Emergence of a novel catalytic radical reaction: Titanocene-catalyzed reductive opening of epoxides

Article abstract of DOI:10.1021/ja981635p

The preparatively important catalytic opening of epoxides to β-titanoxy radicals via single-electron transfer (SET) is described. These radicals can be reduced to alcohols or participate in C-C bond-forming reactions. A key step in the catalytic cycle is the conceptually novel protonation of titanium-oxygen and -carbon bonds. Our method combines the advantages of radical reactions, e.g., high functional group tolerance and stability of radicals under protic conditions, with the ability of organometallic complexes to determine the course of transformations in reagent-controlled reactions.

Full text of DOI:10.1021/ja981635p

J. Am. Chem. Soc. 1998, 120, 12849-12859
12849
Emergence of a Novel Catalytic Radical Reaction:
Titanocene-Catalyzed Reductive Opening of Epoxides
Andreas Gansa1uer,* Harald Bluhm, and Marianna Pierobon
Contribution from the Institut fu¨r Organische Chemie der Georg-August-UniVersita¨t, Tammanstrasse 2,
D-37077 Go¨ttingen, Germany
ReceiVed May 11, 1998
Abstract: The preparatively important catalytic opening of epoxides to â-titanoxy radicals via single-electron
transfer (SET) is described. These radicals can be reduced to alcohols or participate in C-C bond-forming
reactions. A key step in the catalytic cycle is the conceptually novel protonation of titanium-oxygen and
-carbon bonds. Our method combines the advantages of radical reactions, e.g., high functional group tolerance
and stability of radicals under protic conditions, with the ability of organometallic complexes to determine the
course of transformations in reagent-controlled reactions.
Introduction
are epoxides,7 which are readily available from suitable precur-
sors such as olefins or carbonyl compounds. The resulting
â-alkoxy radicals are interesting synthetic intermediates. How-
ever, the â-metaloxy functionality requires that the subsequent
radical reaction is faster than trapping with a second equivalent
of electron-transfer reagent. The â-metaloxy metal species
resulting from this trapping undergoes rapid elimination, result-
ing in overall deoxygenation of the epoxide. Thus, the sterically
undemanding, highly active electron donor SmI2 is not suitable
for this reaction but leads to deoxygenation.8 Excellent
stoichiometric reagents for the reductive opening without
deoxygenation in most cases are titanocene(III) reagents acces-
sible from titanocene dichloride by simple in situ reduction with
zinc powder.7 Intra- and intermolecular C-C bond-forming
reactions as well as reduction to alcohols with hydrogen atom
donors are possible. Although very good results can be obtained
in this fashion, a disadvantage of this reaction is the inevitable
use of stoichiometric amounts of titanocene dichloride. Clearly,
it is more desirable to use only catalytic amounts of the complex,
especially when titanocenes are to be used for the improvement
of reagent control, that have to be synthesized in a number of
steps.9
The development of efficient chain reactions has led to
numerous free radical transformations since the beginning of
the 1980s.1 The factors affecting the control of stereo- and
chemoselectivity of these transformations are by now well-
understood.2 However, once the free radical is generated, usually
from halides or organomercury compouds, subsequent trans-
formations are substrate controlled, and selectivities cannot
readily be influenced or overruled by reagents. An interesting
alternative access to radicals is the formation of radical anions
via single-electron transfer (SET) from low-valent metal com-
plexes.3 Here, the course of the reaction is determined by the
steric and electronic influences of the metal and its ligands.
When this influence overrules the selectivity imposed by the
substrate, a reagent-controlled reaction is obtained. Although
this concept is well established in organometallic reactions, a
realization of this concept in radical chemistry has remained
elusive. Radical precursors are usually carbonyl compounds such
as aldehydes or ketones.4 The resulting anions can be dimerized
(pinacol coupling) or can add inter- or intramolecularly to double
bonds. The development of highly active electron donor
reagents, e.g., SmI2, has led to intense activity in this field
recently.5 However, more traditional and cost-effective reagents,
e.g., titanium(III) complexes, can often be used with similar
efficiency.6 Attractive substrates for reductive opening via SET
An intriguing recent development in this respect is the
emergence of catalytic redox reactions from stoichiometric
processes. The general idea is to remove oxygen-containing
products of the stoichiometric transformations from active metal
species while regenerating a metal chloride by silylation with
Me3SiCl. In situ reduction to the redox-active low-valent metal
halide with a suitable, readily available stoichiometric reductant,
usually a metal powder, closes the catalytic cycle. The first
* To whom correspondence should be addressed. Tel.: +49/551-393240.
Fax: +49/551-392944. E-mail: agansae@gwdg.de.
(1) (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-
Carbon Bonds; Pergamon Press: Oxford, 1986. (b) Motherwell, W. B.;
Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic
Press: London, 1991.
(2) (a) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc.,
Chem. Commun. 1980, 482. (b) Smadja, W. Synlett 1994, 1. (c) Curran, D.
P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH:
Weinheim, 1996.
(3) Fu¨rstner, A., Ed. ActiVe Metals; VCH: Weinheim, 1996.
(4) (a) Robertson, G. M. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Pattenden, G., Eds.; Pergamon Press: Oxford, 1991;
Vol. 3, p 563. (b) Wirth, T. Angew. Chem. 1996, 108, 65; Angew. Chem.,
Int. Ed. Engl. 1996, 35, 61. (c) Molander, G. A.; Harris, C. R. Chem. ReV.
1996, 96, 307.
(6) (a) McMurry, J. E. Acc. Chem. Res. 1983, 16, 405. (b) Raubenheimer,
H. G.;. Seebach, D. Chimia 1986, 40, 12. (c) Handa, Y.; Inanaga, J.
Tetrahedron Lett. 1987, 28, 5717. (d) Barden, M. C.; Schwartz, J. J. Am.
Chem. Soc. 1996, 118, 5484.
(7) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988, 110,
8561. (b) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1989, 111,
4525. (c) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J. Am. Chem.
Soc. 1990, 112, 6408. (d) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem.
Soc. 1994, 116, 986.
(8) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693. (b) Matsukawa, M.; Tabuchi, T.; Inanaga, J.; Yamaguchi, M.
Chem. Lett. 1987, 2101.
(5) (a) Kagan, H. B. New J. Chem. 1990, 14, 453. (b) Molander, G. A.
Chem. ReV. 1992, 92, 29. (c) Curran, D. P.; Fevig, T. L.; Jasperse, C. P.;
Totleben, M. J. Synlett 1992, 943.
(9) Halterman, R. L. Chem ReV. 1992, 92, 965.
10.1021/ja981635p CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/24/1998

12850 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Gansa¨uer et al.
Figure 2. Acids used in this study.
Figure 1. Anticipated mechanism for reductive opening of epoxides.
example of the successful realization of this concept is Fu¨rstner’s
McMurry coupling, catalytic in titanium.10 The stoichiometric
reagent combination applied was zinc powder and Me3SiCl.
Even more useful is the Nozaki-Hiyama coupling catalytic in
chromium developed by the same group.11 Subsequently, similar
processes for catalytic pinacol couplings12 and various other
transformations13 have been devised by other groups. However,
limitations exist. First, groups sensitive to the highly reactive
Me3SiCl, e.g., epoxides, alcohols, and certain aldehydes, are
not tolerated. Second, readily reducible groups can be activated
by Me3SiCl toward electron transfer, e.g., aromatic aldehydes
and ketones in pinacol couplings.14 Third, although the high
oxophilicity of Me3SiCl allows efficent trapping of metal oxo
species, straightforward conversion of less polar carbon-metal
bonds to alkyl silanes and metal chlorides is, for the same reason,
precluded. Also, recycling of (Me3Si)2O, the byproduct of the
reaction after hydrolysis, is hard to achieve. Thus, stoichiometric
amounts of waste are inevitably produced. This is especially
disadvantageous for applications on a large scale.
Figure 3. Reductive opening of epoxide 7.
epoxide but must be strong enough to protonate titanium-
oxygen bonds. (2) The acid must not oxidize the metal powder
or any catalytically active titanium(III) species. (3) The resulting
base must not coordinate to and deactivate any titanium species
in the catalytic cycle. (4) The metal powder must reduce
titanocene dichloride fast and efficiently to the redox-active
titanium(III) species. (5) The resulting alcohols should not
deactivate any titanium species in the catalytic cycle. (6) The
Lewis acid formed during the reduction of titanocene dichloride
must not interfere with the catalytic cycle.
To achieve protonation of the metal-oxygen bond, the acidity
of the proton donor must be higher than that of typical alcohols
To ensure complete protonation, the pKa difference with typical
alcohols (MeOH ) 15.5)17 should be at least 3. The acid should
not have a pKa lower than that of pyridine hydrochloride (5.25),
which opens epoxides to chlorohydrins as a mild acid in
chloroform.18 A resonable window for the pKa is thus 5.25-
12.5. See Figure 2 for the acids tested in this investigation.
Optimization of the Reaction. We decided to optimize the
reductive opening of epoxide 7 in the presence of 1,4-
cyclohexadiene as hydrogen atom donor, a stoichiometric
reductant, and the indicated acid as outlined in Figure 3. Table
1 summarizes the results of our studies.
In this full paper, we wish to disclose our results on the
development of a conceptually novel titanocene-catalyzed
reductive opening of epoxides,15 exploiting the fact that radicals
are normally stable under protic conditions1a,2c,16 and avoiding
the above-mentioned disadvantages of silylation. The resulting
transformation is a rare example of a transition-metal-catalyzed
radical reaction with reagent control.12c,d,15,16
Results and Discussion
With the above-mentioned points in mind, we decided to
investigate protonation of titanium-oxygen and -carbon bonds
as a means to achieve catalytic turnover. The anticipated
mechanism for the catalytic reaction is depicted in Figure 1.
Several requirements for efficient turnover become apparent.
(1) The acid employed must be weak enough not to open the
Expectedly, the strong acid 1 gave almost exclusively 9 by
opening of the epoxide via an SN1 mechanism. Pyridine
hydrochloride 2 and 2,6-lutidine hydrochloride 3 yielded some
of the desired product 8 with Zn as reductant. However,
chlorohydrin 9 could also be detected in the crude reaction
mixture. Thus, the SN1 pathway was still operating to a
significant amount. 2,4,6-Collidine hydrochloride 4 with zinc
powder as reductant lead to a distinct improvement. The amount
(10) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468.
(11) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533. (b)
Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc 1996, 118, 12349.
(12) (a) Hirao, T.; Hasegawa, T.; Muguruma, Y.; Ikeda, I. J. Org. Chem.
1996, 61, 366. (b) Nomura, R.; Matsuno, T.; Endo, T. J. Am. Chem. Soc.
1996, 118, 11666. (c) Gansa¨uer, A. J. Chem. Soc., Chem. Commun. 1997,
457. (d) Gansa¨uer, A. Synlett 1997, 363. (e) Lipski, T. A.; Hilfiker, M. A.;
Nelson, S. G. J. Org. Chem. 1997, 62, 4566.
(13) (a) Corey, E. J.; Zheng, G. Z. Tetrahedron Lett. 1997, 38, 1045.
(b) Grigg, R.; Putnikovic, B.; Urch, C. J. Tetrahedron Lett. 1997, 38, 6307.
(14) So, J.-H.; Park, M. K.; Boudjouk, P. J. Org. Chem. 1988, 53, 5871.
(15) Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem. 1998, 110,
107; Angew. Chem., Int. Ed. 1998, 37, 101.
(17) (a) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; pp 248-253. (b) Handbook of Chemistry and Physics, 78th
ed.; Lide, D. R., Ed.; CRC Press: Boca Raton, FL, 1997; 8-45-8-55.
(18) Loreto, M. A.; Pellacani, L.; Tardella, P. A. Synth. Commun. 1981,
11, 287.
(16) Gansa¨uer, A.; Bauer, D. J. Org. Chem. 1998, 63, 2070.

Titanocene-Catalyzed ReductiVe Opening of Epoxides
Table 1. Optimization of the Reductive Opening of 7
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12851
Table 2. Influence of Substitution on Regioselectivity of Epoxide
Opening
acid
metal
time/h
7:8:9a
1
1
2
2
3
3
4
4
5
5
6
6
Zn
Mn
Zn
Mn
Zn
Mn
Zn
Mn
Zn
Mn
Zn
16
16
35
16
36
16
36
16
16
16
16
16
2:0:98
1.5:0.5:98
28:32:26
50:4:46
30:43:22b
2:92:6c
15:73:12d
2:96:2e
77:13:10
82:12:6
82:6:12
84:6:10
Mn
1
a Determined by GC analysis and H NMR of the crude mixture.
b 5% of a product containing an aldehyde group are also formed. c 85%
isolated yield. d 71% isolated yield. e 88% isolated yield.
a Substrate was a mixture of cis and trans isomers. b Formed as 94:6
mixture of 1- and 2-dodecanol. c Two equivalents of collidine added
to the mixture.
Figure 4. Deoxygenation of epoxides without 1,4-cyclohexadiene.
of chlorohydrin was reduced and conversion significantly
improved. With manganese as reductant and 4, hardly any 9
was formed. 8 could be isolated in 88% yield. The difference
between Mn and Zn was even more pronounced in the case of
2,6-lutidine hydrochloride 3. Only 6% of 9 and 92% of 8 could
be detected in the crude mixture. The isolated yield of 8 was
85%. Presumably, ZnCl2, formed during the reduction of
Cp2TiCl2, complexed and slowly opened the epoxide in addition
to protic opening. MnCl2 was not Lewis-acidic enough to initiate
this side reaction. Without 1,4-cyclohexadiene as hydrogen atom
donor, a complex mixture of products was obtained, consisting
mainly of the deoxygenated product and 9. Deoxygenation
occurs via trapping of the radical with titanium(III) and
subsequent elimination of titanium-oxo species as shown in
Figure 4.
Figure 5. Catalyst acitivation by binding of 1-dodecanol.
equivalent of 4, 7, and Mn results in a catalytic system with
activity similar to that observed at the beginning of the reaction.
Scope and Limitation of the Reductive Opening. With this
efficient system in hand, we turned our attention to the scope
of substrates. Various differently substituted epoxides containing
a number of functional groups were tested as substrates.
As in the stoichiometric transformation,7 1,1-disubstituted
epoxides, e.g., 7, are opened to give the less substituted alcohols
via formation of the higher substituted radical (Table 2). The
same holds true for trisubstituted epoxide 10. 1,2-Disubstited
epoxides, e.g., the cis and trans mixture of cyclododecane oxide
12, yield the corresponding alcohols cleanly. A more difficult
example is the reaction of 1-dodecene oxide 14. Under the
standard conditions, conversion to 1- and 2-dodecanol of about
only 50% could be achieved, even after prolonged reaction
times. Also, 22% of deoxygenation was observed. It seems that
the sterically relatively unhindered radical can be intercepted
by a second equivalent of titanium(III) reagent, resulting in
reductive elimination of a titanium-oxo species. This was,
however, the only case where deoxygenation was observed. We
found that addition of 2 equiv of collidine to the mixture
significantly accelerated the reaction and led to quantitative
conversion to products after 19 h. The reason for acceleration
of the reaction in the presence of excess collidine could be
removal of 1- or 2-dodecanol or water by means of hydrogen
bonding from some titanium species in the catalytic cycle. Thus,
the active form of the catalyst can be regenerated by binding
of dodecanol, as shown in Figure 5, and the reaction is allowed
to proceed to completion smoothly.
Thus, the combination of 4, manganese dust, and 1,4-
cyclohexadiene constitutes an ideal combination for the
titanocene-catalyzed reductive opening of epoxides. Although
3 also constitutes an excellent acid, 4 was preferred since it is
a distinctly less hygroscopic compound and is thus more
convenient to handle.
Phenols 5 and 6 did not lead to conversions greater than 20%
after 16 h. It seems that the formed titanocene(IV) phenoxides
cannot be efficiently reduced to redox-active titanocene(III)
derivates. Similar observations have been made in studies
concerning the reduction of titanocene(IV) derivatives and
stoichiometric titanocene induced pinacol couplings with triflate
counterions.6d,19 An economically attractive feature of our
conditions was that both collidine and lutidine could be easily
recovered after the reaction by simple acid-base extraction.
Although the reaction takes about 16 h to go to completion
with 4, the initial rate of formation of 8 is high. Conversion of
7 to 8 is 65%, 72%, 80%, and 85% after 0.5, 1, 2, and 3 h,
respectively. This decrease in reaction rate seems to be due to
the lowering of the concentration of 7. Addition of a second
(19) (a) Green, M. L. H.; Lucas, C. R. J. Chem. Soc., Dalton Trans.
1972, 1000. (b) Coutts, R. S. P.; Wailes, P. C.; Martin, R. L. J. Organomet.
Chem. 1973, 47, 375. (c) Sekutowski, D.; Jungst, R.; Stucky, G. D. Inorg.
Chem. 1978, 17, 1848. (d) Stephan, D. W. Organometallics 1992, 11, 996.
Dodecanol was isolated in 55% yield as a 94:6 mixture of 1-
and 2-dodecanol. This ratio is somewhat higher than the 88:12
ratio obtained in the stoichiometric system.7 Two different

12852 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Gansa¨uer et al.
Table 3. Functional Groups Tolerated under the Optimized
Conditions
Figure 6. Possible pathways leading to the formation of 2-dodecanol.
mechanisms for the formation of 2-dodecanol are shown in
Figure 6.
The thermodynamic path seems to be less likely since
formation of the less substituted radical was not observed in
any other example. This should have been the case, especially
for the trisubstituted epoxide 10. Also, the ratio of products
should depend on the radical trap used if the radicals were
equilibrating. This was not observed in addition reactions to
acrylates, as will be discussed later. The same 94:6 ratio of
products was obtained. Therefore, it seems that, after complex-
ation of the epoxide and electron transfer, the steric interaction
of the titanocene and the substituent of the epoxide is responsible
for the regioselectivity of the opening. This results in the kinetic
pathway described in Figure 6. 1- and 2-dodecanol formed
during the course of the reaction seem to complex the catalyst.
Therefore, its steric demand increases, and the selctivity of the
reaction is improved.
the catalytic cycle by complexation of titanium species nor
decomposed base sensitive substrates or products of the reaction.
Tosylates 18 and 19 did not yield any products of elimination.
Also, protecting groups that are prone to migration under basic
conditions such as pivalate or silyl ethers did not migrate at
all, even when kinetically favorable. Remote unactived double
bonds as in 16 or 17, being in principle susceptibe to attack by
radicals, were not affected under the reaction conditions. It
seems that hydrogen atom abstraction from 1,4 cyclohexadiene
was faster than addition to the double bond. The simple access
of epoxides via sulfur ylide chemistry22 of suitable unsaturated
ketones or metal catalyzed epoxidations23 allows free choice
of the positioning of the alcohol after reductive opening.
Hydroboration allows formation of the alcohol only at the less
substituted, sterically less demanding double bond.25 Thus,
2-methyl-1,11-dodecadiene would yield predominatly the
alcohol resulting from attack at the monosubstituted double bond
and not alcohol 17 obtained by our method. A number of
functional groups not compatible with boranes, e.g., alcohols,
double bonds, and ketones, are readily tolerated.25
From a synthetic point of view, our method offers a simple
and convenient way of catalytically opening epoxides in a
manner opposite to that of SN2 reactions.20
Chemoselectivity of the Catalytic Opening. Since the
stoichiometric parent system is highly tolerant to sensitive
functionality,7 achieving the same kind of tolerance in catalytic
reactions requires an exceptionally mild and selective stoichio-
metric reductive system with respect to chemoselectivity in
electron transfer. Table 3 summarizes the results of our
investigations regarding this important aspect of the reaction.
Esters 24 and 27, ketones, and even aromatic ketones (note
entries 8 and 9 for two competition experiments) did not
interfere.14 Tosylates 18 and 19 and chlorides 26 and 27, which
are reduced using samarium diiodide,8a,21 remained intact
without any sign of decomposition. It seems that manganese
selectively reduces titanocene dichloride19c to the catalytically
active electron-transfer reagent.
(22) Aube´, J. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Pattenden, G., Eds.; Pergamon Press: Oxford, 1991; Vol. 1,
pp 819-834.
(23) For some recent reviews, see: (a) Rao, A. S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Pattenden, G., Eds.; Pergamon
Press: Oxford, 1991; Vol. 7, pp 358-375. (b) Meunier, B. Chem. ReV.
1992, 92, 1411. (c) Gansa¨uer, A. Angew. Chem. 1997, 109, 2701; Angew.
Chem., Int. Ed. Engl. 1997, 36, 2591.
Collidine formed during the course of the reaction by
protonation of the titanium oxygen bond neither interfered with
(24) Soderquist, J. A. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L., Ed.; Wiley: New York, 1995; Vol. 2, pp 622-630.
(25) (a) Brown, H. C.; Heim, P. J. Am. Chem. Soc. 1970, 92, 1637. (b)
Negishi, E. I. In ComprehensiVe Organometallic Chemistry; Wilkinson, G.,
Stone, F. G. A., Abel, E. W., Eds.; Pergamon Press: Oxford, 1982; Vol. 7,
p 255. (c) Molin, H.; Pring, B. G. Tetrahedron Lett. 1985, 26, 677.
(20) (a) Bickborn, B.; Quartucci, J. J. Org. Chem. 1964, 29, 3185. (b)
Bickborn, B.; Lamke, W. E. J. Org. Chem. 1967, 32, 537. (c) Brown, H.
C.; Narasimham, S.; Somayayi, V. J. Org. Chem. 1983, 48, 3091. (d) Corey,
E. J.; Tins, M. A. J. Am. Chem. Soc. 1980, 102, 7612.
(21) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.

Titanocene-Catalyzed ReductiVe Opening of Epoxides
Table 4. Cyclization Studies under Optimized Conditions
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12853
Figure 7. Mechanism of cyclization reactions.
the synthetically valuable alcohol function is obtained in the
product. Table 4 summarizes the results of our investigations
Diastereoselectivities for the formation of five-membered
rings are in the usual range for radical cyclizations.27 In
accordance with the Beckwith-Houck model,28 the cis-disub-
stituted products are formed preferentially. In the case of
substrate 34, the 5-exo and 6-exo products were formed as a
91:9 mixture, reflecting the regioselectivity of epoxide opening.
36 yields 37 as the sole product. The allyl alcohol moiety in 35
and 36 allows further synthetic elaboration of the products.
In the cyclization reaction yielding the bicyclic product 39,
stereoselectivitiy is in the same range as in the stoichiometric
reaction.7 However, in the case of 41, diastereoselectivity is
significantly higher and almost complete (98:2) under our
conditions. A 90:10 ratio is obtained with the parent system.7
It seems that binding of some alcohol present in the reaction
mixture by titanium(III) increases the steric demand of the
catalyst enough to allow better control of selectivity. The five-
membered rings in 39 and 41 are exclusively cis-fused.7 Thus,
the diastereomeric mixtures are epimers at the methyl group
bearing carbon atoms, and so only two of four possible
diastereoisomers are formed. Our cyclization conditions are
being tested in the synthesis of natural products containing five-
membered rings in our laboratories.
Intermolecular Addition Reactions to r,â-Unsaturated
Carbonyl Compounds. An important reaction in radical
chemistry is the intermolecular addition to electron-deficient
activated olefins. Our method offers a convenient catalytic
access to δ-hydroxyesters, δ-lactones, and δ-hydroxynitriles.
δ-Lactones are ubiquitous in nature. Hydroxyesters and nitriles
are crucial intermediates in the synthesis of important classes
of compounds, e.g., amino alcohols. See Figure 8 for details.
The mechanism of the catalytic reaction is depicted in Figure
9. After addition of the â-titanoxy radical to the double bond,
an enol radical is formed that is trapped by titanium(III) to yield
an enolate. Both titanium-oxygen bonds are protonated to
liberate the product.
a cis:trans 88:12. b cis:trans 86:14. c As 91:9 mixture of 5-exo and
6-exo products. d As 52:48 mixture of epimers. e As 98:2 mixture of
epimers.
Cyclization Reactions with Protonation of Titanium
Carbon Bonds. Radical cyclizations are among the most
powerful and versatile methods for the construction of mono-
and polycyclic systems. A fruitful interplay between synthetic
and physical organic chemistry has allowed a deep understand-
ing of this transformation. An especially important type of
reaction is the formation of five-membered rings via 5-exo
cyclization. The application of this methodology has culminated
in the elegant total synthesis of a number of natural products.26
Suitably unsaturated epoxides constitute interesting substrates
for this important reaction.
In the cases investigated here, the radical formed after
cyclization is trapped with the redox-active titanocene(III)
derivative to give an alkyl or vinyl titanocene(IV) chloride, as
depicted in Figure 7.
Both titanium-oxygen and -carbon bonds are protonated
by collidine hydrochloride to regenerate titanocene dichloride
and liberate the cyclization products. Thus, no hydrogen atom
donor, i.e., 1,4-cyclohexadiene, is necessary in these reactions,
and both additional protons present in the product of the reaction
originate from HCl. This efficient way of conducting the reaction
becomes possible because the intermediate radicals formed by
reductive opening of the epoxide are stable toward protic
conditions. The final anionic products after reductive trapping
with titanocene(III) chloride are acid sensitive.
Our approach reduces the amount of titanium complex needed
by a factor of 40. Effectively, titanocene dichloride is replaced
by collidine hydrochloride, except for the amount needed for
catalysis. Compared to cyclization reactions conducted in the
presence of stannanes, no toxic and sensitive reagents are
needed, and no toxic side-products are generated. Additionally,
With Mn as reductant, yields were low, even after prolonged
reaction times. We reasoned that this was due to complexation
of titanium by the product, as indicated in Figure 10.
There are two ways of avoiding this problem by binding of
the substrate. A stronger Lewis acid, e.g., ZnCl2, could replace
(26) (a) Giese, B.; Kopping, B.; Go¨bel, T.; Thoma G.; Dickhaut, J.;
Kulicke, K. J.; Trach, F. In Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1996; Vol. 48, p 301. (b) Bazukis, P.; Campos, O. O.
S.; Bazukis, M. L. F. J. Org. Chem. 1976, 41, 3261. (c) Bu¨chi, G.; Wu¨est,
H. J. Org. Chem. 1979, 44, 546. (d) Curran, D. P.; Rakiewicz, D. M. J.
Am. Chem. Soc. 1985, 107, 1448. (e) Curran, D. P.; Chen. M.-H.
Tetrahedron Lett. 1985, 26, 4991.
(27) (a) Beckwith, A. L. J.; Easton, C. J.; Lawrence, T.; Serelis, A. K.
Aust. J. Chem. 1983, 36, 545. (b) Beckwith, A. L. J.; Lawrence, T.; Serelis,
A. K. J. Chem. Soc., Chem. Commun. 1980, 484. (c) A. L. J. Beckwith, A.
L. H.; Schiesser, C. H. Tetrahedron Lett. 1985, 26, 373, (d) Spellmeyer,
D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959. (e) RajanBabu, T. V.
Acc. Chem. Res. 1991, 24, 139.
(28) Lehn, J. M. Supramolecular Chemistry; VCH: Weinheim, 1995.

12854 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Gansa¨uer et al.
Table 5. Optimization of Addition Reactions to R,â-unsaturated
Carbonyl Compounds
entry
acceptor
time/h
product
yield/%
1
2
3
4
5
6
7
8
9
42a
42b
42c
43
66
16
44
16
43
12
14
65
16
45
45
45
47
47
47
46
47
47
68
81
73
83
73
88
80
21
72
43c
43b
43a,b
44a
44b
a Mn as reductant. b One equivalent of ZnCl2. c One mole % catalyst.
Figure 8. Addition reactions to R,â-unsaturated carbonyl compounds.
Table 6. Addition Reactions under Optimized Conditions
50
51
52
Figure 9. Mechanism of addition reactions to R,â-unsaturated carbonyl
compounds.
a No ZnCl2 added. b 43 as acceptor, 12 h of reflux to complete
reaction.
with Zn as reductant. Here, ZnCl2 was formed during reduction
of Cp2TiCl2. With acrylonitrile as radical acceptor, lactone 47
was obtained as the sole product of the reaction after aqueous
workup. Hydroxynitrile was formed in 85% yield after 3 h.
ZnCl2-induced cyclization then resulted in formation of 47 in
80% yield after 16 h. Activation of the catalyst by ZnCl2 enabled
the use of 1 mol % of catalyst without significant reduction in
isolated yields. Compared to the stoichiometric system,7 the
amount of titanium is reduced by a factor of 200!
Figure 10. Catalyst deactivation by product inhibition.
Interestingly, with Mn and ZnCl2, only hydroxynitrile 46 was
formed after 8 h in high yield. MnCl2 formed during reduction
of Cp2TiCl2 seemed to complex and protect the nitrile group
from nucleophilic attack. ZnCl2 should be binding the hydroxy
group.
Table 6 summarizes the results of some reactions performed
under the optimized conditions.
As expected, a number of functional groups is tolerated, and
higher substituted epoxides react without problems to give the
desired products in good yields. To achieve sterically more
demanding additions to the nitrile group, the reaction mixture
had to be refluxed.
Figure 11. Restoring catalyst activity by binding of the products.
Binding the reaction products by a carefully chosen Lewis
acid thus allows a highly efficient entry to δ-lactones, δ-hy-
droxyester, and δ-hydroxynitriles via radicals. These transfor-
mations amply demonstrate the usefulness of our concept to
combine the advantages of organometallic and radical chemistry.
titanium to liberate the active precatalyst. A suitable hydrogen
bond acceptor should bind the alcohol to reactivate the catalyst
acting as a supramolecular cofactor.28 See Figure 11 for an
illustration of this concept.
Table 5 summarizes the results of our investigations of
addition reactions with 14 in the presence of Lewis acids.
With ZnCl2 as additive, catalyst activity increased dramati-
cally. Although less pronounced, the same effect was observed
Hydrogen bonding also constituted a convenient means to
achieve catalyst activation. However, if the hydrogen bond
acceptor was a powerful ligand, e.g., DMPU, deactivation was
observed. 2,4,6-Collidine proved to be a suitable base. Obvi-

Titanocene-Catalyzed ReductiVe Opening of Epoxides
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12855
1
Table 7. Collidine as Supramolecular Cofactor in Addition
Rf (10% MTBE, 90% PE): 0.15. H NMR (300 MHz, CDCl3): 9a
Reactions
δ ) 7.32-7.20 (m, CHAr, 5H), AB-system (δA ) 3.69, δB ) 3.63, JAB
3
) 11.8 Hz, additionally split by J ) 6.8 Hz, CH2OH), AB-system
(δA ) 2.85, δB ) 2.77, JAB ) 13.6 Hz, additionally split by 3JA, 3JA )
3
3
5.9 Hz, JB, JB ) 5.6 Hz, CH2Ar), 2.21-2.01 (m, CHCH2CH2Ar),
1.97 (t, 3J ) 6.9 Hz, 3J ) 6.9 Hz, OH), 1.61 (s, CH3); 9a (only clearly
separated signals) δ ) AB-system (δA ) 3.57, δB ) 3.55, JAB ) 9.8
Hz, CH2Cl), 2.74 (m, CH2Ar), 1.35 (s, CH3). 13C NMR (50 MHz,-
CDCl3): 9a δ ) 141.35, 128.44, 128.31, 126.00, 75.21, 71.05, 42.33,
30.82, 26.14; 9b δ ) 141.88, 128.24, 125.92, 71.94, 54.20, 41.14, 30.13,
24.40. IR (film): 3405, 3035, 2935, 2925, 2865, 1600, 1495, 1455,
1380, 1170, 1060 cm-1. Anal. Calcd for C11H15ClO (198.7): C, 66.50;
H, 7.61. Found: C, 66.22; H, 7.76.
2-Methyl-4-phenylbutan-1-ol 830 (Table 1, Entry 6). To a suspen-
sion of 3 (215 mg, 1.5 mmol) in THF (10 mL) was added epoxide 731
(0.165 mL, 1.0 mmol), 1,4-cyclohexadiene (0.41 mL, 4.3 mmol),
titanocene dichloride (12.5 mg, 0.05 mmol), and manganese (82 mg,
1.5 mmol). After the mixture was stirred for 16 h, excess manganese
was decanted off and MTBE (50 mL) was added. The organic layer
was washed with H2O (30 mL), 2 N HCl (30 mL), H2O (30 mL),
saturated aqueous NaHCO3 (30 mL), and H2O (30 mL) and dried
(MgSO4). After removal of the volatiles, the crude product was purified
by flash chromatography on silica gel (25% MTBE, 75% PE) to give
140 mg of 7 (85%).
ously, complexation of a titanium species in the catalytic cycle
was not occurring.
Table 7 summarizes the results of the reactions run under
buffered protic conditions. Addition to acrylic acid methyl ester
proceeds smoothly to give 47 in good yield. Thus, collidine
acts as a supramolecular cofactor to restore catalyst activity via
hydrogen bonding. To the best of our knowledge, the concept
of restoring catalyst activity via hydrogen bonding is without
precedent in the literature.
General Procedure 1. Reductive opening of epoxides in the presence
of 4.
In summary, we have demonstrated that 2,4,6-collidine or
2,6-lutidine hydrochloride and manganese constitute an excep-
tionally mild stoichiometric system for titanocene-catalyzed
highly regioselective reductive opening reactions of epoxides.
Our catalytic conditions feature excellent chemoselectivity,
should allow for applications of this chemistry on a large scale,
and broaden the usefullness of epoxides as valuable intermedi-
ates in synthesis even further. Cyclization reactions can proceed
with exceptional diastereoselectivity and allow simple access
to structures important for natural product synthesis. Intermo-
lecular additions to R,â-unsaturated carbonyl compounds yield
the desired products in high yields, even with 1 mol % of
catalyst.
2-Methyl-4-phenylbutan-1-ol 8 (Table 1, Entry 8). To a suspension
of 4 (236 mg, 1.50 mmol) in THF (10 mL) was added epoxide 7 (165
µL, 1.00 mmol), 1,4-cyclohexadiene (0.410 mL, 4.3 mmol), titanocene
dichloride (12.5 mg, 0.05 mmol), and manganese (82 mg, 1.50 mmol).
After the mixture was stirred for 16 h, excess manganese was decanted
off, and MTBE (50 mL) was added. The organic layer was washed
with H2O (30 mL), 2 N HCl (30 mL), H2O (30 mL), saturated aqueous
NaHCO3 (30 mL), and H2O (30 mL) and dried (MgSO4). After removal
of the volatiles, the crude product was purified by flash chromatography
on silica gel (25% MTBE, 75% PE) to give 144 mg of 8 (88%).
1-Cyclohexylethanol 11.7 According to general procedure 1, 4 (472
mg, 3.0 mmol), 1032 (0.280 mL, 2.0 mmol), 1,4-cyclohexadiene (0.85
mL, 8.50 mmol), titanocene dichloride (25.0 mg, 0.10 mmol), and
manganese (164 mg, 3.0 mmol) were reacted for 16 h. After silica gel
chromatography (25% MTBE, 75% PE), 208 mg of 11 was obtained
(81%).
Experimental Section:
Cyclododecanol 13. According to general procedure 1, 4 (236 mg,
1.5 mmol), 12 (182 mg, 1.0 mmol), 1,4-cyclohexadiene (0.41 mL, 4.3
mmol), titanocene dichloride (12.5 mg, 0.05 mmol), and manganese
(60 mg, 1.1 mmol) were reacted for 30 h. After silica gel chromatog-
raphy (25% MTBE, 75% PE), 153 mg of 13 was obtained (83%).
1-Dodecanol 15 (Table 2, Entry 4). According to general procedure
1, 4 (236 mg, 1.5 mmol), 14 (0.220 mL, 1.0 mmol), 1,4-cyclohexadiene
(0.41 mL, 4.3 mmol), titanocene dichloride (12.5 mg, 0.05 mmol), and
manganese (60 mg, 1.1 mmol) were reacted for 30 h. After silica gel
chromatography (25% MTBE, 75% PE), 86 mg of 13 was obtained
(47%) as a 94:6 mixture of 1- and 2-dodecanol.
1-Dodecanol 15, (Table 2, Entry 5). According to general procedure
1, 4 (236 mg, 1.5 mmol), 14 (0.220 mL, 1.0 mmol), 1,4-cyclohexadiene
(0.41 mL, 4.3 mmol), titanocene dichloride (12.5 mg, 0.05 mmol), 2,4,6-
collidine (0.265 mL, 2.0 mmol), and manganese (60 mg, 1.1 mmol)
were reacted for 30 h. After silica gel chromatography (25% MTBE,
75% PE), 104 mg of 13 was obtained (55%) as a 94:6 mixture of 1-
and 2-dodecanol.
General Procedures. All reactions were performed in oven-dried
(100 °C) glassware under N2. THF was freshly distilled from LiAlH4.
CH2Cl2 was freshly distilled from CaH2. Products were purified by
flash chromatography29 on Merck silica gel 50 (eluents given in
brackets, MTBE refers to tert-butyl methyl ether and PE to petrol ether,
30-60 °C fractions). Yields refer to analytically pure samples. Isomer
ratios were determined from suitable 1H NMR integrals of cleanly
separated signals or by GC analysis: 1H, tetramethylsilane (0.00 ppm)
in the indicated solvent, benzene-d5 (7.15 ppm) and CHCl3 (7.26 ppm)
as internal standard in the same solvent; 13C NMR, tetramethylsilane
(0.00 ppm) in the indicated solvent or CDCl3 (77.00 ppm) and benzene-
d6 (128.00 ppm) as internal standards in the same solvent; Bruker AMX
300 and Varian XR 200; integrals in accord with assignments, coupling
constants are measured in hertz. Combustion analyses were done by
F. Hambloch, Institute of Organic Chemistry, University of Go¨ttingen.
IR spectra were obtained using a Perkin-Elmer 1600 series FTIR as
KBr pellets or as neat films on NaCl plates.
2-Chloro-2-methyl-4-phenylbutan-2-ol 9. To a suspension of 1 (843
mg, 6.0 mmol) and zinc chloride (307 mg, 2.3 mmol) in THF (15 mL)
was added 7 (243 mg, 1.5 mmol). The resulting mixture was stirred
for 12 h at room temperature. After addition of MTBE (50 mL), the
mixture was extracted with 2 N HCl (2 × 10 mL), saturated NaHCO3
(10 mL), and brine (10 mL). After drying (MgSO4) and evaporation of
the solvents, the crude material was purified by silica gel chromatog-
raphy (10% MTBE, 90% PE) to give 238 mg of 9 as an 84:16 mixture
of 2-chloro-2-methyl-4-phenylbutan-2-ol 9a and 1-chloro-2-methyl-4-
phenylbutan-1-ol 9b (80%).
General Procedure 2. Addition of trimethylsulfoxonium ylide to
ketones.
1,2-Epoxy-2-methyldodec-11-ene 16. To a suspension of trimeth-
ylsulfoxonium iodide (1.54 g, 7.0 mmol) in THF (50 mL) was added
sodium hydride (144 mg, 6.0 mmol), and the mixture was stirred for
(30) Namy, J. L.; Boireau, G.; Abenhaim, D. Bull. Soc. Chim. Fr. 1971,
3191.
(31) Charlton, J. J.; Williams, G. J.; Lypka, G. N. Can. J. Chem. 1980,
58, 1271.
(32) Mousseron, M.; Jacquier, R.; Mousseron-Canet, M.; Zagdoun, R.
Bull. Soc. Chim. Fr. 1952, 1042.
(29) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

12856 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Gansa¨uer et al.
30 min at room temperature. After addition of dodec-11-en-2-one33 (910
mg, 5.0 mmol), stirring was continued for 16 h. The mixture was poured
into MTBE (50 mL), washed with H2O (2 × 50 mL), and dried
(MgSO4). After evaporation of the volatiles, the crude product was
purified by chromatography on silica gel (5% MTBE, 95% PE) to give
522 mg of 16 (53%).
by silica gel chromatography (12% MTBE, 88% PE) to give 2.75 g of
28 as a colorless solid.
Mp: 39 °C. Rf (12% MTBE, 88% PE): 0.20. 1H NMR (300 MHz,
CDCl3): δ ) 4.31 (s, CH2OPiv, 2H), 3.80 (s, CH2OPiv, 2H), 2.98 (s,
CHOCH, 2H), 1.70 (d, 2J ≈ 14.7 Hz, 2H), 1.18 (d, 2J ≈ 14.7 Hz, 2H),
1.13 (s, C(CH3)3), 1.12 (s, C(CH3)3). 13C NMR (50 MHz, CDCl3): δ
) 177.31, 177.08, 68.14, 67.23, 57.52, 44.49, 38.88, 38.86, 33.93,
Rf (5% MTBE, 95% PE): 0.58. 1H NMR (300 MHz, CDCl3): δ )
27.23. IR (KBr): 2975, 1730, 1480, 1395, 1365, 1285, 1165, 990 cm-1
.
5.81 (ddt, 3J ) 17.0 Hz, 3J ) 10.2 Hz, 3J ) 6.8 Hz, CH2CHCH2), 4.99
3
(ddt, 3J ) 17.0 Hz, 2J ≈ J ≈ 1.5 Hz, CHCHZHE), 4.93 (dm, 3J ) 10.2
Anal. Calcd for C17H28O5 (312.4): C, 65.36; H, 9.03. Found: C, 65.66;
H, 9.13.
Hz, CHCHEHZ), AB-system (δA ) 2.57, δB ) 2.60, JAB ) 4.9 Hz,
COCH2), 2.04 (td, 3J ) 7.2 Hz, 3J ) 6.8 Hz, CH2CH2CH2, 2H), 1.30-
1.63 (m, 14H), 1.28 (s, -CH3). 13C NMR (50 MHz, benzene-d6): δ )
139.18, 114.50, 56.13, 53.10, 37.02, 34.19, 30.03, 29.91, 29.79, 29.48,
29.30, 25.52, 21.03. IR (film): 3075, 3030, 2975, 2925, 2855, 2985,
1820, 1730, 1640, 1485, 1465, 1455, 1415, 1390, 1370, 1270, 1145,
1110, 1060, 995, 905, 800, 725, 705, 630 cm-1. Anal. Calcd for C13H24O
(196.3): C, 79.53; H, 12.32. Found: C, 79.28; H, 12.02.
2-Methyldodec-11-en-1-ol 17. According to general procedure 1,
16 (182 mg, 0.93 mmol), 4 (219 mg, 1.40 mmol), titanocene dichloride
(11.0 mg, 0.05 mmol), manganese (76.0 mg, 1.40 mmol), and 1,4-
cyclohexadiene (0.420 mL, 4.3 mmol) were reacted for 16 h. After
silica gel chromatography (30% MTBE, 70% PE), 132 mg of 17 was
obtained (72%).
1
Rf (20% MTBE, 80% PE): 0.26. H NMR (300 MHz, CDCl3): δ
3
3
3
) 5.81 (ddt, J ) 17.0 Hz, J ) 10.2 Hz, J ) 6.8 Hz, CH2CHCH2),
Toluene-4-sulfonic Acid (10,11-Epoxy-10-methylundecyl) Ester
18. According to general procedure 2, toluenesulfonic acid (10-
oxoundecenyl) ester34 (1.80 g, 5.3 mmol), trimethylsulfoxonium iodide
(1.54 g, 7.0 mmol), and sodium hydride (144 mg, 6.0 mmol) were
reacted for 16 h. After silica gel chromatography (40% MTBE, 60%
PE), 656 mg of 18 was obtained (34%).
4.99 (ddt, J ) 17.0 Hz, J ≈ 2.1 Hz, J ) 1.5 Hz, CHCHZHE), 4.93
3
2
4
(ddt, J ) 10.2 Hz, J ≈ 2.1 Hz, J ≈ 1.1 Hz, CHCHEHZ), AB-signal
3
2
4
3
(δA ) 3.42, δB ) 3.51, JAB ≈ 10.6 Hz, additionally split by J ) 5.7
3
3
3
Hz, J ) 6.8 Hz, CHCH2OH), 2.04 (td, J ) 7.2 Hz, J ) 6.8 Hz,
CH2CHCH2), 1.53-1.66 (mc, CHCH2OH), 1.49 (s,1-OH), 1.05-1.44
(m, 14H), 0.91 (d, 3J ) 6.4 Hz, CH3). 13C NMR (50 MHz, CDCl3): δ
) 139.19 (CH), 114.06 (CHCH2), 68.35 (CH2OH), 35.74, 33.81, 33.14,
29.92, 29.58, 29.49, 29.14, 29.03, 28.93, 26.96, 16.59 (CH3). IR
(film): 3335, 2925, 2860, 1640, 1465, 1035, 990, 910 cm-1. Anal.
Calcd for C13H26O (198.3): C, 78.72; H, 13.21. Found: C, 78.44; H,
13.47.
1
Rf (40% MTBE, 60% PE): 0.37. H NMR (300 MHz, CDCl3): δ
) AA′XX′-signal centered at δ ) 7.34 and 7.78, 4.01 (t, 3J ≈ 6.6 Hz,
11′-H2), AB-signal (δA ) 2.57, δB ) 2.60, JAB ≈ 5.1 Hz, COCH2),
2.45 (s, Ar-CH3), 1.47-1.65 (m, 4H), 1.23-1.42 (m, 12H), 1.30 (s,
CH3). 13C NMR (50 MHz, C6D6): δ ) 144.1, 134.58, 129.78, 128.13,
70.32, 56.17, 53.14, 36.97, 29.94, 29.72, 29.59, 29.17, 29.09, 25.57,
25.45, 21.12, 21.05. IR (film): 3035, 2930, 2855, 1715, 1600, 1495,
Toluene-4-sulfonic Acid (11-Hydroxy-10-methylundecyl) Ester
19. According to general procedure 1, 18 (300 mg, 0.85 mmol), 4 (189
mg, 1.20 mmol), titanocene dichloride (10.0 mg, 0.04 mmol), manga-
nese (66.0 mg, 1.20 mmol), and 1,4-cyclohexadiene (0.360 mL, 4.25
mmol) were reacted for 16 h. After silica gel chromatography (60%
MTBE, 40% PE), 176 mg of 19 was obtained (58%).
1465, 1390, 1360, 1305, 1290, 1190, 1175, 1100, 955, 815, 665 cm-1
.
Anal. Calcd for C19H30O4S (354.4): C, 64.37; H, 8.53. Found: C, 64.51;
H, 8.80.
2,2-Dimethylpropionic Acid (10,11-Epoxy-10-methylundecyl)
Ester 24. According to general procedure 2, 2,2-dimethyl-propionic
acid (10-oxoundecenyl) ester (1.35 g, 5 mmol), trimethylsulfoxonium
iodide (1.54 g, 7.0 mmol), and sodium hydride (144 mg, 6.0 mmol)
were reacted for 13 h. After silica gel chromatography (20% MTBE,
80% PE), 840 mg of 24 was obtained (59%).
1
Rf (60% MTBE, 40% PE): 0.48. H NMR (300 MHz, CDCl3): δ
) AA′XX′-signal centered at δ ) 7.34 and 7.79, 4.01 (t, 3J ≈ 6.6 Hz,
11′-H2), AB-signal (δA ) 3.42, δB ) 3.50, JAB ) 10.4 Hz, additionally
3
3
split by J ≈ 5.9 Hz, J ≈ 6.6 Hz, CH2OH), 2.45 (s, 4-CH3), 1.57-
3
1.67 (mc, CHCH2OH), 1.42 (s,OH), 1.06-1.41 (m, 14H), 0.91 (d, J
1
Rf (20% MTBE, 80% PE): 0.52. H NMR (300 MHz, CDCl3): δ
) 6.8 Hz, 2′-CH3). 13C NMR (APT-spectrum, 50 MHz, CDCl3): δ )
“-” 144.59, “-” 133.13, “+” 129.76, “+” 127.83, “-” 70.71, “-”
68.34, “+” 35.73, “-” 33.11, “-” 29.83, “-” 29.42, “-” 29.34, “-”
28.89, “-” 28.79, “-” 26.92, “-” 25.57, “-” 25.30, “+” 21.63 (Ar-
CH3), “+” 16.59 (-CH3). IR (film): 3555, 3385, 2925, 2855, 1600,
1495, 1465, 1360, 1305, 1290, 1210, 1190, 1175, 1095, 1040, 945,
815, 770, 725, 665, 575, 555 cm-1. Anal. Calcd for C19H32O4S
(356.5): C, 64.01; H, 9.05. Found: C, 64.19; H, 9.18.
3
) 4.04 (t, J ≈ 6.6 Hz, CH2OPiv), AB-signal (δA ) 2.57, δB ) 2.60,
JAB ≈ 5.1 Hz, COCH2), 1.47-1.63 (m, 4H), 1.28-1.40 (m, 12 H),
1.30 (s, CH3), 1.19 s, -C(CH3)3. 13C NMR (50 MHz, CDCl3): δ )
178.61 (-C(O)OR), 64.43, 57.03, 53.92, 38.74 (-C(CH3)3), 36.76,
29.65, 29.49, 29.42, 29.30, 29.21, 27.24 (-C(CH3)3), 25.92, 25.25,
20.93 (CH3). IR (film): 3030, 2930, 2855, 1730, 1540, 1480, 1460,
1395, 1365, 1285, 1155, 1035, 940, 900, 800, 770 cm-1. Anal. Calcd
for C17H32O3 (284.4): C, 71.79; H, 11.34. Found: C, 72.03; H, 11.33.
2-(9-Chlorononyl)-2-methyloxirane 26. According to general pro-
cedure 2, 11-chloro-2-undecanone (1.02 g, 5.0 mmol), trimethylsul-
foxonium iodide (1.54 g, 7.0 mmol), and sodium hydride (144 mg, 6.0
mmol) were reacted for 13 h. After silica gel chromatography (8%
MTBE, 92% PE), 853 mg of 26 was obtained (78%).
4-(tert-Butyldiphenylsilyloxy)-2-methylbutan-1-ol 21. According
to general procedure 1, 2035 (340 mg, 1.0 mmol), 4 (236 mg, 1.50
mmol), titanocene dichloride (12.5. mg, 0.05 mmol), manganese (82
mg, 1.50 mmol), and 1,4-cyclohexadiene (0.425 mL, 4.3 mmol) were
reacted for 16 h. After silica gel chromatography (25% MTBE, 75%
PE), 294 mg of 21 was obtained (86%).
Rf (8% MTBE, 92% PE): 0.40. 1H NMR (300 MHz, CDCl3): δ )
1
Rf (25% MTBE, 80% PE): 0.30. H NMR (300 MHz, CDCl3): δ
3.53 (t, 3J ≈ 6.8 Hz, CH2Cl), AB-signal (δA ) 2.60, δB ) 2.56, JAB
≈
) 7.69-7.88 (m, CHAr, 4H), 7.44-7.36 (m, CHAr, 6H), 3.80-3.66
(m, CH2OSi, 2H), AB-signal (δA ) 3.53, δB ) 3.47, JAB ≈ 10.9 Hz,
additionally split by 3J ) 5.3 Hz, 3J ) 6.4 Hz, CHCH2OH), 1.86 (ddddq,
3J ) 6.4 Hz, CHCH2OH), 1.69-1.44 (m, SiOCH2CH2, 2H), 1.05 (s,
3
4.9 Hz, COCH2), 1.76 (tt, J ≈ 7.2 Hz, 2H), 1.60-1.29 (m, 14 H),
1.30 (s, CH3). 13C NMR (50 MHz, CDCl3): δ ) 56.17, 53.14, 37.02,
32.87, 30.00, 29.82, 29.42, 29.72, 29.15, 27.10, 25.52, 21.07 (CH3).
IR (film): 2930, 2855, 1465, 1390, 1310, 900, 800 cm-1. Anal. Calcd
for C12H23ClO (218.8): C, 65.88; H, 10.60. Found: C, 66.09; H, 10.34.
2,2-Dimethylpropionic Acid 3-(2,2-Dimethylpropionyloxymethyl)-
6-oxabicyclo[3.1.0]hex-3-yl Methyl Ester 28. To an ice-cooled solution
of 2,2-dimethylpropionic acid 1-(2,2-dimethylpropionyloxymethyl)-
cyclopent-3-enyl methyl ester (2.964 g, 10 mmol) in CH2Cl2 (50 mL)
was added mCPBA (70%) (3.700 g, 15 mmol), and the mixture was
stirred for 12 h. After washing with 2 N NaOH (20 mL), drying
(MgSO4), and evaporation of the solvent, the crude product is purified
3
9H), 0.90 (d, J ) 6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3): δ )
135.52, 133.37, 129.67, 127.67, 68.24, 62.48, 36.75, 33.88, 26.79, 19.11.
IR (film): 3360, 3070, 2930, 2860, 1590, 1470, 1430, 1390, 1110,
1000 cm-1. Anal. Calcd for C21H30O2Si (342.2): C, 73.63; H, 8.82.
Found: C, 73.62; H, 9.09.
4-Benzyloxy-2-methylbutan-1-ol 23.36 According to general pro-
cedure 1, 2237 (192 mg, 1.0 mmol), 4 (236 mg, 1.50 mmol), titanocene
dichloride (12.5. mg, 0.05 mmol), manganese (82 mg, 1.50 mmol),
(35) Weigand, S.; Bru¨ckner, R. Synthesis 1996, 475.
(36) Grisenti, P.; Ferraboschi, P.; Casati, S.; Santaniello, E. Tetrahedron
Asymmetry 1993, 4, 997.
(33) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Org. Chem. 1993, 58,
7789.
(34) Tsuji, J. Synthesis 1984, 369.
(37) Gill, M.; Smredel, A. F. Tetrahedron Asymmetry 1990, 1, 453.

Titanocene-Catalyzed ReductiVe Opening of Epoxides
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12857
and 1,4-cyclohexadiene (0.425 mL, 4.3 mmol) were reacted for 16 h.
After silica gel chromatography (30% MTBE, 70% PE), 130 mg of 23
was obtained (67%).
malonate38 (1.08 g, 5.0 mmol) and cinnamyl bromide (1.48 g, 7.5 mmol)
in THF (30 mL) was added sodium hydride (132 mg, 5.5 mmol) at 0
°C. After being stirred for 70 h at room temperature, the mixture was
poured on MTBE (50 mL), washed with H2O (3 × 50 mL), and dried
(MgSO4). Silica gel chromatography (25% MTBE, 75% PE) gives 1.59
g of a pale yellow oil. After Kugelrohr distillation, 1.49 g of 32 was
obtained as a clear oil (89%).
2,2-Dimethylpropinoic Acid (11-Hydroxy-10-methylundecyl)
Ester 25. According to general procedure 1, 24 (279 mg, 1.0 mmol),
4 (236 mg, 1.50 mmol), titanocene dichloride (12.0 mg, 0.05 mmol),
manganese (82.0 mg, 1.50 mmol), and 1,4-cyclohexadiene (0.450 mL,
4.80 mmol) were reacted for 16 h. After silica gel chromatography
(20% MTBE, 80% PE), 212 mg of 25 was obtained (69%).
1
Rf (20% MTBE, 80% PE): 0.32. H NMR (300 MHz, CDCl3): δ
3
3
) 7.19-7.33 (mc, Ph), 6.47 (d, J ) 15.4 Hz, PhCH), 6.06 (dt, Jtrans
3
3
) 15.4 Hz, J ) 7.6 Hz, PhCHCH), 4.23 (q, J3′ ) 7.2 Hz, OCH2),
1
Rf (20% MTBE, 80% PE): 0.25. H NMR (300 MHz, CDCl3): δ
3
3
4.22 (q, J ) 7.2 Hz, OCH2), 2.99-3.05 (mc, CHOCH2), 2.97 (dd, J
) 7.6 Hz, 4J ) 1.5 Hz, CH2CHCHPh), 2.76 (dd, 2J ≈ 5.1, 3Janti ) 4.1
Hz, CHOCHsynHanti), 2.46 (dd, 2J ≈ 5.1, 3Jsyn ) 2.6 Hz, CHOCHantiHsyn),
AB-signal (δA ) 2.04, δB ) 2.23, JAB ) 14.7 Hz, additionally split by
3J ) 7.2 Hz, 3J ) 4.9 Hz, 3-CH2CHOCH2), 1.27 (t, 3J ) 7.2 Hz, CH3),
1.26 (t, 3J ) 7.2 Hz, CH3). 13C NMR (APT-spectrum, 50 MHz,
CDCl3): δ ) “-” 170.77, “-” 170.70, “-” 137.00, “+” 134.35, “+”
128.53, “+” 127.49, “+” 126.24, “+” 123.73 (C-7), “-” 61.62, “-”
61.52, “-” 56.80, “+” 48.54, “-” 46.83, “-” 37.29, “-” 36.36, “+”
14.11 (CH3). IR (film): 3025, 2980, 2935, 1730, 1600, 1575, 1495,
1465, 1445, 1390, 1365, 1320, 1290, 1245, 1210, 1155, 1095, 1030,
970, 860, 745, 695 cm-1. Anal. Calcd for C19H24O5 (332.4): C, 68.66;
H, 7.28. Found: C, 68.41; H, 7.49.
) 4.04 (t, J ) 6.8 Hz, CH2O), AB-signal (δA ) 3.42, δB ) 3.51, JAB
3
3
≈ 10.6 Hz, additionally split by J ) 5.7 Hz, J ) 6.8 Hz, CHCH2-
3
3
OH), 1.61 (tt, J ) 6.8 Hz, J ) 6.8 Hz, CH2CH2OPiv), 1.51 (br s),
3
1.42 (s, OH), 1.28-1.36 (m, 14 H), 1.19 s, -C(CH3)3, 0.91 (d, J )
6.8 Hz, 2′-CH3). 13C NMR (50 MHz, CDCl3): δ ) 178.64 -(C(O)-
OR), 68.34, 64.45, 38.71 (-C(CH3)3), 35.74, 33.12, 29.88, 29.47, 29.19,
28.57, 27.19 (-C(CH3)3), 26.95, 26.90, 25.88, 16.59 (2′-CH3). IR
(film): 3395, 2960, 2930, 2855, 1730, 1540, 1480, 1460, 1400, 1365,
1285, 1155, 1035 cm-1. Anal. Calcd for C17H34O3 (286.5): C, 71.28;
H, 11.96. Found: C, 71.02; H, 12.16.
11-Chloro-2-methylundecan-1-ol 27. According to general proce-
dure 1, 26 (219 mg, 1.0 mmol), 4 (236 mg, 1.50 mmol), titanocene
dichloride (12.0 mg, 0.05 mmol), manganese (82.0 mg, 1.50 mmol),
and 1,4-cyclohexadiene (0.450 mL, 4.80 mmol) were reacted for 16 h.
After silica gel chromatography (20% MTBE, 80% PE), 163 mg of 27
was obtained (74%).
3-(2,3-Epoxyprop-1-yl)-2-prop-2-ynylmalonic Acid Diethyl Ester
34. According to the procedure described for 32, (2.169 g, 8.5 mmol)
34 was obtained from 3-(2,3-epoxypropyl)malonic acid diethyl ester
(2.162 g, 10 mmol) and propargyl bromide (80% solution in toluene,
14 mmol) after silica gel chromatography (15% MTBE, 85% PE) in
85% yield.
1
Rf (20% MTBE, 80% PE): 0.27. H NMR (300 MHz, CDCl3): δ
) 3.53 (t, 3J ) 6.8 Hz, CH2Cl), AB-signal (δA ) 3.42, δB ) 3.51, JAB
3
3
Rf (15% MTBE, 85% PE): 0.30. 1H NMR (300 MHz, benzene-d6):
δ ) 4.02-3.93 (m, CH2OCO, 4H), 2.87 (mc, CHOCH2), AB-signal
≈ 10.4 Hz, additionally split by J ) 5.7 Hz, J ) 6.8 Hz, CH2OH),
3
3
3
1.77 (tt, J ) 7.4 Hz, J ) 6.8 Hz, CH2CH2Cl), 1.61 (qddm, J ) 6.8
3
3
4
Hz, J ) 6.4 Hz, J ) 5.7 Hz, CHCH2OH), 1.48 (br s, OH), 1.05-
1.44 (m, 14H), 0.91 (d, 3J ) 6.8 Hz, CH3). 13C NMR (APT spectrum,
50 MHz, benzene-d6): δ ) “-” 68.1, “-” 44.99, “+” 36.14, “-” 33.61,
“-” 32.89, “-” 30.37, “-” 29.96, “-” 29.85, “-” 29.22, “-” 27.46,
“-” 27.14, “+” 16.90 (CH3). IR (film): 3340, 2925, 2855, 1465, 1375,
1310, 1035, 905, 725, 650 cm-1. Anal. Calcd for C12H25ClO (220.8):
C, 65.28; H, 11.41. Found: C, 65.07; H, 11.37.
(δA ) 3.16, δB ) 3.08, JAB ≈ 17.0 Hz, additionally split by J ) 2.6
Hz, 4J ) 2.6 Hz, CH2CCH), AB-signal (δA ) 2.62, δB ) 2.21, JAB
≈
3
3
14.7 Hz, additionally split by J ) 4.2 Hz, J ) 4.1 Hz, CH2CHO),
2
3
2
2.40 (t, J ) 3.7 Hz, J ) 3.7 Hz, CHOCHtransCHcis), 2.07 (dd, J )
3
4
3.7 Hz, J ) 5.7 Hz, CHOCHtransCHcis), 1.68 (t, J ) 2.6 Hz, CCH),
0.91 (t, 3J ) 6.7 Hz, CH3), 0.91 (t, 3J ) 7.2 Hz, CH3). 13C NMR (APT-
spectrum, 50 MHz, benzene-d6): δ ) “-” 169.65, “-” 79.16, “+”
72.15, “-” 65.86, “-” 61.73, “-” 56.09, “+” 48.09, “-” 46.16, “-”
36.36, “-” 24.04, “+” 13.91 (CH3). IR (film): 3280, 2985, 2935, 1735,
1440, 1290, 1200, 1095, 860 cm-1. Anal. Calcd for C13H18O5 (254.3):
C, 61.41; H, 7.14. Found: C, 61.44; H, 7.07.
2,2-Dimethylpropionic Acid 1-(2,2-Dimethylpropionyloxymethyl)-
3-hydroxycyclopentyl Methyl Ester 29. According to general proce-
dure 1, 28 (313 mg, 1.0 mmol), 4 (236 mg, 1.50 mmol), titanocene
dichloride (12.5. mg, 0.05 mmol), manganese (82 mg, 1.50 mmol),
and 1,4-cyclohexadiene (0.450 mL, 4.80 mmol) were reacted for 16 h.
After silica gel chromatography (30% MTBE, 70% PE), 212 mg of 29
was obtained (67%).
3-(2,3-Epoxyprop-1-yl)-2-prop-2-ynylmalonic Acid Diethyl Ester
36. According to the procedure described for 32, (1.140 g, 4.3 mmol)
36 was obtained from 3-(2,3-epoxypropyl)-3-methylmalonic acid diethyl
ester (1.151 g, 5 mmol) and propargyl bromide (80% solution in toluene,
14 mmol) after silica gel chromatography (15% MTBE, 85% PE) in
85% yield.
1
Rf (30% MTBE, 70% PE): 0.20. H NMR (300 MHz, CDCl3): δ
) 4.39-4.38 (br m, CHOH), 4.07 (s, CH2OPiv, 2H), 3.91 (s, CH2-
OPiv, 2H), 1.91-1.70 (m, 4H), 1.58-1.54 (m, 3H), 1.20 (s, C(CH3)3,
9H), 1.19 (s, C(CH3)3, 9H). 13C NMR (50 MHz, CDCl3): δ ) 178.42,
178.38, 73.31, 68.11, 67.35, 44.97, 41.32, 38.89, 34.55, 29.71, 27.16.
1
Rf (15% MTBE, 85% PE): 0.30. H NMR (300 MHz, CDCl3): δ
) 4.27-4.16 (mc, CH2OCO, 4H), AB-signal (δA ) 3.03, δB ) 2.89,
4
4
IR (film): 3505, 2965, 2875, 1465, 1730, 1475, 1285, 1160, 1035 cm-1
.
JAB ≈ 17.0 Hz, additionally split by J ) 2.6 Hz, J ) 2.6 Hz, CH2-
CCH), AB-signal (δA ) 2.72, δB ) 2.54, JAB ≈ 4.5 Hz, CCH2O), AB-
Anal. Calcd for C17H30O5 (314.4): C, 64.94; H, 9.62. Found: C, 64.66;
H, 9.42.
4
signal (δA ) 2.53, δB ) 2.31, JAB ≈ 16.5 Hz, CH2CH2O), 2.04 (t, J
2
3
) 2.7 Hz, CCH), 2.07 (dd, J ) 3.7 Hz, J ) 5.7 Hz, CHOCHtrans
-
2-Methyl-4-phenylbutan-1-ol 8 and 4-Phenyl-2-butanone (Table
3, Entry 8). According to general procedure 1, 7 (313 mg, 1.0 mmol),
4 (236 mg, 1.50 mmol), titanocene dichloride (12.5. mg, 0.05 mmol),
manganese (82 mg, 1.50 mmol), 4-phenyl-2-butanol (148 mg, 1.0
mmol), and 1,4-cyclohexadiene (0.450 mL, 4.80 mmol) were reacted
for 48 h. After silica gel chromatography (20% MTBE, 80% PE), 124
mg of 8 (75%) and 140 mg of 4-phenyl-2-butanone (95%) were
obtained.
CHcis), 1.29 (s, CH3), 1.27 (t, 3J ) 7.1, CH2CH3), 1.26 (t, 3J ) 7.1 Hz,
CH2CH3), 0.91 (t, J ) 7.2 Hz, CH3). 13C NMR (APT-spectrum, 50
3
MHz, benzene-d6): δ ) “-” 169.82, “-” 169.62, “-” 79.52, “+”
72.34, “-” 61.67, “-” 56.13, “-” 54.13, “-” 53.86, “-” 38.63, “-”
22.27, “+” 13.88, “+” 13.88 (CH3). IR (film): 3280, 2980, 2940, 1730,
1440, 1290 cm-1. Anal. Calcd for C13H18O5 (254.3): C, 62.67; H, 7.51.
Found: C, 62.39; H, 7.57.
General Procedure 3. Cyclization reactions in the presence of 4.
3-Hydroxymethyl-4-methylcyclopentane-1,1-dicarboxylic Acid
Diethyl Ester 31.7 To a mixture of 4 (394 mg, 2.50 mmol), 30 (256
mg 1.0 mmol), and manganese (82 mg, 1.50 mmol) in THF (10 mL)
was added titanocene dichloride (12.5 mg, 0.05 mmol), and the resulting
mixture was stirred for 30 h. After addition of MTBE (50 mL), the
mixture was washed with H2O (30 mL), 2 N HCl (30 mL), H2O (30
2-Methyl-4-phenylbutan-1-ol 8 and Acetophenone (Table 3,
Entry 9). According to general procedure 1, 7 (313 mg, 1.0 mmol), 4
(236 mg, 1.50 mmol), titanocene dichloride (12.5 mg, 0.05 mmol),
manganese (82 mg, 1.50 mmol), acetophenone (0.120 mL, 1.0 mmol),
and 1,4-cyclohexadiene (0.450 mL, 4.80 mmol) were reacted for 48 h.
After silica gel chromatography (20% MTBE, 80% PE), 136 mg of 8
(82%) and 114 mg of acetophenone (93%) were obtained.
3-(2,3-Epoxy-prop-1-yl)-3-(3-phenylprop-2-en-1-yl)malonic Acid
Diethyl Ester 32. To a solution of 2-(2,3-epoxy-prop-1-yl) diethyl
(38) Temnikowa, T. I.; Semenowna, S. N. J. Org. Chem. USSR (Engl.
Transl.) 1966, 2, 1171.

12858 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Gansa¨uer et al.
mL), saturated aqueous NaHCO3 (30 mL), and H2O (30 mL) and dried
(MgSO4). After removal of the volatiles, the crude product was purified
by flash chromatography on silica gel (25% MTBE, 75% PE f 50%
MTBE, 50% PE) to give 202 mg of 31 as an 88:12 mixture of cis and
trans isomers (78%).
zinc (131 mg, 2.0 mmol), and titanocene dichloride (12.0 mg, 0.05
mmol) were reacted for 61 h. After silica gel chromatography, 102 mg
of 41 was obtained (66%) as a 98:2 mixture of diastereoisomers.
General Procedure 4. Intermolecular additions to R,â-unsaturated
carbonyl compounds in the presence of 4.
3-Benzyl-4-hydroxymethylcyclopentane-1,1-dicarboxylic Acid
Diethyl Ester 33. According to general procedure 3, 32 (332 mg, 1.0
mmol), 4 (394 mg, 2.5 mmol), manganese (82.0 mg, 1.5 mmol), and
titanocene dichloride (12.0 mg, 0.05 mmol) were reacted for 39 h. After
silica gel chromatography, 185 mg of 33 was obtained (55%) as an
86:14 mixture of cis and trans isomers.
4-Hydroxymethyltetradecanoic Acid tert-Butyl Ester 45 (Table
5, Entry 2). To a mixture of 4 (940 mg, 6 mmol), 14 (440 µL, 2.0
mmol), Zn (260 mg, 4.0 mmol), ZnCl2 (273 mg, 2.0 mmol), and tert-
butylacrylate (0.880 mL, 6.0 mmol) in THF (20 mL) was added
titanocene dichloride (25.0 mg, 0.10 mmol), and the resulting mixture
was stirred for 16 h. After addition of MTBE (50 mL), the mixture
was washed with H2O (30 mL), 2 N HCl (30 mL), H2O (30 mL),
saturated aqueous NaHCO3 (30 mL), and H2O (30 mL) and dried
(MgSO4). After removal of the volatiles, the crude product was purified
by flash chromatography on silica gel (20% MTBE, 80% PE) to give
509 mg of 45 as a 94:6 mixture of regioisomers (81%).
1
Rf (40% MTBE, 60% PE): 0.16. H NMR (300 MHz, CDCl3): δ
3
3
) 7.1-7.30 (mc, 5H), 4.19 (q, J ≈ 7.2 Hz, CH2OH), 4.16 (qd, J )
7.2 Hz, 3J ) 0.8 Hz, CH2O), 3.56-3.81 (mc, CH2OH), 3.44-3.64 (mc,
CH2OH), AB-signal (δA ) 2.78, δB ) 2.83, JAB ) 10.7 Hz, CH2Ph),
2.11-2.61 (m, 4H), 2.00 (dd, 3J ) 13.6 Hz, J ) 8.7 Hz, CHCH2OH),
3
3
3
1.67 (t, J ≈ 5.8 Hz, OH), 1.24 (t, J ) 7.2 Hz, 3CH3), 1.21 (t, J )
7.2 Hz, CH3). 13C NMR (APT-spectrum, 50 MHz, CDCl3): δ ) “-”
173.58, “-” 172.86, “-” 141.08, “+” 129.21, “+” 128.9, “+” 128.84,
“+” 128.54, “+” 126.20 “+” 126.09, “-” 64.66, “-” 62.52, “-” 61.71,
“-” 61.64, “-” 61.54, “-” 58.75, “+” 46.9, “+” 43.9, “+” 43.07,
“+” 42.55, “-” 40.63, “-” 40.30, “-” 39.04, “-” 37.19, “-”
36.51,“-” 35.53, “+” 14.05. IR (film): 3445, 3085, 3025, 2980, 2935,
1730, 1600, 1495, 1455, 1390, 1365, 1255, 1180, 1160, 1115, 1095,
1070, 1030, 860, 740, 700 cm-1. Anal. Calcd for C19H26O5 (334.4):
C, 68.24; H, 7.84. Found: C, 68.13; H, 7.92.
1
Rf (20% MTBE, 80% PE): 0.20. H NMR (300 MHz, CDCl3): δ
) 3.58-3.43 (m, CH2OH), AB-signal (δA ) 2.47, δB ) 2. 25, JAB
)
7.6 Hz, additionally split by 3J ) 4.2, 3.4 Hz), 1.77 (t, 3J ) 4.2,
CH2OH), 1.67-1.57 (m, 2H), 1.44 (s, C(CH3)3), 1.26 (m, 14H), 0.88
3
(t, J ) 7.0 Hz, CH3, 3H). 13C NMR (50 MHz, CDCl3): δ )173.68,
80.29, 64.95, 40.32, 32.95, 31.93, 31.00, 30.01, 29.67, 29.63, 29.34,
28.14, 27.02, 25.96, 22.68, 14.08. IR (film): 3410, 2920, 2860, 1730,
1655, 1460, 1360 cm-1. Anal. Calcd for C19H38O3 (314.5): C, 72.56;
H, 12.18. Found: C, 72.89; H, 12.13.
4-Hydroxymethyltetradecanoic Acid tert-Butyl Ester 45 (Table
5, Entry 3). According to general procedure 4, 14 (7.00 mL, 32 mmol),
4 (12.60 g, 80 mmol), tert-butylacrylate (7.0 mL, 48 mmol), Zn (3.14
g, 48 mmol), and titanocene dichloride (80.0 mg, 0.32 mmol) were
reacted for 44 h. After silica gel chromatography, 7.36 g of 45 was
obtained (73%) as a colorless oil.
3-Hydroxymethyl-4-methylenecyclopentane-1,1-dicarboxylic Acid
Diethyl Ester 35. According to general procedure 3, 34 (254 mg, 1.0
mmol), 4 (465 mg, 3.0 mmol), manganese (170 mg, 3.0 mmol), and
titanocene dichloride (12.0 mg, 0.05 mmol) were reacted for 24 h. After
silica gel chromatography, 187 mg of 35 was obtained (73%) as a 91:9
mixture of 5-exo and 6-exo products.
5-Decyltetrahydropyran-2-one 47 (Table 5, Entry 4). According
to general procedure 4, 14 (3.30 mL, 15 mmol), 4 (6.30 g, 40 mmol),
acrylonitrile (2.0 mL, 30 mmol), Zn (1.5 g, 23 mmol), and titanocene
dichloride (190.0 mg, 0.75 mmol) were reacted for 16 h. After silica
gel chromatography, 2.95 g of 47 was obtained as a 94:6 mixture of
regioisomers (82%).
Rf (40% MTBE, 60% PE): 0.20; 1H NMR (300 MHz, benzene-d6):
4
4
δ ) 4.90 (q, J ) 1.9 Hz, CCH2, 1H), 4.79 (q, J ) 1.9 Hz, CCH2,
1H), 3.97 (m, CH2OCO, 4H), AB-signal (δA ) 3.40, δB ) 3.34, JAB
)
10.7 Hz, additionally split by 3J ) 4.9 Hz, 3J ) 5.7 Hz, CH2OH), 3.11
(m, CHCH2OH), AB-signal (δA ) 2.77, δB ) 2.71, JAB ) 8.3 Hz),
3
AB-signal (δA ) 2.50, δB ) 2.19, JAB ) 11.7 Hz), 0.88 (t, J ) 7.2
1
Rf (40% MTBE, 60% PE): 0.30. H NMR (300 MHz, CDCl3): δ
Hz, CH3, 6H). 13C NMR (APT-spectrum, 50 MHz, benzene-d6): δ )
“-” 171.63, “-” 171.59, “-” 149.73, “-” 107.61, “-” 64.92, “-”
61.54, “-” 61.38, “-” 59.18, “+” 45.42, “-” 41.84, “-” 37.37, “+”
13.97; 6-exo product, “-” 171. 30, “-” 170.42, “-” 141.73, “-”
112.86, “+” 67.54, “-” 61.55, “-” 61.24, “-” 56.12, “-” 39.49, “-”
39.46, “+” 13.97. IR (film): 3445, 2980, 2935, 1730, 1655, 1450, 1370,
1255, 1190, 1070 cm-1. Anal. Calcd for C13H20O5 (256.3): C, 60.92;
H, 7.86. Found: C, 61.13; H, 7.73.
2
3
4
2
) 4.33 (ddd, J ) 11.3, J ) 4.6, J ) 1.9, CH2O), 3.94 (dd, J )
11.0, 3J ) 9.8, CH2O), 2.62 (ddd, 2J ) 17.7, 3J ) 7.1, 3J ) 4.5, CH2-
2
3
3
CO), 2.48 (ddd, J ) 17.7, J ) 8.6, J ) 7.2, CH2CO), 2.05-1.83
3
(m, 2H), 1.58-1.44 (m, 1H), 1.29-1.25 (m, 18H), 0.83 (t, J ) 7.0
Hz, CH3). 13C NMR (50 MHz, CDCl3): δ ) 171.45, 73.59, 32.72,
31.80, 31.46, 29.54, 29.49, 29.38, 29.22, 28.99, 26.70, 25.42, 22.59,
14.03. IR (film): 2925, 2855, 1740, 1460, 1245, 1180, 1055 cm-1
.
Anal. Calcd for C15H28O2 (240.4): C, 74.95; H, 11.74. Found: C, 74.73;
H, 11.51.
3-Hydroxymethyl-3-methyl-4-methylenecyclopentane-1,1-dicar-
boxylic Acid Diethyl Ester 37. According to general procedure 3, 36
(272 mg, 1.0 mmol), 4 (465 mg, 3.0 mmol), manganese (170 mg, 3.0
mmol), and titanocene dichloride (12.0 mg, 50 µmol) were reacted for
40 h. After silica gel chromatography, 188 mg of 37 was obtained
(70%).
5-Decyltetrahydropyran-2-one 47 (Table 5, Entry 5). According
to general procedure 4, 14 (440 µL, 2.0 mmol), 4 (940 mg, 6.0 mmol),
acrylonitrile 270 µL, 4.0 mmol), Zn (260 mg, 4.0 mmol), and titanocene
dichloride (2.5 mg, 0.02 mmol) were reacted for 43 h. After silica gel
chromatography, 349 mg of 47 was obtained (73%).
5-Decyltetrahydropyran-2-one 47 (Table 5, Entry 6). According
to general procedure 4, 14 (440 µL, 2.0 mmol), 4 (940 mg, 6.0 mmol),
acrylonitrile 270 µL, 4.0 mmol), Zn (260 mg, 4.0 mmol), ZnCl2 (273
mg, 2.0 mmol), and titanocene dichloride (12.0 mg, 0.05 mmol) were
reacted for 12 h. After silica gel chromatography, 423 mg of 47 was
obtained (88%).
1
Rf (40% MTBE, 60% PE): 0.20. H NMR (300 MHz, CDCl3): δ
3
4
) 5.03 (t, J ) 1.8 Hz, CCH2, 1H), 4.82 (t, J ) 1.7 Hz, CCH2, 1H),
4.18 (q, 3J ) 6.8 Hz, CH2OCO, 2H), 4.17 (q, J ) 6.9 Hz, CH2OCO,
3
2H), AB-signal (δA ) 3.39, δB ) 3.30, JAB ) 10.9 Hz, additionally
3
split by J ) 3.4 Hz, CH2OH), AB-signal (δA ) 3.10, δB ) 3.02, JAB
3
3
) 10.9 Hz, additionally split by J ) 1.5 Hz CH2C), 2.50 (d, J )
3
3
13.9 Hz), 2.20 (d, J ) 13.9 Hz), 1.81 (br t, J ) 3.5 Hz, CH2OH),
1.22 (t, J ) 7.2 Hz, CH3, 6H), 1.11 (s, CH3). 13C NMR (50 MHz,
3
4-Hydroxymethyltetradecane Nitrile 46 (Table 5, Entry 7).
According to general procedure 4, 14 (440 µL, 2.0 mmol), 4 (940 mg,
6.0 mmol), acrylonitrile 270 µL, 4.0 mmol), Mn (220 mg, 4.0 mmol),
ZnCl2 (273 mg, 2.0 mmol), and titanocene dichloride (12.0 mg, 0.05
mmol) were reacted for 14 h. After silica gel chromatography, 382 mg
of 46 was obtained as a 93:7 mixture of regioisomers (80%).
CDCl3): δ ) 172.26, 171.92, 154.13, 106.92, 69.57, 61.72, 61.63,
57.69, 47.43, 43.08, 41.47, 24.20, 14.00. IR (film): 3445, 2980, 2935,
1730, 1660, 1470, 1255, 1190, 1185 cm-1. Anal. Calcd for C14H22O5
(270.3): C, 62.20; H, 8.20. Found: C, 61.99; H, 8.35.
(3-Methyloctahydroinden-3a-yl)methanol 39.7 According to gen-
eral procedure 3, 387 (166 mg, 1.0 mmol), 4 (394 mg, 2.5 mmol), zinc
(131 mg, 2.0 mmol), and titanocene dichloride (12.0 mg, 0.05 mmol)
were reacted for 61 h. After silica gel chromatography, 130 mg of 39
was obtained (77%) as a 52:48 mixture of diastereomisomers.
(3-Methylhexahydopentalen-3a-yl)methanol 41.7 According to
general procedure 3, 407 (152 mg, 1.0 mmol), 4 (394 mg, 2.5 mmol),
1
Rf (20% MTBE, 80% PE): 0.20. H NMR (300 MHz, CDCl3): δ
2
3
2
3
) 3.66 (dt, J ) 9.0, J ) 2.5, CH2OH), 3.54 (dt, J ) 9.0, J ) 2.5,
3
CH2OH), 2.43 (t, J ) 7.9, CH2CN), 1.85-1.58 (m, 3H), 1.30-1.26
(m, 16H), 0.88 (t, 3J ) 7.0 Hz, CH3, 3H). 13C NMR (50 MHz,
CDCl3): δ ) 120.08, 64.66, 39.43, 31.90, 30.57, 29.89, 29.62, 29.58,
29.34, 27.29, 26.83, 22.70, 15.10, 14.13. IR (film): 3430, 2925, 2860,

Titanocene-Catalyzed ReductiVe Opening of Epoxides
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12859
2250, 1465, 1045 cm-1. Anal. Calcd for C15H29NO (239.4): C, 75.25;
H, 12.21; N, 5.85. Found: C, 75.47; H, 12.41; N, 5.70.
4.00 (dd, 2J ) 11.3, 4J ) 1.1, CH2O), 2.65-2.55 (m, 4H), 1.82 (dt, 2J
3
2
3
) 14.7, J ) 6.2, 1H), 1.73 (dd, J ) 14.7, J ) 6.2, 1H), 1.69-1.64
(m, 2H), 1.11 (s, CH3). 13C NMR (50 MHz, CDCl3): δ ) 171.59,
141.66, 128.50, 126.04, 128.17, 77.27, 39.83, 32.32, 31.16, 29.98, 27.12,
5-Decyltetrahydropyran-2-one 47 (Table 5, Entry 9). According
to general procedure 4, 14 (440 µL, 2.0 mmol), 4 (940 mg, 6.0 mmol),
methylacrylate (360 µL, 4.0 mmol), Zn (260 mg, 4.0 mmol), ZnCl2
(273 mg, 2.0 mmol), and titanocene dichloride (25.0 mg, 0.10 mmol)
were reacted for 16 h. After silica gel chromatography, 340 mg of 47
was obtained (72%).
22.05. IR (film): 3025, 2935, 1735, 1600, 1455, 1190, 1055 cm-1
.
Anal. Calcd for C14H18O2 (218.3): C, 77.03; H, 8.31. Found: C, 76.88;
H, 8.39.
4-Hydroxymethyltetradecane Nitrile 46 (Table 7, Entry 1).
According to general procedure 4, 14 (440 µL, 2.0 mmol), 4 (950 mg,
6.0 mmol), acrylonitrile (270 µL, 4.0 mmol), Mn (220 mg, 4.0 mmol),
collidine (1.320 mL, 10 mmol), and titanocene dichloride (25.0 mg,
0.10 mmol) were reacted for 37 h. After silica gel chromatography,
365 mg of 46 was obtained (75%) as a 93:7 mixture of regioisomers.
4-Methyl-2-oxaspiro[5.5]undecan-3-one 49 (Table 6, Entry 1).7
According to general procedure 4, 48 (240 µL, 2.0 mmol), 4 (950 mg,
6.0 mmol), methylmethacrylate (580 µL, 4.0 mmol), Zn (260 mg, 4.0
mmol), ZnCl2 (273 mg, 2.0 mmol), and titanocene dichloride (25.0
mg, 0.10 mmol) were reacted for 24 h. After silica gel chromatography,
314 mg of 49 was obtained (86%).
13-Chloro-4-hydroxymethyl-4-methyltridecanenitrile 53 (Table
7, Entry 2). According to general procedure 4, 26 (437 mg, 2.0 mmol),
4 (950 mg, 6.0 mmol), acrylonitrile (270 µL, 4.0 mmol), Mn (220 mg,
4.0 mmol), collidine (1.320 mL, 10 mmol), and titanocene dichloride
(25.0 mg, 0.10 mmol) were reacted for 36 h. After silica gel
chromatography, 397 mg of 53 was obtained (73%).
1-Methyl-2-oxaspiro[5.5]undecan-3-one 50 (Table 6, Entry 2).
According to general procedure 4, 10 (260 µL, 2.0 mmol), 4 (950 mg,
6.0 mmol), methylacrylate (360 µL, 4.0 mmol), Zn (260 mg, 4.0 mmol),
ZnCl2 (273 mg, 2.0 mmol), and titanocene dichloride (25.0 mg, 0.10
mmol) were reacted for 16 h. After silica gel chromatography, 264 mg
of 50 was obtained (78%).
Rf (40% MTBE, 60% PE): 0.4. 1H NMR (300 MHz, CDCl3): δ )
1
Rf (15% MTBE, 85% PE): 0.20. H NMR (300 MHz, CDCl3): δ
3.53 (t, 3J ) 6.8, CH2Cl), br AB-signal (δA ) 3.38, δB ) 3.36, JAB
)
3
2
) 4.24 (q, J ) 6.8, CHO), 2.61-2.42 (m, CH2CO), 1.94 (dt, J )
3
3
10.9 Hz, CH2OH), 2.36-2.31 (m, 2H, CH2CO), 1.81-1.67 (m, 4H),
1.44-1.22 (m, 15H), 0.86 (s, CH3). 13C NMR (50 MHz, CDCl3): δ )
120.66, 68.77, 45.19, 37.23, 36.24, 32.62, 32.52, 30.37, 29.46, 29.42,
28.84, 26.84, 23.27, 21.24, 12.20. IR (film): 3455, 2930, 2850, 2250,
1470, 1310, 1045 cm-1. Anal. Calcd for C15H28ClNO (273.9): C, 65.79;
H, 10.31; N, 5.12. Found: C, 65.64; H, 10.11; N, 4.94.
14.1, J ) 7.6, CH2CH2CO, 1H), 1.67-1.32 (m, 11H), 1.29 (d, J )
6.8, CH3). 13C NMR (50 MHz, CDCl3): δ )172.05, 83.74, 34.76, 33.29,
29.03, 26.72, 26.43, 26.04, 21.23, 20.93, 15.47. IR (film): 2930, 2860,
1730, 1450, 1210, 1060 cm-1. Anal. Calcd for C11H18O2 (182.3): C,
72.49; H, 9.95. Found: C, 72.42; H, 9.97.
13-Chloro-4-hydroxymethyl-4-methyltridecanoic Acid tert-Butyl
Ester 51 (Table 6, Entry 3). According to general procedure 4, 26
(437 mg, 2.0 mmol), 4 (950 mg, 6.0 mmol), tert-butylacrylate (600
µL, 4.0 mmol), Zn (260 mg, 4.0 mmol), ZnCl2 (273 mg, 2.0 mmol),
and titanocene dichloride (25.0 mg, 0.10 mmol) were reacted for 12 h.
After silica gel chromatography, 571 mg of 51 was obtained (91%).
3-(1-Hydroxymethylcyclohexyl)-2-methylpropionitrile 54 (Table
7, Entry 3). According to general procedure 4, 48 (370 µL, 2.0 mmol),
4 (945 mg, 6.0 mmol), Mn (260 mg, 4.0 mmol), methacrylonitrile (340
µL, 4.0 mmol), collidine (1.320 mL, 10 mmol), and titanocene
dichloride (25.0 mg, 0.10 mmol) were reacted for 36 h. After silica
gel chromatography, 263 mg of 54 was obtained (73%).
Rf (25% MTBE, 75% PE): 0.3. 1H NMR (300 MHz, CDCl3): δ )
3
3.53 (t, J ) 6.8, CH2Cl), AB-signal (δA ) 3.27, δB ) 3.24, JAB
)
Rf (50% MTBE, 50% PE): 0.4. 1H NMR (300 MHz, CDCl3): δ )
12.8 Hz, additionally split by 3J ) 6.4 Hz), 2.20 (t, 3J ) 7.5, CH2CO),
2.02 (t, 3J ) 6.4, CH2OH), 1.76 (quin, 3J ) 6.8, 1H), 1.55 (t, 3J ) 7.5,
CH2CH2CO), 1.44 (s, C(CH3)3), 1.28-1.18 (m, 10H), 0.82 (s, CH3,
3H). 13C NMR (50 MHz, CDCl3): δ ) 174.34, 80.47, 68.81, 45.18,
37.26, 36.61, 32.64, 30.53, 29.99, 29.53, 29.46, 28.89, 28.06, 26.88,
23.31, 21.55. IR (film): 3430, 2930, 2855, 1730, 1710, 1650, 1155,
1040 cm-1. Anal. Calcd for C19H37ClO3 (314.5): C, 65.40; H, 10.69.
Found: C, 65.50; H, 10.80.
br AB-signal (δA ) 3.61, δB ) 3.53, JAB ) 11.0 Hz, CH2OH), 2.73
3
2
3
(dqd, J ) 10.6, 7.2, 3.1, CHCN), 1.89 (dd, J ) 14.3, J ) 10.6,
CH2CHCN, 1H), 1.49-1.43 (m, 10H), 1.35 (d, J ) 7.1, CH3). 13C
3
NMR (50 MHz, CDCl3): δ ) 124.56, 67.32, 40.37, 37.35, 32.98, 32.47,
26.16, 21.45, 21.34, 20.56, 19.97. IR (film): 3450, 2930, 2855, 2240,
1455, 1050 cm-1. Anal. Calcd for C11H19NO (181.3): C, 72.88; H,
10.56; N, 7.37. Found: C, 72.68; H, 10.52; N, 7.37.
6-Methyl-6-phenethyltetrahydropyran-2-one 52 (Table 6, Entry
4). According to general procedure 4, 7 (330 µL, 2.0 mmol), 4 (950
mg, 6.0 mmol), acrylonitrile (270 µL, 4.0 mmol), Zn (260 mg, 4.0
mmol), and titanocene dichloride (25.0 mg, 0.10 mmol) were reacted
for 10 h at room temperature and 12 h at reflux. After silica gel
chromatography, 285 mg of 52 was obtained (65%).
Acknowledgment. A.G. thanks the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft for stipends.
M.P. is indebted to the Socrates Program of the European Union
for a fellowship. We express our gratitude to Prof. Bru¨ckner
for his constant generous support and encouragement.
1
Rf (30% MTBE, 70% PE): 0.30. H NMR (300 MHz, CDCl3): δ
2
4
) 7.32-7.16 (m, CHar, 5H), 4.09 (dd, J ) 11.3, J ) 0.8, CH2O),
JA981635P