Dramatic rate acceleration in titanocene catalyzed epoxide openings: Cofactors and Lewis acid cocatalysis

Article abstract of DOI:10.1039/a805246h

High synthetic efficiency concerning yield and catalytic turn-over in intermolecular C-C bond forming reactions of radicals derived from epoxides can be achieved by means of hydrogen bonding with cofactors or by Lewis acid cocatalysis.

Full text of DOI:10.1039/a805246h

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Dramatic rate acceleration in titanocene catalyzed epoxide openings: cofactors
and Lewis acid cocatalysis
Andreas Gansäuer*† and Harald Bluhm
Institut für Organische Chemie der Georg-August-Universität, Tammannstr. 2, D-37077 Göttingen, Germany
High synthetic efficiency concerning yield and catalytic
turn-over in intermolecular C–C bond forming reactions of
radicals derived from epoxides can be achieved by means of
hydrogen bonding with cofactors or by Lewis acid cocatal-
ysis.
seemed to be at hand. Since alcohols are formed during the
course of the reaction, complexation of the products by
hydrogen bond formation with a suitable acceptor, e.g. a
sterically demanding amine, should be possible.4 On the other
5
hand a Lewis acid stronger than Cp2TiCl2 should be com-
plexed by the reaction products and thus allow for catalyst
activation and thus higher turnover.6 Table 1 summarizes the
results of our initial optimization studies. Other Lewis acids not
included, e.g. AlCl3, gave vastly inferior results.
Catalytic reactions emerging from stoichiometric transforma-
tions have become increasingly important over the last three
years.1,2 We have developed protonation of carbon–titanium
and oxygen–titanium bonds as an alternative to silylation for
achieving catalytic turnover.3 This has allowed highly
diastereoselective pinacol couplings and chemo- and regio-
selective reductive openings of epoxides. Here we describe an
efficient method for the addition of radicals derived from
epoxides to a,b-unsaturated carbonyl compounds yielding
synthetically important d-lactones, hydroxy esters and hydroxy
nitriles in high yield, with low catalyst loading in short times.
Under the standard conditions for the reductive opening of
epoxides with hydrogen atom donors3a dodec-1-ene oxide gives
only 21 and 40% yield of the addition products to methyl
acrylate (7) and acrylonitrile (6), respectively, after 72 h in the
presence of 5 mol% Cp2TiCl2 (Scheme 1). Moreover, the
products are contaminated with polymeric material derived
from the radical acceptor. We reasoned that low yields and
turnovers are due to product inhibition. Compound 6 and MeOH
formed after lactonization seemed to be able to efficiently
complex at least one of the titanocene species in the catalytic
cycle. Similar problems were noticed in reactions of higher
substituted epoxides as well as in addition reactions to tert-butyl
acrylate. Since this type of product inhibition could be a general
problem in the de novo design of catalytic electron transfer
reactions with densely functionalized molecules, a widely
applicable solution is of interest for this rapidly expanding
field.
Gratifyingly, using Zn as stoichiometric reductant7 led to a
distinct acceleration of the reaction. It seems that ZnCl2 formed
during the course of the reduction of Cp2TiCl2 acts as a Lewis
acid strong enough to bind MeOH and restore catalyst activity.
This effect is even more pronounced when 1 equiv of ZnCl2 is
added to the reaction mixture. The same effect could be
observed in addition reactions to tert-butyl acrylate. Inter-
estingly in the reaction of 1 with 3, lactone 7 is isolated as the
sole product of the reaction in high yield after aqueous work-up
when Zn is used as stoichiometric reductant. A detailed kinetic
analysis reveals formation of 85% of 6 after 3 h. Subsequently,
ZnCl2-initiated cyclization occurs. Thus, it seems that ZnCl2
first allows for efficient formation of 6 and then activates the
nitrile strongly towards intramolecular attack by the hydroxy
group. The resulting imino ester is hydrolyzed during work-up.
Compared to other methods of lactone formation from hydroxy
nitriles8,9 our reaction conditions are clearly milder and a wider
variety of functional groups is tolerated. Also the product is
formed in a one step procedure without the necessity of isolating
and purifing any intermediates.10 However, with Mn as
reductant and ZnCl2 as an additional Lewis acid only 6 is
formed after 8 h. Thus, MnCl2 seems to coordinate the nitrile
group without allowing activation towards cyclization. Accord-
ingly, the beneficial role of ZnCl2 involves prevention of
product inhibition by complexation of the hydroxy group. The
utility of our approach was further demonstrated by the fact that
catalyst loading in these reactions can be reduced to 1 mol%
without significant decrease in yields when reaction times are
prolonged.
Two conceptually different and novel approaches towards
binding of the reaction products and thus catalyst activation
CO2But
Table 2 summarizes some of the examples conducted under
the optimized reaction conditions. While sterically more
O
i
iv
CO2Me
O
O
OH
( )9
Table 1 Optimization of the addition of 1-dodecene oxide to a,b-
( )9
ButO2C
unsaturated carbonyl compounds
5
4
2
1
( )9
Acceptor
Reductant
Additive
t/h
Product Yield (%)a
ii
7
CN
iii
2
2
2
3
3
3
3
4
4
Mn
Zn
—
ZnCl2
—
—
—
ZnCl2
ZnCl2
—
66
16
44
16
43
12
14
65
16
5
5
5
7
7
7
6
7
7
68
81
73
83
73
88
80
21
72
NC
CN
3
O
3
Znb
Zn
OH
( )9
O
Znb
Zn
Mn
Mn
Zn
6
( )9
ZnCl2
7
Scheme 1 Reagents and conditions: i, ZnCl2, Zn, collidine·HCl; ii, ZnCl2,
Mn, collidine·HCl; iii, ZnCl2, Zn, collidine·HCl, or collidine, collidine·HCl;
iv, ZnCl2, Zn, collidine·HCl, or collidine, collidine·HCl
a As 94:6 mixture of 5-substituted pyran-2-one 7 and 6-substituted pyranone
or 94:6 mixture of 4-hydroxymethyltetradecanenitrile or ester 6 or 5 and
5-hydroxypentadecanenitrile or ester. b 1 mol% of catalyst employed.
Chem. Commun., 1998
2143

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Table 2 Addition reactions of other epoxides to a,b-unsaturated carbonyl
compounds with Lewis acid cocatalysis
Table 3 Collidine as cofactor in addition reactions
Substrate
t/h
Product
Yield (%)
Reductant/
additive
1
36
6
75
Substrate
t/h Product
Yield (%)
HO
NC
O
36
36
73
73
O
Cl
( )2
Zn/ZnCl2 24
Zn/ZnCl2 16
86
Cl
O
O
( )9
O
O
OH
CN
O
O
78
HO
ButO2C
O
Zn
64
93a
91
Ph
( )2
Addition to 3 proceeded smoothly to give the desired product 6
in good yields and in reasonable reaction times. It seems that
collidine is indeed able to bind hydroxy groups of the reaction
products via hydrogen bonding. Thus, collidine acts as a
cofactor to restore catalytic activity via hydrogen bonding.
Ph
( )2
HO
ButO2C
O
Zn/ZnCl2 12
Cl
( )9
Cl
( )9
O
O
O
Zn
10
65b
Notes and References
Ph
( )2
( )2 Ph
† E-mail: agansae@gwdg.de
a
Reaction performed in the presence of 4-phenyl-2-butanone (95%
1 For a recent review see A. Fürstner, Chem. Eur. J. 1998, 4, 567.
2 A. Fürstner and A. Hupperts, J. Am. Chem. Soc., 1995, 117, 4468; A.
Fürstner and N. Shi, J. Am. Chem. Soc., 1996, 118, 2533; 1996, 118, 12
349; T. Hirao, T. Hasegawa, Y. Muguruma and I. Ikeda, J. Org. Chem.,
1996, 61, 366; R. Nomura, T. Matsuno and T. Endo, J. Am. Chem. Soc.,
1996, 118, 11 666; A. Gansäuer, Chem. Commun., 1997, 457; A.
Gansäuer, Synlett, 1997, 363; E. J. Corey and G. Z. Zheng, Tetrahedron
Lett., 1997, 38, 1045; T. A. Lipski, M. A. Hilfiker and S. G. Nelson,
J. Org. Chem., 1997, 62, 4566; A. Svatos and W. Boland, Synlett, 1998,
549.
b
recovery).
reaction.
Compound 3 as acceptor, 12 h reflux to complete the
demanding hydroxy nitriles can be readily obtained in the
presence of ZnCl2, refluxing of the reaction mixture yields the
lactones in good yields. The reaction conditions tolerate a
number of functional groups, e.g. ketones and halides, sensitive
to stronger SET reagents, e.g. SmI2.11
Lewis acid cocatalysis thus offers an attractive means for
catalyst activation and alteration of selectivity in titanocene-
catalyzed addition reactions of radicals derived from epoxides
to a,b-unsaturated carbonyl compounds. Compared to the
stoichiometric parent system12 the amount of Cp2TiCl2 to be
utilized is reduced by a factor of 200 and only 1.2 equiv. of
radical acceptor have to be used compared to the 10 equiv.
usually employed under stoichiometric conditions. No sig-
nificant reduction in isolated yields is observed. Also deoxygen-
ation, constituting a major side reaction under stoichiometric
conditions especially for monosubstituted epoxides, was never
observed.12 Our catalytic conditions are therefore clearly
superior to the stoichiometric conditions.
3 (a) A. Gansäuer, M. Pierobon and H. Bluhm, Angew. Chem., 1998, 110,
107; Angew. Chem., Int. Ed., 1998, 37, 101; (b) A. Gansäuer and D.
Bauer, J. Org. Chem., 1998, 63, 2070.
4 J.-M. Lehn, Supramolecular Chemistry, VCH, Weinheim, 1995.
5 M. T. Reetz, in Organometallics in Synthesis, A Manual, ed. M.
Schlosser, Wiley, New York, 1994, p. 195.
6 S. Shamyati and S. L. Schreiber, in Comprehensive Organic Synthesis,
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7 M. L. H. Green and C. R. Lucas, J. Chem. Soc., Dalton Trans., 1972,
1000; R. S. P. Coutts, P. C. Wailes and R. L. Martin, J. Organomet.
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10 D. L. J. Clive, P. L. Beaulieu and L. Lu, J. Org. Chem., 1984, 49,
1313.
11 G. A. Molander, Chem. Rev., 1992, 92, 29.
Hydrogen bonding also constitutes a convenient way to
achieve catalyst activation and to obtain the desired products
under mild conditions. However, care has to be taken in
choosing the appropriate hydrogen bond acceptor. If the
acceptor represents a powerful ligand, e.g. DMPU, catalyst
deactivation was observed. If a base is chosen as acceptor
instead, it should not constitute a sterically accessible ligand and
12 W. A. Nugent and T. V. RajanBabu, J. Am. Chem. Soc., 1988, 110,
8561; T. V. RajanBabu and W. A. Nugent, J. Am. Chem. Soc., 1989,
111, 4525; T. V. RajanBabu, W. A. Nugent and M. S. Beattie, J. Am.
Chem. Soc., 1990, 112, 6408; T. V. RajanBabu and W. A. Nugent,
J. Am. Chem. Soc., 1994, 116, 986.
13 J. March, Advanced Organic Chemistry, 4th edn., Wiley, New York,
1992, p. 248; Handbook of Chemistry and Physics, 78th edn., ed. D. R.
Lide, CRC Press, Boca Raton, 1997, pp. 8–45.
13
its hydrochloride must not have a higher pKa than collidine
hydrochloride. Otherwise proton transfer precludes catalytic
turnover.3
Accordingly we decided to test collidine and ran the reaction
under buffered protic conditions. Table 3 summarizes the
results of our investigations. Clearly collidine has a beneficial
role on both catalytic activity and yields of the products.
Received in Cambridge, UK, 7th July 1998; 8/05246H
2144
Chem. Commun., 1998