Titanocene-promoted stereoselective eliminations on epoxy alcohols derived from R-(-)-carvone

Article abstract of DOI:10.1016/j.tet.2012.11.093

The reaction of several stereoisomeric epoxy alcohols, obtained from R-(-)-carvone, and their corresponding formates, acetates, and benzoates, promoted by Cp₂TiCl has been studied. The different outcomes of the reaction of epoxy derivatives are rationalized in terms of mechanistically biased processes. The radicals emerging from oxirane cleavage provide two types of reaction: dehydroxylation (deoxycarbonylation) and dehydrogenation. The results offer considerable support for the radical elimination theory of hydroxyl, formyloxyl, and acetoxyl groups. The inability of tertiary radicals to be reduced by the Ti(III) complex is demonstrated unequivocally.

Full text of DOI:10.1016/j.tet.2012.11.093

Tetrahedron 69 (2013) 1611e1616
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Titanocene-promoted stereoselective eliminations on epoxy alcohols
derived from R-(ꢀ)-carvone
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:
The reaction of several stereoisomeric epoxy alcohols, obtained from R-(ꢀ)-carvone, and their corre-
sponding formates, acetates, and benzoates, promoted by Cp2TiCl has been studied. The different out-
comes of the reaction of epoxy derivatives are rationalized in terms of mechanistically biased processes.
The radicals emerging from oxirane cleavage provide two types of reaction: dehydroxylation (deoxy-
carbonylation) and dehydrogenation.
Received 5 September 2012
Received in revised form 30 October 2012
Accepted 27 November 2012
Available online 7 December 2012
The results offer considerable support for the radical elimination theory of hydroxyl, formyloxyl, and
acetoxyl groups. The inability of tertiary radicals to be reduced by the Ti(III) complex is demonstrated
unequivocally.
Keywords:
Radical reactions
Alcohols
Ó 2012 Elsevier Ltd. All rights reserved.
Titanium
Elimination
Esters
1. Introduction
In a previous paper1 we studied the reaction of a series of
noncyclic 2,3-epoxy alcohols and their corresponding formates,
acetates, and benzoates, promoted by Cp2TiCl. The different out-
comes of the reaction of epoxy derivatives were rationalized in
terms of mechanistically biased processes. After homolytic oxirane
cleavage, four main types of reaction were found: (a) dehydrox-
ylation2 (for alcohols), (b) deoxycarbonylation (for esters)3 (c) de-
hydrogenation,4 and (d) deoxygenation.5 The reaction products
varied according to the substitution pattern. The radical nature of
these eliminations was demonstrated using a kinetic method (see
Scheme 1).3b
In that paper1 we found that the primary alcohol trisubstituted
epoxide system (R¼H, R1¼n-Hex, R2¼R3¼H) and its formate
(R¼HC]O) led exclusively to hydroxyl and formyloxyl elimination,
to afford the allylic alcohol A in 85% and 83% yield, respectively. The
corresponding primary epoxy acetate (R¼MeeC]O) and epoxy
benzoate (R¼PheC]O) mainly afforded the elimination of hydro-
gen to give the allylic alcohol B, in 64% and 73% yield, respectively.1
While the secondary alcohol trisubstituted epoxide system
(R¼R1¼R3¼H, R2¼n-Hex) gave a mixtureof dehydroxylation A (34%)
dehydrogenation B (23%) and deoxygenation C (27%) products, its
formate (R¼HC]O) only gave the deoxycarbonylation product A
Scheme 1. Elimination reactions induced by titanocene on epoxy alcohols and
epoxyesters.
(88%). The corresponding secondary epoxy acetate (R¼MeeC]O)
afforded
a mixture of deoxycarbonylation A (66%) and de-
hydrogenation B (17%) and the epoxy benzoate (R¼PheC]O) gave
a mixture of A (45%) and B (50%).1
The tertiary alcohol trisubstituted epoxide system (R¼R1¼H,
R3¼R2¼n-Bu) afforded deoxygenation product C (53%) as the major
product, but dehydrogenation B (4%) and dehydroxylation A (27%)
* 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 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.093

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A. Fernandez-Mateos et al. / Tetrahedron 69 (2013) 1611e1616
1612
products were also obtained. These experimental data show that
elimination of the hydroxy groups is faster for primary alcohols.
Among the esters, the formyloxyl was the fastest leaving group. The
acetate and benzoate of the secondary alcohols were eliminated
faster than the primary ones.1
All three epoxy alcohol isomers were prepared from R-(ꢀ)-car-
vone 1, following the procedure described by S. Kirsch and T. Bach.7
The corresponding esters (formates, acetates, benzoates) were
obtained by standard procedures (see Scheme 3).
2. Results and discussion
In all these reactions the main intermediate is a tertiary radical
that arises from the regioselective homolytic rupture of the oxirane,
promoted by Ti (III). If as has been stated, the tertiary radicals are
not reduced with Ti(III), due to steric hindrance,1e6 deoxygenation
product C from secondary alcohol trisubstituted epoxide systems I
(R2¼n-Hex, R3¼H), and tertiary alcohol trisubstituted epoxide
system I (R2¼R3¼n-Bu)1 should not have been formed. To explain
this, we suggest that the deoxygenation process that leads to C
could occur in terms of an equilibrium between the intermediate II
and the regioisomer IIa through a six-membered TiIV intermediate
V. The equilibrium should clearly be displaced to the right for the
tertiary epoxy-alcohol1 (Scheme 2).
Scheme 3. Synthesis of epoxy alcohols 3, 7, and 12, and their ester derivatives. (a)
NaBH4, CeCl3, MeOH, 75%; (b) H2O2, NaOH, MeOH, 92%; (c) mCPBA, CH2Cl2, 88%; (d)
FAM; (e) Ac2O, DMAP, pyr; (f) PhCOCl; (g) NaBH4, CeCl3, MeOH, 91%; (h) L-Selectride,
THF, 94%.
2.1. Radical reactions induced by titanocene chloride
The reaction of these epoxyderivatives with titanocene chloride
was carried out by adding a substrate solution in tetrahydrofuran to
another of Ti (III) in the same solvent at room temperature.1 The
extraction and isolation of the reaction products were performed
by the usual procedures. The only reaction products obtained were
those resulting from the b-elimination of OR and/or hydrogen. In no
case, oxirane deoxygenation products were obtained. The results
are quoted in Scheme 4.
The data in Scheme 4 show that the predominant reaction with
epoxy alcohols and epoxy formates was in all cases dehydrox-
ylation or deformylation, whatever the orientation, axial/equato-
rial, of the leaving group. The major product in these cases was 16
(þ)-trans-carveol8 or 24 (þ)-cis-carveol.9 For epoxyacetates, de-
hydrogenation predominated, except for 9, which gives 16
(þ)-trans-carveol as the major product, resulting from the deace-
toxylation.10 The difference in reactivity of 9, can be attributed to
the axial orientation of the acetoxy group in the transition state; in
the other acetates the orientation was equatorial. For epoxy ben-
zoates, the main reaction was the dehydrogenation. Debenzoylox-
ylation did not occur.
Scheme 2. Equilibration of intermediates.
Tables 1 and 2 show the optical rotation of compounds 16,
(þ)-trans-carveol, and 24, (þ)-cis-carveol, depending on which
epoxy derivative they came from.
To check the above hypothesis and to observe the influence of
the spatial orientation of both the epoxydes as the leaving groups,
in the removal rate, we chose some derivatives of cyclohexane with
a rigid conformation, in which the functional groups involved in the
reaction were substituents with varying orientations (see Fig. 1).
The results shown in Scheme 4 lend considerable support to the
radical elimination theory of hydroxyl, formyloxyl, acetoxyl and
benzoyloxyl groups, which we have reported previously.1 They also
add further to the already numerous examples that illustrate the
inability of the complex of Ti (III) to reduce tertiary radicals. In the
hypothetical case that this reduction takes place with the radical
intermediates 3A, 7A, 12A, resulting from the opening of the epoxy
alcohols 3, 7, 12, the CeTi(IV) complexes 3B, 7B, 12B, represented in
Scheme 5 would be obtained. The major products of the evolution
of such intermediates would correspond to the oxirane de-
oxygenation product,1,4 which would afford (ꢀ)-cis-carveol,
(ꢀ)-trans-carveol and (ꢀ)-cis-carveol from 3, 7, and 12, respectively.
This result is the inverse of those obtained experimentally. The
reaction of epoxy alcohols 7 and 12 with Ti (III) should not evolve
through the bicyclic intermediates 7C and 12C, similar to in-
termediate V in Scheme 2, since in that case mixtures of carveols
(racemic) would be obtained, as shown in Scheme 6.
Fig. 1. Cyclohexane derivatives with a rigid conformation.

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A. Fernandez-Mateos et al. / Tetrahedron 69 (2013) 1611e1616
1613
Scheme 4. Elimination reaction on epoxy alcohols and epoxyesters.
Table 1
Optical rotation of (þ)-trans-carveol
20
Entry
From
16 [a]
D
1
2
3
4
5
3
4
7
8
9
þ151.5
þ143.8
þ114.0
þ139.6
þ129.3
Table 2
Optical rotation of (þ)-cis-carveol
20
Entry
From
24 [a]
D
Scheme 5. Evolution of hypothetical intermediates.
1
2
3
12
13
14
þ30.6
þ16.1
þ17.6
3. Conclusion
In sum, we have demonstrated that the reaction of several ste-
reoisomeric epoxy alcohols, obtained from R-(ꢀ)-carvone and their
corresponding formates, acetates, and benzoates, promoted by
Cp2TiCl, evolves in two ways through the radical arising from
oxirane cleavage: dehydroxylation (decarboxylation) and de-
hydrogenation. The different outcomes of the reaction of epoxy
derivatives are rationalized in terms of mechanistically biased
processes. The epoxy alcohols 3 and 7 mainly produced (þ)-trans-
carveol and 12 gave (þ)-cis-carveol. In a similar way, the epoxy
Scheme 6. Evolution of hypothetical intermediates.

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A. Fernandez-Mateos et al. / Tetrahedron 69 (2013) 1611e1616
1614
formates 4 and 8 mainly afforded (þ)-trans-carveol and 13 afforded
(þ)-cis-carveol. Radical elimination of the acetoxyl group only oc-
curred predominantly for the epoxy acetate 9, due to its original
axial orientation. These results mean that elimination of hydroxyl,
formyloxyl, and acetoxyl groups could only occur in a radical way in
the form OTiIV, or ROCOTiIV. Benzoyloxyl elimination was not ob-
served with any of the epoxy benzoates tested. All these results
strongly support the radical elimination theory, of hydroxyl, for-
myloxyl, and acetoxyl groups. The inability of tertiary radicals to be
reduced by the Ti(III) complex is demonstrated unequivocally.
(100), 55 (20); HRMS (ESI): calcd for C10H16ONa 175.1099; found
175.1101. [
Data for 17: IR,
NMR (400 MHz, CDCl3)
a]
20 151.5 (CHCl3, c 4 mg/mL).
D
n
¼3354, 2914, 1432, 1368, 1167, 1028 cmꢀ1
;
1H
d
¼1.73 (s, 3H), 1.2e2.7 (m, 5H), 4.00 (br s,
1H), 4.56 (br s, 1H), 4.72 (br s, 2H), 5.01 (br s, 1H), 5.10 (br s,
1H) ppm; 13C NMR (100 MHz, CDCl3)
d¼20.8 (CH3), 37.5 (CH), 38.6
(CH2), 41.9 (CH2), 68.7 (CH), 73.4 (CH), 107.4 (CH2), 109.3 (CH2),
148.1 (C), 152.1 (C) ppm; MS EI, m/z (relative intensity): 150
(Mþꢀ18, 3),132 (21), 94 (12), 86 (34), 71 (85), 55 (100); HRMS (ESI):
calcd for C10H16O2Na 191.1048; found 191.1449.
4. Experimental section
4.4. Reaction of (1S,2R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-yl formate 4 with Cp2TiCl
R-(ꢀ)-Carvone was purchased, [
a
]
20 ꢀ55.6 (CHCl3, c 40 mg/mL),
D
from Aldrich Chemical Company, Inc.
According to GP1, reaction of 4 (100 mg, 0.6 mmol) with Cp2TiCl
followed by flash chromatography (hexane 8:2 AcOEt) furnished 16
(57 mg, 67%) and 18 (14 mg, 14%).
4.1. General methods
Data for 16: [
Data for 18: IR,
(200 MHz, CDCl3)
a]
20 143.8 (CHCl3, c 12 mg/mL).
D
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.
n
¼2977, 2923, 1723, 1168 cmꢀ1
;
1H NMR
d¼1.0e2.7 (m, 5H), 1.72 (s, 3H), 4.05 (br s, 1H),
4.73 (m, 4H), 5.03 (m, 1H), 8.09 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3)
d¼20.7 (CH3), 36.6 (CH2), 38.0 (CH2), 40.7 (CH), 71.4 (CH),
74.1 (CH), 108.0 (CH2), 109.2 (CH2), 148.0 (2C), 160.7 (CH) ppm; MS
EI, m/z (relative intensity): 150 (Mþꢀ46, 3), 132 (11), 121 (51), 94
(32), 86 (38), 67 (100), 55 (52); HRMS (ESI): calcd for C11H16O3Na
219.0992; found 219.0993.
4.5. Reaction of (1S,2R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-yl acetate 5 with Cp2TiCl
According to GP1, reaction of 5 (100 mg, 0.5 mmol) with Cp2TiCl
followed by flash chromatography (hexane 7:3 diethyl ether) fur-
nished 19 (67 mg, 85%): IR,
n
¼2947, 1738, 1459, 1370, 1252, 1030,
899 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
¼1.71 (s, 3H), 1.2e2.8 (m,
5H), 2.12 (s, 3H), 4.53 (s, 1H), 4.71 (br s, 1H), 4.88 (s, 2H), 4.96 (s, 1H),
4.2. General procedure 1 (GP1)
5.63 (dd, J1¼5.1 Hz, J2¼11.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼20.7 (CH3), 21.0 (CH3), 37.2 (CH), 38.3 (CH2), 38.5 (CH2), 71.0 (CH),
4.2.1. Reaction of epoxides with Cp2TiCl. A mixture of Cp2TiCl2
(2.20 mmol) and 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 compound (1 mmol)
was dissolved in strictly deoxygenated THF (10 mL). The green
Ti(III) solution was slowly added via cannula to the epoxide solu-
tion. 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 satu-
rated NaHCO3 and brine, dried (Na2SO4), and filtered. After removal
of the solvent, the crude product was purified by flash
chromatography.
73.2 (CH), 107.5 (CH2), 109.5 (CH2), 147.8 (2C), 170.1 (C) ppm; MS EI,
m/z (relative intensity): 168 (Mþꢀ42, 2), 150 (10), 135 (8), 121 (31),
106 (10), 92 (37), 81 (45), 71 (100), 58 (91); HRMS (ESI): calcd for
20
C12H18O3Na 233.1148; found 233.1150. [
mL).
a
]
ꢀ80.9 (CHCl3, c 2 mg/
D
4.6. Reaction of (1S,2R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-yl benzoate 6 with Cp2TiCl
According to GP1, reaction of 6 (100 mg, 0.4 mmol) with Cp2TiCl
followed by flash chromatography (hexane 7:3 diethyl ether) fur-
nished 20 (95 mg, 95%): IR,
n
¼2917, 2665, 1697, 1430, 1295, 1113,
939 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
¼1.76 (s, 3H), 1.2e2.3 (m,
5H), 4.13 (br s, 1H), 4.76 (m, 4H), 5.20 (dt, J1¼4.4 Hz, J2¼10.8 Hz, 1H),
4.3. Reaction of (1S,2R,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-ol 3 with Cp2TiCl
7.2e7.5 (m, 3H), 8.0e8.2 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼20.9 (CH3), 36.9 (CH), 38.0 (CH2), 38.4 (CH2), 71.8 (CH), 73.3 (CH),
108.0 (CH2), 109.2 (CH2), 128.5 (2CH), 129.5 (CH), 130.2 (2CH), 133.7
(C), 147.6 (C), 148.3 (C), 171.9 (C) ppm; MS EI, m/z (relative in-
tensity): 150 (Mþꢀ122, 3), 135 (2), 122 (1), 117 (6), 105 (100), 91 (4),
77 (28), 51 (11); HRMS (ESI): calcd for C17H20O3Na 295.1305; found
295.1311.
According to GP1, reaction of 3 (100 mg, 0.6 mmol) with Cp2TiCl
followed by flash chromatography (hexane/EtAcO 7:3) furnished
(1R,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol 16 (78 mg,
79%) and (1R,3R,5S)-2-methylene-5-(prop-1-en-2-yl)cyclohexane-
1,3-diol 17 (12 mg, 12%).
Data for 16: IR,
n
¼3325, 3078, 2923, 1645, 1443, 1378, 1171,
1061 cmꢀ1 1H NMR (200 MHz, CDCl3)
;
d
¼1.57 (dt, J1¼4.0 Hz,
4.7. Reaction of (1S,2S,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-ol 7 with Cp2TiCl
J1¼13.2 Hz, 1H), 1.7e2.4 (m, 4H), 1.73 (s, 3H), 1.78 (s, 3H), 3.99 (br s,
1H), 4.70 (s, 2H), 5.55 (d, J¼5.6 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3)
d
¼20.6 (2CH3), 30.8 (CH2), 35.0 (CH), 36.7 (CH2), 68.1 (CH),
According to GP1, reaction of 7 (100 mg, 0.6 mmol) with Cp2TiCl
followed by flash chromatography (hexane 7:3 AcOEt) furnished
(1R,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol 16 (68 mg,
108.7 (CH2), 124.9 (CH), 134.3 (C), 149.0 (C) ppm; MS EI, m/z (rela-
tive intensity): 134 (Mþꢀ18, 5), 119 (11), 99 (2), 94 (12), 86 (18), 71

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A. Fernandez-Mateos et al. / Tetrahedron 69 (2013) 1611e1616
1615
20
75%), [
a]
20 114 (CHCl3, c 4 mg/mL) and (1R,3R,5S)-2-methylene-5-
furnished 24 (53 mg, 68%), [
a
]
16.1 (CHCl3, c 18 mg/mL) and 25
D
D
(prop-1-en-2-yl)cyclohexane-1,3-diol 21 (5 mg, 5%).
(18 mg, 18%).
Data for 25: IR,
(200 MHz, CDCl3)
Data for 21: IR,
n
¼3353, 2912, 1430, 1362, 1169, 1031 cmꢀ1
;
1H
n
¼3420, 2929, 1720, 1462, 1191 cmꢀ1
;
1H NMR
NMR (400 MHz, CDCl3)
d
¼1.73 (s, 3H), 1.2e2.7 (m, 5H), 4.56 (m, 2H),
d
¼0.9e2.2 (m, 5H), 1.72 (s, 3H), 4.11 (m, 1H), 4.77
4.73 (br s, 2H), 5.02 (s, 1H), 5.10 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3)
(m, 2H), 4.85 (m, 1H), 5.01 (s, 1H), 5.14 (s, 1H), 8.16 (s, 1H) ppm; 13C
NMR (100 MHz, CDCl3)
d¼20.8 (CH3), 37.5 (CH), 38.6 (CH2), 42.0 (CH2), 68.8 (CH), 73.4
d¼20.9 (CH3), 26.1 (CH2), 32.0 (CH2), 39.4
(CH), 107.5 (CH2), 109.3 (CH2), 148.1 (C), 152.2 (C) ppm; MS EI, m/z
(relative intensity): 150 (Mþꢀ18, 2),132 (23), 94 (15), 86 (24), 71 (65),
55(100); HRMS (ESI): calcd forC10H16O2Na 191.1048; found 191.1450.
(CH), 70.7 (CH), 73.9 (CH), 109.5 (CH2), 110.4 (CH2), 147.5 (C), 148.5
(CH), 160.5 (CH) ppm; MS EI, m/z (relative intensity): 150 (Mþꢀ46,
2), 132 (3), 121 (34), 94 (14), 86 (58), 67 (97), 55 (100); HRMS (ESI):
calcd for C11H16O3Na 219.0991; found 219.0992.
4.8. Reaction of (1S,2S,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-yl formate 8 with Cp2TiCl
4.13. Reaction of (1R,2R,4S,6S)-1-methyl-4-(prop-1-en-2-yl)-
7-oxabicyclo[4.1.0]heptan-2-yl acetate 14 with Cp2TiCl
According to GP1, reaction of 8 (125 mg, 0.6 mmol) with Cp2TiCl
followed by flash chromatography (hexane/EtAcO 8:2) furnished 16
According to GP1, reaction of 14 (100 mg, 0.5 mmol) with
Cp2TiCl followed by flash chromatography (hexane/diethyl ether
(98 mg, 97%), [a]
20 139.6 (CHCl3, c 5 mg/mL).
D
7:3) furnished 24 (9 mg, 12%, [a]
20 17.6 (CHCl3, c 4 mg/mL)) and 26
D
4.9. Reaction of (1S,2S,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-yl acetate 9 with Cp2TiCl
(76 mg, 76%).
Data for 26: IR,
NMR (400 MHz, CDCl3)
n
¼2947, 1734, 1451, 1369, 1248, 1029 cmꢀ1
;
1H
d
¼1.71 (s, 3H), 1.2e2.2 (m, 5H), 2.13 (s, 3H),
According to GP1, reaction of 9 (100 mg, 0.5 mmol) with Cp2TiCl
4.15 (m, 1H), 4.73 (m, 2H), 4.95 (s, 1H), 5.10 (s, 1H), 5.20 (m,
1H) ppm; 13C NMR (100 MHz, CDCl3)
d¼20.5 (CH3), 20.9 (CH3), 37.9
followed by flash chromatography (hexane/diethyl ether 7:3) fur-
20
nished 16 (48 mg, 66%), [
a
]
129.3 (CHCl3, c 23 mg/mL) and 22
D
(CH2), 39.2 (CH), 41.2 (CH2), 70.5 (CH), 71.9 (CH), 101.7 (CH2), 109.9
(CH2), 146.8 (C), 149.2 (C), 169.9 (C) ppm; MS EI, m/z (relative in-
tensity): 168 (Mþꢀ42, 2), 150 (8), 135 (18), 121 (26), 106 (5), 92 (34),
(30 mg, 30%).
Data for 22: IR,
NMR (400 MHz, CDCl3)
n
¼2947, 1738, 1456, 1368, 1241, 1024 cmꢀ1
;
1H
d
¼1.73 (s, 3H), 1.2e2.1 (m, 5H), 2.05 (s, 3H),
81 (41), 71 (100), 58 (98); HRMS (ESI): calcd for C12H18O3Na
20
4.38 (m, 1H), 4.79 (br s, 1H), 4.80 (br s, 2H), 5.19 (br s, 2H), 5.53 (t,
233.1148; found 233.1150. [
a
]
ꢀ19.7 (CHCl3, c 70 mg/mL).
D
J¼3.6 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
¼21.0 (CH3), 21.4
d
(CH3), 32.9 (CH), 36.2 (CH2), 38.9 (CH2), 71.7 (CH), 74.0 (CH), 109.8
(CH2), 116.5 (CH2), 144.5 (C), 147.7 (C), 169.6 (C) ppm; MS EI, m/z
(relative intensity): 168 (Mþꢀ42, 3), 150 (8), 135 (12), 121 (27), 106
(13), 92 (27), 81 (47), 71 (98), 58 (100); HRMS (ESI): calcd for
C12H18O3Na 233.1148; found 233.1149.
4.14. Reaction of (1R,2R,4S,6S)-1-methyl-4-(prop-1-en-2-yl)-
7-oxabicyclo[4.1.0]heptan-2-yl benzoate 15 with Cp2TiCl
According to GP1, reaction of 15 (100 mg, 0.4 mmol) with
Cp2TiCl followed by flash chromatography (hexane/diethyl ether
7:3) furnished 27 (90 mg, 90%): IR,
1114, 937 cmꢀ1 1H NMR (400 MHz, CDCl3)
(m, 5H), 4.25 (m, 1H), 4.77 (s, 2H), 5.09 (s, 1H), 5.16 (s, 1H), 5.47 (s,
1H), 7.3e8.2 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3)
n
¼2911, 2663, 1697, 1428, 1298,
4.10. Reaction of (1S,2S,4S,6R)-1-methyl-4-(prop-1-en-2-yl)-7-
oxabicyclo[4.1.0]heptan-2-yl benzoate 10 with Cp2TiCl
;
d
¼1.75 (s, 3H), 1.3e2.4
d¼20.6 (CH3),
According to GP1, reaction of 10 (100 mg, 0.4 mmol) with
Cp2TiCl followed by flash chromatography (hexane 6:4 diethyl
38.0 (CH2), 39.2 (CH), 41.2 (CH2), 70.6 (CH), 72.3 (CH), 101.9 (CH2),
110.0 (CH2), 128.4 (2CH), 129.6 (2CH), 133.0 (CH), 133.6 (C), 146.8
(C), 149.3 (C), 165.3 (C) ppm; MS EI, m/z (relative intensity): 150
(Mþꢀ122, 3), 135 (3), 122 (2), 117 (7), 105 (98), 91 (6), 77 (18), 55
(100); HRMS (ESI): calcd for C17H20O3Na 295.1305; found 295.1308.
ether) furnished 23 (86 mg, 86%): IR,
1298, 1115, 939 cmꢀ1 1H NMR (400 MHz, CDCl3)
1.5e2.6 (m, 5H), 4.05 (s, 1H), 4.76 (m, 4H), 5.60 (m, 1H), 7.3e7.6 (m,
3H), 8.0e8.2 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3)
n
¼2910, 2664, 1694, 1424,
;
d
¼1.81 (s, 3H),
d
¼20.7 (CH3),
[a
]
20 ꢀ18.4 (CHCl3, c 52 mg/mL).
D
30.9 (CH2), 35.1 (CH), 36.6 (CH2), 68.6 (CH), 71.2 (CH), 108.9 (CH2),
109.4 (CH2), 128.4 (2CH), 128.6 (C), 129.3 (C), 130.1 (2CH), 133.6
(CHþC), 171.9 (C) ppm; MS EI, m/z (relative intensity): 150
(Mþꢀ122, 8), 134 (42), 122 (1), 119 (29), 105 (100), 77 (67), 55 (28);
HRMS (ESI): calcd for C17H20O3Na 295.1305; found 295.1309.
Acknowledgements
Financial support for this work from the Ministerio de Ciencia y
Tecnología of Spain (CTQ2005-05026/BQU) and the Regional Gov-
ernment of Castile & Leon (SA200A12-1) is gratefully acknowl-
edged. We also thank the University of Salamanca for the
fellowship to P.H.T.
4.11. Reaction of (1R,2R,4S,6S)-1-methyl-4-(prop-1-en-2-yl)-
7-oxabicyclo[4.1.0]heptan-2-ol 12 with Cp2TiCl
According to GP1, reaction of 12 (100 mg, 0.6 mmol) with Cp2TiCl
followed by flash chromatography (hexane/EtAcO 7:3) furnished
Supplementary data
(1S,5S)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol 24 (87 mg,
1
¼3322, 3072, 2921, 1443, 1372, 1176, 1054 cmꢀ1; H NMR
Experimental procedures and copies of the 1H and 13C NMR
spectra for all new compounds can be found. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2012.11.093. These data include MOL
files and InChiKeys of the most important compounds described in
this article.
89%): IR,
(200 MHz, CDCl3)
n
d
¼1.2e2.3(m, 5H),1.73(brs,6H), 4.21(brs,1H), 4.73
(s, 2H), 5.50 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
20.8 (CH3), 31.2 (CH2), 38.1 (CH2), 40.6 (CH), 71.1 (CH), 109.3 (CH2),
124.1 (CH), 136.5 (C), 149.2 (C) ppm; [
20 30.6 (CHCl3, c 14 mg/mL).
d
¼19.2 (CH3),
a]
D
4.12. Reaction of (1R,2R,4S,6S)-1-methyl-4-(prop-1-en-2-yl)-
7-oxabicyclo[4.1.0]heptan-2-yl formate 13 with Cp2TiCl
References and notes
According to GP1, reaction of 13 (125 mg, 0.6 mmol) with
Cp2TiCl followed by flash chromatography (hexane/EtAcO 8:2)
ꢀ
ꢀ
ꢀ
1. Fernandez-Mateos, A.; Encinas Madrazo, S.; Herrero Teijon, P.; Rubio Gonzalez,
R. Eur. J. Org. Chem. 2010, 856e861.

ꢀ
A. Fernandez-Mateos et al. / Tetrahedron 69 (2013) 1611e1616
1616
2. Yadav, J. S.; Shekharam, T.; Gadgil, V. R. J. Chem. Soc., Chem. Commun. 1990,
843e844.
3. (a) Fernandez-Mateos, A.; Herrero Teijon, P.; Rabanedo Clemente, R.; Rubio
8. (a) Johnston, R. G.; Read, J. J. Chem. Soc. 1934, 233e237; (b) Schmidt, H. Chem.
Ber. 1953, 86, 1437e1444; (c) Klein, E.; Ohloff, G. Tetrahedron 1963, 19,
1091e1099; (d) Schroeter, S. Liebigs Ann. 1964, 118e121; (e) Hamada, H. Bull.
Chem. Soc. Jpn. 1988, 61, 869e878; (f) Dupuy, C.; Luche, J. L. Tetrahedron 1989,
45, 3437e3444; (g) Rieger, R.; Breitmaier, E. Synthesis 1990, 697e701; (h)
Wang, Z.; Lie, F.; Lim, E.; Li, K.; Li, Z. Adv. Synth. Catal. 2009, 351,1849e1856 Ref. 4b.
ꢀ
ꢀ
ꢀ
ꢀ
Gonzalez, R. Tetrahedron Lett. 2006, 47, 7755e7758; (b) Fernandez-Mateos, A.;
ꢀ
ꢀ
Herrero Teijon, P.; Rabanedo Clemente, R.; Rubio Gonzalez, R. Synlett 2008,
3208e3212.
ꢀ
ꢀ
4. (a) Fernandez-Mateos, A.; Martín de la Nava, E.; Pascual Coca, G.; Ramos Silva,
9. (þ) cis-Carveol: (a) Cravero, R. M.; Gonzalez-Sierra, M.; Labadie, G. R. Helv.
ꢀ
A.; Rubio Gonzalez, R. Org. Lett. 1999, 1, 607e609; (b) Bermejo, F.; Sandoval, C. J.
Chim. Acta 2003, 86, 2741e2753; (b) Rafinski, Z.; Scianowski, J. Tetrahedron:
Asymmetry 2008, 19, 1237e1244 Ref. 8e (ꢀ) cis-carveol; (c) Schroeter, S. H.;
Eliel, E. L. J. Org. Chem. 1965, 30, 1e7; (d) Jang, Y. S.; Yang, Y. C.; Choi, D. S.; Ahn,
Y. J. J. Agric. Food Chem. 2005, 53, 7892e7898; (e) Bourque, L. E.; Cleary, P. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2007, 129, 12602e12603; (f) Dhulut, S.; Bourin,
A.; Lannou, M. I.; Fleury, E.; Lensen, N.; Chelain, E.; Pancrazi, A.; Ardisson, J.;
Fahy, J. Eur. J. Org. Chem. 2007, 5235e5243; (g) Chen, Y.; Ju, T. Org. Lett. 2011, 13,
86e89.
Org. Chem. 2004, 69, 5275e5280; (c) Justicia, J.; Jimenez, T.; Morcillo, S. P.;
Cuerva, J. M.; Oltra, J. E. Tetrahedron 2009, 65, 10837e10841.
5. (a) Nugent, W. A.; RajanBabu, T. V.; Beattie, M. S. J. Am. Chem. Soc. 1990, 112,
6408e6409;(b)RajanBabu,T. V.; Nugent, W. A. J.Am. Chem. Soc.1994,116, 986e997.
~
~
ꢀ
6. (a) 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; (b) Fernandez-Mateos, A.; Herrero Teijon, P.; Mateos Buron, L.;
Rabanedo Clemente, R.; Rubio Gonzalez, R. J. Org. Chem. 2007, 72, 9973e9982.
ꢀ
10. The results obtained by Bermejo, F. and Sandoval, C. (Ref. 4b) from 5 and 9 with
Ti(III) are similar, though they obtained also hydrogenation products.
7. Kirsch, S.; Bach, T. Synthesis 2003, 1827e1836.