Radical reactions on pinene-oxide derivatives induced by Ti(III)

Article abstract of DOI:10.1016/j.tet.2011.10.004

A practical, brief and selective synthesis of several pinene oxide derived terpenoids can be achieved from readily available starting materials. The key step is a radical reaction promoted by titanocene chloride.

Full text of DOI:10.1016/j.tet.2011.10.004

Tetrahedron 67 (2011) 9529e9534
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical reactions on pinene-oxide derivatives induced by Ti(III)
*
ꢀ
ꢀ
ꢀ
A. Fernandez-Mateos , P. Herrero Teijon, R. Rubio Gonzalez
ꢀ
Departamento de Química Organica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2011
Received in revised form 30 September 2011
Accepted 3 October 2011
A practical, brief and selective synthesis of several pinene oxide derived terpenoids can be achieved from
readily available starting materials. The key step is a radical reaction promoted by titanocene chloride.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 10 October 2011
Keywords:
Pinene-derived terpenoids
Titanocene
Radical reactions
a
-Pinene oxide
Epoxides
1. Introduction
The transformation of natural products into other compounds of
high added value is an activity of the chemical industry of huge
economic interest. The chemical reactivity of terpenoids and ste-
roids has been studied in depth for the synthesis of valuable
compounds with low investments.1
In particular, monoterpenes are a vast reserve of optically active
compounds that can be transformed into other products with high
added value as flavours, fragrances, drugs and catalysts.
The development of new chiral ligands for asymmetric synthesis
is one of the fields in which most efforts have been made in recent
years. Several catalysts derived from monoterpenes, such as pule-
gone,
ciency in enantioselective synthesis.2
-Pinene, a very affordable monoterpene from the trementine
b-pinene, limonene and a-pinene have shown great effi-
a
essential oil, is a chiral compound, from whose oxide a large
amount of valuable compounds are derived, such as campholenic
aldehyde,
p-cimene, cineol and verbenone (see Scheme 1). The rearrange-
ment of -pinene oxide by acids has been addressed in many classic
trans-carveol, trans-sobrerol,
iso-pinocamphone,
a
studies in the field of terpenoid chemistry.
Scheme 1. Main products from pinene oxide.
The regioselective oxirane ring opening, promoted by acids,
leads to the formation of a carbocation, which evolves in different
ways following competitive processes, such as the loss of a proton,
cleavage, ring expansion, etc.
Lewis acids mainly lead to cyclopentenic aldehydes, such as
campholenal,3 while Brønsted acids mainly lead to the formation of
trans-carveol and p-mentane derivatives.4
Although most compounds generated in the acid-promoted
isomerization of
industry, pharmacy and the food industry, campholenal and trans-
a-pinene oxide are of interest in the fragrance
* Corresponding author. Tel.: þ34 923 294481; fax: þ34 923 294574; e-mail
ꢀ
address: afmateos@usal.es (A. Fernandez-Mateos).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.004

ꢀ
A. Fernandez-Mateos et al. / Tetrahedron 67 (2011) 9529e9534
9530
carveol stand out from the rest. The aldehyde is highly appreciated
in the elaboration of top-brand perfumes due to its sandal-like
aroma. trans-Carveol is the basis of the aroma of the essential or-
ange oil; it is used as a fragrance and food preservative. Crowell
et al. have discovered that it prevents breast cancer.5 Some carveol
derivatives have shown antiproliferative activity against carcino-
genic prostate cells.6
Recently, several studies addressed to the optimization of
a
-pinene oxide isomerization have been developed with the
objective to improve the yields of campholenic aldehyde or trans-
carveol. In a work reported by Noyori et al.7 a 72% yield of trans-
carveol was achieved by reaction of a-pinene oxide with a mixture
of trimethylsilyl trifluoromethanesulfonate, 2,6-lutidine and dia-
zabicycloundecene. Unfortunately, this process does not seem
adequate for large-scale use. An approach aimed at the industrial
production of trans-carveol was developed by Motherwell et al., but
with disappointing results. The authors only obtained a 45% yield of
trans-carveol using MIPs.8
Scheme 2. Reaction of a-pinene oxide with Ti(III).
Better results have been achieved by Gusevskaya et al.9 using
catalytic amounts of the acid H3PW12O40 as a promoter of the
isomerization of a-pinene oxide. Using this catalyst both the po-
larity and the basicity of the solvent strongly influence the result of
the reaction. Basic and polar solvents, such as DMF favour the for-
mation of trans-carveol, and the neutral non-polar solvents, such as
cyclohexane favour the formation of campholenic aldehyde.
Thus, whatever method of isomerization is chosen, the reaction
always affords a mixture of compounds.
Scheme 3. Reaction of b-pinene oxide with Ti(III).
Although many studies have been carried out to transform
a
-pinene oxide into valuable compounds by means of a highly se-
lective process, few of them have been regarded with interest by
industry. This problem still remains unsolved. Most past studies
were based in ionic reactions that evolve through carbocations,
contributing to their lack of selectivity.
Here we focus on the problem from a different point of view. Our
strategy is based on the use of radical reactions promoted by
Ti(III).10 Our study is contrasted with that published by Volcho
et al.11 who used montmorillonite as the reagent.
2. Results and discussion
2.1. Radical reactions induced by titanocene chloride
The reaction of a
-pinene oxide 112 with 2 equiv of Cp2TiCl in THF
Scheme 4. Reaction of myrtenol oxide with Ti(III).
leads solely to the formation of trans-carveol 213 at an excellent 89%
yield.
The reaction starts with the homolytic cleavage of the oxirane 1
induced by Ti(III), to give the radical 1A, and evolves through a new
cleavage to the radical 1B, which loses a hydrogen atom from
a methyl group, to afford the carveol 2 (Scheme 2).
Encouraged by this result we attempted a catalytic version of
the reaction using only 10% of Cp2TiCl, and collidine hydrochloride
as a source of hydrogen.14 Unfortunately, using this method only
Nevertheless, when myrtenol oxide 5 was treated with Cp2TiCl
in THF only (þ)-trans-pinocarveol 620 was obtained in 90% yield.
The reaction of pinocarveol oxide 7 with montmorillonite as
described by Volcho et al.11 led to a complex mixture from which
pinocamphone C (6%) and an aldehyde analogous to campholenic
aldehyde D could be isolated (19%) (Scheme 5).
However, pinocarveol oxide 7 with Ti(III) afforded a mixture of
trans-pinocarveol 6 (42%), myrtenol 8 (24%) and the diols 9a/9b
(18%) in a ratio of 20:80. It is worth noting that while myrtenol
oxide 5 afforded only the product of hydroxyl elimination, trans-
pinocarveol 6, the pinocarveol oxide 7 gave a mixture of four
products. Although the two starting materials were isomers, the
first one 5 is a primary alcohol and the last one 7 is secondary. It
seems that the elimination rate depends on the type of hydroxyl
group.21 In light of the experimental data, we suggest a faster se-
quence from 5 to 6, through intermediates 5A and 5B. From 7, the
faster sequence passes through 7A, 7C, 5A, 5B and finally 6. The
slower pathway passes through 7A, 7B and 8. The equilibrium
through intermediate 7C is clearly shifted to 5A (Scheme 6).
The reported reaction of cis-verbenol oxide 10 with montmo-
rillonite by Volcho’s method,11 led to a mixture of the diol 11 (47%)
12% of trans-carveol 2 was produced, although 70% of
a-pinene
oxide was recovered.
The acid-mediated rearrangement of
b
-pinene oxide 315 has
been widely studied with the aim of obtaining the valuable peril-
lalcohol 4,16 and perillaldehyde.17 In our hands the reaction of
b-pinene oxide 3 with Cp2TiCl in THF led to the formation of per-
illalcohol 4a in 80% yield. A small amount of the hydrogenated
product phellandrol 4b18 was observed, probably due to adventi-
tious water in the reaction medium. It is known that Ti(III) promotes
the transference of hydrogen from water to radicals19 (Scheme 3).
The reaction of myrtenol oxide 5 with montmorillonite was
described by Volcho et al.11 to produce a mixture of the aromatic
alcohol A (16%) and the cyclopentenic hydroxyaldehyde B (27%)
(Scheme 4).

ꢀ
A. Fernandez-Mateos et al. / Tetrahedron 67 (2011) 9529e9534
9531
With zinc bromide in benzene, only the aldehyde H (30%) was
obtained23 (Scheme 8).
Scheme 5. Reaction of pinocarveol oxide with Ti(III).
Scheme 8. Volcho’s reactions of verbenone oxide.
The reaction of verbenone oxide 12 with Ti(III) afforded only the
deoxygenation product verbenone 13 (96%). This result can be ra-
tionalized in terms of the kinetic regioselective cleavage of the
oxirane to afford a stabilized enol radical 12A, which evolves
through a titanium enolate 12B to yield verbenone by the elimi-
nation of titanocene oxide. With the transformation of 12 to 13
a new deoxygenation method for
(Scheme 9).
a,b-epoxyketones is established
Scheme 6. Proposed mechanism for the reaction of 7 and 5 with Ti(III).
Scheme 9. Deoxygenation of verbenone oxide with Ti(III).
and the hydroxyketone E (5%). Meanwhile, treatment of 11 with
Cp2TiCl afforded a mixture of the diols 11a11 and 11b (78%) at a ratio
of 40:60 (Scheme 7).
2.2. Tandem radical reactions
Tandem and multicomponent reactions, from the aforemen-
tioned substrates, allow the synthesis of complex molecules in
a few steps, which is why attention has been paid to this issue.
In a previous study, the reaction of
a-pinene oxide 1 with
Cp2TiCl and acetonitrile was investigated.24 The products obtained
were the trans-carveol 2, and the hydroxyketone J, at a ratio of
40:60. This means that radical addition to acetonitrile is slower
than cyclobutane radical cleavage and faster than hydrogen elimi-
nation. The rate constant of the cyclobutane radical cleavage in
pinene derivatives calculated by the radical clock method25 was
1.1ꢀ107 sꢁ1 (Scheme 10).
Scheme 7. Reaction of cis-verbenol oxide with Ti(III).
The higher proportion of the diol 11b respect to diol 11a should
be due, in this case, to hydrogen transfer from the alcohol 11eTi(III)
complex to the radical precursor of 11b.22
Volcho’s treatment of verbenone oxide 12 with montmorillonite
afforded a mixture of the hydroxyketones F (22%) and G (36%).10
Scheme 10. Tandem reaction of pinene oxide and acetonitrile induced by Ti(III).

ꢀ
A. Fernandez-Mateos et al. / Tetrahedron 67 (2011) 9529e9534
9532
In order to study the behaviour of the radical afforded by the
reaction of -pinene oxide 1 and Ti(III), we tested different addi-
a
tives: water, methanol, 1,4-cyclohexadiene (1,4-CHD), acrylonitrile
and methyl acrylate.
Recently water has been introduced as a source of hydrogen
atoms in Ti(III)19-mediated radical chemistry. Also, methanol22 and
1,4-CHD transfer hydrogen atoms in this Ti(III) chemistry. To ex-
plore the scope of the hydrogen transfer, a study of the reaction
between Ti(III), a-pinene oxide and water, MeOH, and 1,4-CHD was
carried out. The results are summarized in Table 1.
Table 1
Hydrogen transfer comparison
Source of H
Equivalents
2 (%)
14 (%)
2/14
Scheme 12. Tandem reaction of pinene oxide and methyl acrylate or acrylonitrile
induced by Ti(III).
MeOH
H2O
1,4-CHD
10
10
10
24
13
27
61
63
68
2,5
4,8
2,5
3. Conclusion
The radical reactions of pinene-oxide derivatives induced by
titanocene chloride selectively afford a series of valuable com-
pounds, such as trans-carveol 2, perilla alcohol 5, (þ)-trans-pino-
carveol 7, menthane diol 12 and verbenone 14. It has been observed
that radical primary hydroxyl elimination is faster than the sec-
ondary one, as shown by the relative behaviour of myrtenol oxide 6
and pinocarveol oxide 8 against Ti(III). The deoxygenation reaction
of verbenone oxide, promoted by Ti(III) in a selective manner is
noteworthy. Throughout this work we observed that reactions of
titanocene chloride with pinene-oxide compounds afforded com-
pletely different results from those obtained with acidic reagents,
and noted the radical character of those reactions. The kinetic
From Table 1, it may be observed that the wateretitanocene
complex is the best source of hydrogen. It is also observed that the
transfer of hydrogen from different sources is slower than the
cleavage of the cyclobutane ring; so, no neopinocampheol was
obtained.
The addition of PhSH as a hydrogen source afforded a mixture of
dihydro trans-carveol 14 (18%)18 and neopinocampheol 15 (60%).26
A higher rate of hydrogen transfer from PhSH to radicals than hy-
drogen transfer from radicals to Ti(III) was observed. The hydrogen
transfer rate constant from PhSH (k20¼9ꢀ107 Mꢁ1 sꢁ1 27
)
was
higher than the previous hydrogen sources, and higher than
cyclobutane radical cleavage (Scheme 11).
regioselective addition of radical, arising from a-pinene oxide and
Ti(III), to hydrogen transfer agents, methyl acrylate and acryloni-
trile is also worthy of mention.
4. Experimental section
4.1. General methods
Melting points are uncorrected. 1H NMR spectra were measured
at either 200 or 400 MHz and 13C NMR were measured at 50 or
100 MHz in CDCl3 and referenced to TMS (1H) or solvent (13C),
except where indicated otherwise. IR spectra were recorded for
neat samples on NaCl plates, unless otherwise stated. Standard
mass spectrometry data were acquired using a GCeMS system in EI
mode with a maximum m/z range of 600. When required, all sol-
vents and reagents were purified by standard techniques: tetra-
hydrofuran (THF) was purified by distillation from sodium and
benzophenone ketyl and degassed before use. All reactions were
conducted under a positive pressure of argon, utilizing standard
bench-top techniques for the handling of air-sensitive materials.
Chromatographic separations were carried out under pressure on
silica gel using flash-column techniques on Merck silica gel 60
(0.040e0.063 mm). The yields reported are for chromatographi-
cally pure isolated products unless otherwise stated.
Scheme 11. Tandem reactions of pinene oxide and hydrogen donors induced by Ti(III).
The reaction with methyl acrylate afforded the hydroxyester 16
(65%). This result could be explained in terms of the homolytic
cleavage of oxirane, further cyclobutane opening,25 and trapping of
the tertiary radical by the double bond of methyl acrylate. Never-
theless, the reaction with acrylonitrile afforded exclusively the ni-
trile 17 (74%) by trapping of the radical 1A. The subsequent work-up
in aqueous-acid media led to the formation of lactone 18 exclu-
sively. It is clear from the latter reactions that the rate constant for
radical acrylate addition is lower than cyclobutane radical cleavage
in pinene namely,25 k¼1.1ꢀ107 sꢁ1 and higher for acrylonitrile. It is
also worth noting the absolute stereoselectivity of acrylonitrile
addition to radical 1A. The kinetic regioselectivity and the total
stereoselectivity observed could find application in organic syn-
thesis (Scheme 12).
The oxides 3, 5, 7, 10 and 12 were obtained following the
methods described by Volcho.11,23
a-Pinene oxide 1 was acquired
from SigmaeAldrich.
The following known compounds were isolated as pure samples
and showed NMR spectra matching those reported previously: 2,13
4a,18 6,20 8,11 1311 and 15.26
4.2. General procedure 1 (GP1)
Reaction of epoxides with Cp2TiCl.
A mixture of Cp2TiCl2
(2.20 mmol) and granulated Zn (6.60 equiv) in strictly

ꢀ
A. Fernandez-Mateos et al. / Tetrahedron 67 (2011) 9529e9534
9533
deoxygenated THF (10 mL) was stirred at room temperature until
4.8. Reaction of cis-verbenol oxide 10 with Cp2TiCl
the red solution turned green. In a separate flask, the epoxy com-
pound (1 mmol) was dissolved in strictly deoxygenated THF
(10 mL). The green Ti(III) solution was slowly added via cannula to
the epoxide solution. After 30 min, an excess of saturated NaH2PO4
was added, and the mixture was stirred for 20 min. The mixture
was filtered to remove insoluble titanium salts. The product was
extracted into ether, and the combined organic layers were washed
with saturated NaHCO3 and brine, dried (Na2SO4), and filtered.
After removal of the solvent, the crude product was purified by
flash chromatography.
According to GP1, reaction of 10 (50 mg, 0.30 mmol) with Cp2TiCl
followed by flash chromatography (hexane/diethyl ether 1:1) fur-
nished a mixture of (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-
3-ene-1,2-diol 11a and (1R,2R,6S)-6-isopropyl-3-methylcyclohex-3-
ene-1,2-diol 11b (4:6, 78 mg, 78%). IR,
n (liquid film) 3362, 2938,
1447, 1132, 997 cmꢁ1; 1H NMR (200 MHz CDCl3)
d: 0.95 (d, J¼6.0 Hz,
3H), 0.99 (d, J¼6.0 Hz, 3H), 1.0e2.5 (m, 7H), 1.81 (s, 6H), 1.83 (s, 3H),
3.82 (br s, 2H), 3.92 (br s,1H), 4.00 (br s,1H), 4.87 (br s,1H), 4.99 (br s,
1H), 5.66 (br s, 2H) ppm; 13CNMR (50 MHzCDCl3)
d:20.65(CH3), 20.74
(2CH3), 21.00 (CH3), 22.57 (CH3), 24.52 (CH2), 25.31 (CH2), 28.70 (CH),
38.89 (CH), 39.81 (CH), 70.81 (CH), 71.17 (CH), 71.94 (CH), 72.72 (CH),
111.57 (CH2),125.29 (CH),126.01 (CH),131.56 (C),131.64 (C),145.65 (C)
ppm.
4.3. General procedure 2 (GP2)
Reaction of epoxides and additives with Cp2TiCl. A mixture of
Cp2TiCl2 (2.20 mmol) and granulated Zn (6.60 equiv) in strictly
deoxygenated THF (10 mL) was stirred at room temperature until
the red solution turned green. In a separate flask, the epoxy com-
pound (1 mmol) and the additive (10 mmol) were dissolved in
strictly deoxygenated THF (10 mL). The green Ti(III) solution was
slowly added via cannula to the epoxide and nitrile solution. After
30 min, an excess of saturated NaH2PO4 was added, and the mix-
ture was stirred for 45 min. The mixture was filtered to remove
insoluble titanium salts. The product was extracted into ether, and
the combined organic layers were washed with saturated NaHCO3
and brine, dried (Na2SO4), and filtered. After removal of the solvent,
the crude product was purified by flash chromatography.
4.9. Reaction of verbenone oxide 12 with Cp2TiCl
According to GP1, reaction of 12 (100 mg, 0.60 mmol) with
Cp2TiCl followed by flash chromatography (hexane/diethyl ether
1:1) furnished verbenone 13 (96 mg, 96%).
4.10. Reaction of a-pinene oxide 1 with Cp2TiCl/MeOH
According to GP2, reaction of 1 (99 mg, 0.66 mmol) and MeOH
(0.27 mL, 6.60 mmol) with Cp2TiCl followed by flash chromatog-
raphy (hexane/diethyl ether 7:3) furnished a mixture of (1S,5R)-2-
methyl-5-(prop-1-en-2-yl)cyclohex-2-enol
2 (24 mg, 24%) and
(1S,5R)-5-isopropyl-2-methylcyclohex-2-enol 14 (61 mg, 61%).
4.4. Reaction of a-pinene oxide 1 with Cp2TiCl
4.11. Reaction of a-pinene oxide 1 with Cp2TiCl/H2O
According to GP1, reaction of 1 (100 mg, 0.66 mmol) with
Cp2TiCl followed by flash chromatography (hexane/diethyl ether
According to GP2, reaction of 1 (100 mg, 0.66 mmol) and H2O
(0.12 mL, 6.60 mmol) with Cp2TiCl followed by flash chromatog-
raphy (hexane/diethyl ether 7:3) furnished a mixture of (1S,5R)-2-
8:2) furnished trans-carveol 2 ½a D20
ꢁ190.0 (CHCl3, c 14 mg/mL)
ꢂ
(89 mg, 89%).
methyl-5-(prop-1-en-2-yl)cyclohex-2-enol
(1S,5R)-5-isopropyl-2-methylcyclohex-2-enol 14 (63 mg, 63%).
2 (13 mg, 13%) and
4.5. Reaction of b-pinene oxide 3 with Cp2TiCl
According to GP1, reaction of 3 (125 mg, 0.82 mmol) with
Cp2TiCl followed by flash chromatography (hexane/diethyl ether
4.12. Reaction of a-pinene oxide 1 with Cp2TiCl/1,4-CHD
7:3) furnished perillylalcohol 4a ½a D20
ꢁ88.0 (MeOH, c 12 mg/mL)
ꢂ
According to GP2, reaction of 1 (100 mg, 0.66 mmol) and 1,4-
Cyclohexadiene (0.63 mL, 6.60 mmol) with Cp2TiCl followed by
flash chromatography (hexane/diethyl ether 7:3) furnished a mix-
(99 mg, 80%). A small amount of phellandrol 4b was observed.
4.6. Reaction of myrtenol oxide 5 with Cp2TiCl
ture of (1S,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol
2
(27 mg, 27%) and (1S,5R)-5-isopropyl-2-methylcyclohex-2-enol 14
(68 mg, 68%).
According to GP1, reaction of 5 (100 mg, 0.60 mmol) with
Cp2TiCl followed by flash chromatography (hexane/diethyl ether
85:15) furnished (þ)-trans-pinocarveol 6 ½a D20
þ53.1 (CHCl3, c
ꢂ
4.13. Reaction of a-pinene oxide 1 with Cp2TiCl/PhSH
8 mg/mL) (86 mg, 90%).
According to GP2, reaction of 1 (100 mg, 0.66 mmol) and PhSH
(0.63 mL, 6.60 mmol) with Cp2TiCl followed by flash chromatog-
raphy (hexane/diethyl ether 7:3) furnished a mixture of (1S,5R)-5-
isopropyl-2-methylcyclohex-2-enol 14 (18 mg, 18%) and neo-
pinocampheol 15 (60 mg, 60%).
4.7. Reaction of pinocarveol oxide 7 with Cp2TiCl
According to GP1, reaction of 7 (100 mg, 0.60 mmol) with Cp2TiCl
followed by flash chromatography furnished: (hexane/diethyl ether
85:15): (þ)-trans-pinocarveol 6 (38 mg, 42%), (hexane/diethyl ether
85:15):myrtenol8(22 mg, 24%)andwith(hexane/diethylether1:1):
a mixture of (1S,5R)-2-(hydroxymethyl)-5-(prop-1-en-2-yl)cyclo-
hex-2-enol9a and(1S,5R)-2-(hydroxymethyl)-5-isopropylcyclohex-
4.14. Reaction of
acrylate
a-pinene oxide 1 with Cp2TiCl/methyl
2-enol 9b (2:8, 16 mg, 18%). IR,
n
(liquid film) 3364, 2935, 1455, 1128,
According to GP2, reaction of 1 (100 mg, 0.66 mmol) and methyl
acrylate (0.59 mL, 6.60 mmol) with Cp2TiCl followed by flash chro-
matography (hexane/diethyl ether 7:3) furnished methyl 4-((1R,5S)-
5-hydroxy-4-methylcyclohex-3-enyl)-4-methyl penta noate 16
999 cmꢁ1; 1H NMR (200 MHz CDCl3)
d: 0.89 (d, J¼6.7 Hz, 3H), 0.92
(3d, J¼6.7 Hz, 3H),1.2e2.3 (m,11H), 4.21 (m, 4H), 4.32 (br s,1H), 4.36
(br s,1H), 4.74 (br s,1H), 4.76 (br s,1H), 5.87 (br s, 2H) ppm; 13C NMR
(50 MHz CDCl3)
d: 19.42 (CH3),19.58 (CH3), 23.39 (CH3), 26.35 (CH2),
(102 mg, 65%). ½a D20
ꢂ
ꢁ15.8 (CHCl3, c 31 mg/mL) IR,
n: 3404, 2940,
d: 0.83 (s, 6H), 1.3e2.3
28.80 (CH2), 31.85 (CH), 33.89 (CH), 34.06 (CH), 35.23 (CH2), 36.11
(CH), 66.61 (CH), 66.80 (CH), 67.22 (2CH2),109.23 (CH2),129.65 (CH),
130,02 (CH), 136.99 (C), 137.11 (C), 148.79 (C) ppm.
1728, 1445 cmꢁ1; 1H NMR (400 MHz, CDCl3)
(m, 9H),1.76 (br s, 3H), 3.64 (s, 3H), 3.99 (br s,1H), 5.54 (m,1H) ppm;
13C NMR (50 MHz, CDCl3)
: 20.74 (CH3), 24.03 (CH3), 24.11 (CH3),
d

ꢀ
A. Fernandez-Mateos et al. / Tetrahedron 67 (2011) 9529e9534
9534
3. (a) Vialemaringe, M.; Campagnole, M.; Bourgeois, M. J.; Mountadon,, E. C. R.
Acad. Sci. Paris, Ser. II 1999, 449e454 And references cited therein; (b) Arata, K.;
Tanabe, K. Chem. Lett. 1979, 1017e1018; (c) Joshi, V. S.; Dev, S. Tetrahedron 1977,
33, 2955e2957; (d) Ravasioa, N.; Zaccheriab, F.; Guidottia, M.; Psaroa, R. Top.
Catal. 2004, 27, 157e167.
4. (a) Kaminska, J.; Schwegler, M. A.; Hoefnagel, A. J.; Van Bekkum, H. Recl. Trav.
Chim. Pays-Bas 1992, 111, 432e437; (b) Royals, E. E.; Leffingwell, J. C. J. Org.
Chem. 1964, 29, 2098e2099; (c) Hartshorn, M. P.; Kirk, D. N.; Wallis, A. F. A. J.
Chem. Soc. 1964, 5491e5493; (d) King, L. C.; Farber, H. J. Org. Chem. 1961, 26,
326e329; (e) Chapman, H. A.; Herbal, K.; Motherwell, W. B. Synlett 2010,
595e598.
26.59 (CH2), 28.99 (CH2), 32.56 (CH2), 33.77 (C), 34.87 (CH2), 35.24
(CH), 51.54 (CH3), 68.79 (CH), 125.73 (CH), 134.23 (C), 174.93 (C)
ppm; EIMS, m/z (relative intensity) 222 (Mþꢁ18,12),191 (1),149 (8),
133 (28), 93 (64); 74 (100), 55 (100); HRMS (ESI): calcd for
C14H24O3Na 263.1623; found 263.1627.
4.15. Reaction of a-pinene oxide 1 with Cp2TiCl/acrylonitrile
According to GP2, reaction of 1 (100 mg, 0.66 mmol) and methyl
acrylate (0.44 mL, 6.60 mmol) with Cp2TiCl followed by flash
chromatography (hexane/diethyl ether 7:3) furnished 4-((1R,5S)-5-
hydroxy-4-methylcyclohex-3-enyl)-4-methylpentane nitrile 17
5. Crowell, P. L.; Kennan, W. S.; Haag, J. D.; Ahmad, S.; Vedejs, E.; Gould, M. N.
Carcinogenesis 1992, 13, 1261e1264.
6. Chen, J.; Lu, M.; Jingb, Y.; Dong, J. Bioorg. Med. Chem. 2006, 14, 6539e6547.
7. Murata, S.; Suzuki, M.; Noyori, R. Bull. Chem. Soc. Jpn. 1982, 55, 247e254.
8. Motherwell, W. B.; Bingham, M. J.; Pothier, J.; Six, Y. Tetrahedron 2004, 60,
3231e3241.
(101 mg, 74%). ½a D20
ꢂ
þ4.8 (CHCl3, c 9 mg/mL) IR,
n: 3436, 2925, 1453,
; d: 1.03 (s, 3H), 1.07 (s, 3H),
9. Silva, K. A.; Hoehne, J. L.; Gusevskaya, E. V. Chem.dEur. J. 2008, 14, 6166e6172.
10. (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1994, 116, 986e997; (b)
1060 cmꢁ1 1H NMR (400 MHz, CDCl3)
1.25 (s, 3H), 1.0e2.6 (m, 10H), 4.24 (m, 1H) ppm; 13C NMR (50 MHz,
CDCl3) : 12.53 (CH2), 24.78 (CH3), 25.34 (CH3), 28.56 (CH3), 29.66
ꢀ
Fernandez-Mateos, A.; Martin de la Nava, E.; Pascual Coca, G.; Ramos Silvo, A.;
ꢀ
€
Rubio Gonzalez, R. Org. Lett. 1999, 1, 607e610; (c) Gansauer, A.; Bluhm, H. Chem.
d
€
Rev. 2000, 100, 2771e2788; (d) Gansauer, A.; Narayan, S. Adv. Synth. Catal. 2002,
344, 465e475; (e) Gansauer, A.; Lauterbach, T.; Narayan, S. Angew. Chem., Int.
Ed. 2003, 42, 5556e5573; (f) Cuerva, J. M.; Justicia, J.; Oller-Lopez, J. L.; Oltra, J.
E. Top. Curr. Chem. 2006, 264, 63e91; (g) Cuerva, J. M.; Justicia, J.; Oller-Lopez, J.
(CH2), 32.50 (CH2), 39.11 (CH2), 39.55 (C), 40.60 (CH), 41.44 (C),
51.73 (CH), 72.48 (CH), 120.93 (C) ppm; EIMS, m/z (relative in-
tensity) 177 (Mþꢁ30, 15), 149 (100), 135 (2), 76 (14), 55 (16); HRMS
(ESI): calcd for C13H21NO3Na 230.1515; found 230.1517. Due to the
work-up in aqueous-acid media compound 17 leads to the forma-
€
ꢀ
ꢀ
L.; Bazdi, B.; Oltra, J. E. Mini Rev. Org. Chem. 2006, 3, 23e35; (h) Barrero, A. F.;
ꢀ
Quílez del Moral, J. F.; Sanchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006,
€
1627e1641; (i) Gansauer, A.; Justicia, J.; Fan, C. A.; Worgull, D.; Piestert, F. Top.
tion of the lactone 18. ½a D20
ꢂ
ꢁ20.3 (CHCl3, c 28 mg/mL) IR,
n: 3412,
Curr. Chem. 2007, 279, 25e52.
2929, 1733, 1451, 1248, 1141, 1017 cmꢁ1; 1H NMR (400 MHz, CDCl3)
11. Il’ina, I. V.; Volcho, K. P.; Korchagina, D. V.; Barkhash, V. A.; Salakhutdinov, N. F.
Helv. Chim. Acta 2007, 90, 353e368.
d
: 0.98 (s, 3H), 1.21 (s, 3H), 1.27 (s, 3H), 1.2e2.6 (m, 10H), 4.26 (d,
12. (a) Moore, R. N.; Golumbic, C.; Fisher, G. S. J. Am. Chem. Soc. 1956, 78, 1173e1176;
J¼7.4 Hz, 1H) ppm; 13C NMR (50 MHz, CDCl3)
d: 24.14 (CH3), 26.10
ꢀ
(b) Lavallee, P.; Bouthillier, G. J. Org. Chem. 1986, 51, 1362e1365.
13. (a) Hamada, H. Bull. Soc. Chim. Jpn. 1988, 61, 869e887; (b) Yasui, K.; Fugami, K.;
Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995, 60, 1365e1380; (c) Lajunen, M. K.;
Maunula, T.; Koskinen, A. M. P. Tetrahedron 2000, 56, 8167e8171.
(CH3), 26.87 (CH2), 27.33 (CH2), 27.95 (CH3), 33.40 (CH2), 34.22
(CH2), 38.62 (C), 39.03 (CH), 39.50 (C), 52.44 (CH), 79.79 (CH),
174.37 (C) ppm; EIMS, m/z (relative intensity) 193 (Mþꢁ15, 5), 165
(6), 135 (12), 96 (64), 81 (41), 67 (51), 55 (100); HRMS (ESI): calcd
for C13H20O2Na 231.1355; found 231.1346.
€
14. (a) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998, 120,
ꢀ
12849e12859; (b) Justicia, J.; Jimenez, T.; Morcillo, S. P.; Cuerva, J. M.; Oltra, J. E.
Tetrahedron 2009, 65, 10837e19841.
15. Thomas, A. F. In The Total Synthesis of Natural Products; ApSimon, J. W., Ed.;
Wiley-Interscience: New York, NY, 1973; Vol. 2, pp 126e128.
ꢁ
16. Thomas, A. F.; Bessiere, Y. In The Total Synthesis of Natural Products; ApSimon, J.
Acknowledgements
W., Ed.; Wiley-Interscience: New York, NY, 1988; Vol. 7, pp 378e380.
17. (a) Furukawa, S.; Tomizawa, Z. J. Chem. Ind., Tokyo 1920, 23, 342e363; (b) Al-
ternative Sweeteners 3rd Edition Editor L. O. Nabors Ed. Dekker: New York
2001.
18. (a) Trachtemberg, E. N.; Nelson, C. N.; Carver, J. R. J. Am. Chem. Soc. 1970, 35,
1653e1658; (b) Human, J. P. E.; Macbeth, A. K.; Rodda, H. J. J. Chem. Soc. 1949,
350e352; (c) Lewis, J. B.; Hedrick, G. W. J. Org. Chem. 1965, 30, 4271e4275.
Financial support for this work from the Ministerio de Ciencia y
Tecnología of Spain (CTQ2005-05026/BQU) and the Regional Gov-
ꢀ
ernment of Castilla & Leon (SA079A06) is gratefully acknowledged.
We alsothankthe UniversityofSalamanca forthe fellowshiptoP.H.T.
~
~
ꢀ
19. Cuerva, J. M.; Campana, A. G.; Justicia, J.; Rosales, A.; Oller-Lopez, J. L.; Robles, R.;
ꢀ
Cardenas, D. J.; Bunuel, E.; Oltra, J. E. Angew. Chem., Int. Ed. 2006, 45,
5522e5526.
Supplementary data
20. (a) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526e5527; (b)
Scheidl, F. Synthesis 1982, 728; (c) Coxon, J. M.; Dansted, E.; Hartshorn, M. P.
Org. Synth. Coll. 1988, Vol. 6, 946. Wiley: New York; (d) Crandall, J. K.; Crawley,
L. C. Org. Synth. Coll. 1988, Vol. 6, 948. Wiley: New York.
Experimental procedures and copies of the 1H and 13C NMR
spectra for all new compounds. Supplementary data associated
with this article can be found in the online version, at doi:10.1016/
j.tet.2011.10.004. These data include MOL files and InChiKeys of the
most important compounds described in this article.
ꢀ
ꢀ
ꢀ
21. Fernandez-Mateos, A.; Encinas Madrazo, S.; Herrero Teijon, P.; Rubio Gonzalez,
R. Eur. J. Org. Chem. 2010, 856e861.
ꢀ
ꢀ
ꢀ
22. Fernandez-Mateos, A.; Herrero Teijon, P.; Mateos Buron, L.; Rabanedo Clem-
ꢀ
ente, R.; Rubio Gonzalez, R. J. Org. Chem. 2007, 72, 9973e9982.
23. Il’ina, I. V.; Volcho, K. P.; Korchagina, D. V.; Barkhash, V. A.; Salakhutdinov, N. F.
Helv. Chim. Acta 2006, 89, 507e514.
24. Fernandez-Mateos, A.; Encinas Madrazo, S.; Herrero Teijon, P.; Rubio Gonzalez,
References and notes
ꢀ
ꢀ
ꢀ
R. J. Org. Chem. 2009, 74, 3913e3918.
ꢀ
ꢀ
25. Fernandez-Mateos, A.; Herrero Teijon, P.; Rabanedo Clemente, R.; Rubio
1. Monteiro, J. L. F.; Veloso, C. O. Top. Catal. 2004, 27, 169e180 and references cited
ꢀ
Gonzalez, R. Synlett 2008, 3208e3212.
therein.
ꢀ
€ €
26. Nishino, C.; Takayanagi, H. Agric. Biol. Chem. 1979, 43, 2399e2402.
27. Newcomb, M.; Choi, S. Y.; Horner, J. H. J. Org. Chem. 1999, 64, 1225e1231.
2. Szakonyi, Z.; Hetenyi, A.; Fulop, F. Tetrahedron 2008, 64, 1034e1039 and ref-
erences cited therein.