3, 128.4, 108.6, 74.9, 61.7, 51.9, 45.5, 36.8, 34.5,
31.7, 25.7, 23.0, 21.2, 7.0, 5.2. Ϫ Tetrabutylammonium fluoride
trihydrate (1.1 g, 4.0 mmol) was added to a solution of this product
(0.71 g, 2.0 mmol) in tetrahydrofuran (4 mL). After 6 h at 25°C,
the mixture was absorbed at silica gel. Elution with diethyl ether
gave the diol 12 as a colorless oil; nD ϭ 1.3972; [α]2D0 ϭ Ϫ24.4
(ethanol, c ϭ 1.0); yield 0.39 g (82%). Ϫ IR (film): ν˜ ϭ 3360 (s,
[8]
20
[9]
1
ν[OϪH]) 3080 (m, ν[CϪH]), 1640 (m, ν[CϭC]). Ϫ H NMR: δ ϭ
[10]
[11]
5.20 (t, J ϭ 6.8 Hz, 1 H), 4.71 (s, 2 H), 4.17 (d, J ϭ 12.0 Hz, 1 H),
3.97 (d, J ϭ 12.0 Hz, 1 H), 3.54 (dt, J ϭ 11.8, 4.3 Hz, 1 H), 2.30
(symm. m, 1 H), 2.0 (m, 5 H), 1.83 (ddd, J ϭ 13.4, 10.1, 3.5 Hz, 1
H), 1.77 (d, J ϭ 0.1 Hz, 3 H), 1.73 (symm. m, 1 H), 1.65 (s, 1 H),
1.48 (symm. m, 1 H), 1.18 (symm. m, 1 H), 0.96 (q, J ϭ 12.2 Hz,
1 H), 0.92 (d, J ϭ 6.6 Hz, 3 H), 0.88 (dt, J ϭ 13.0, 3.7 Hz, 1 H).
T. J. Brocksom, R. B. dos Santos, N. A. Varanda, U. Brocksom,
Synth. Commun. 1988, 18, 1403Ϫ1410.
[12]
[13]
D. Friedrich, F. Bohlmann, Tetrahedron 1988, 44, 1369Ϫ1392.
Alternative route consisting of the oxidation of diol 8 with silver
dioxide to the corresponding α,β-unsaturated acid and sub-
sequent cyclization with N,NЈ-dicyclohexylcarbodiimid: S. B.
Balkrishna, H. W. Pinnick, Heterocycles 1981, 2091Ϫ2104.
M. Schlosser, J. Hartmann, Angew. Chem. 1973, 85, 544Ϫ545;
Angew. Chem. Int. Ed. Engl. 1973, 12, 508Ϫ509.
M. Schlosser, M. Stähle, Angew. Chem. 1980, 92, 497Ϫ499; An-
gew. Chem. Int. Ed. Engl. 1989, 19, 487Ϫ488.
M. Stähle, M. Schlosser, J. Organomet. Chem. 1981, 220,
277Ϫ283.
O. Desponds, L. Franzini, M. Schlosser, Synthesis 1997,
150Ϫ152.
M. Schlosser, J. Porwisiak, F. Mongin, Tetrahedron 1998, 54,
895Ϫ900.
R. H. Pickard, H. Hunten, W. Leweock, H. Smith de Pen-
nington, J. Chem. Soc. 1920, 117, 1248Ϫ1263.
H. Saltzman, J. G. Sharefkin, Org. Synth., Coll. Vol. 1973, 5,
658Ϫ659.
M. Ochiai, E. Fujita, Tetrahedron Lett. 1983, 24, 777Ϫ780.
K. Nishitani, H. Fukuda, K. Yamakawa, Heterocycles 1992,
33, 97Ϫ100.
Ϫ
13C NMR: δ ϭ 150.5, 135.5, 127.5, 110.8, 71.7, 61.5, 52.3, 42.5,
[14]
[15]
[16]
[17]
[18]
[19]
[20]
34.7, 34.6, 31.6, 31.2, 26.1, 22.3, 21.3. Ϫ MS (CI); m/z (%): 221 (1),
125 (14), 81 (100), 107 (73). Ϫ C15H26O2 (238.37): calcd. C 75.58,
H 10.99; found C 75.69, H 11.00.
Acknowledgments
This work was financially supported by the Schweizerische Natio-
nalfonds zur Förderung der wissenschaftlichen Forschung (grant
20-49Ј307-96), Bern, and by the Deutsche Forschungsgemeinschaft
(fellowship Ko-1845/1-1), Bonn-Bad Godesberg.
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G. Rauchschwalbe, M. Schlosser, Helv. Chim. Acta 1975, 58,
1094Ϫ1099.
K. H. Schulte-Elte, G. Ohloff, Helv. Chim. Acta 1967, 50,
153Ϫ165.
G.-f. Zhong, Pure Appl. Chem. 1994, 66, 1423Ϫ1446.
[3]
M. Schlosser, Mod. Synth. Methods, 1992, 6, 227Ϫ271.
[4]
A. Mordini, in Comprehensive Organometallic Chemistry II
(Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), vol. 11 (Ed.:
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[5]
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Received August 12
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[O98363]
462
Eur. J. Org. Chem. 1999, 459Ϫ462