Imidazolinium salts as catalysts for the ring-opening alkylation of meso epoxides by alkylaluminum complexes

Article abstract of DOI:10.1021/ol0161110

(Matrix presented) Imidazolinium salts and their N-heterocyclic carbene (NHC) derivatives catalyze the alkylation of a variety of meso epoxides in the presence of triethylaluminum (yield = 70-90%), under mild conditions. Imidazolinium salts are better catalysts than their NHC derivatives but can lead to dimerization side reactions under extended reaction time. Preformed NHC·AIEt₃ complexes and Wanzlick-type olefins, which are dimers of free NHCs, are also catalysts for this reaction.

Full text of DOI:10.1021/ol0161110

ORGANIC
LETTERS
2
001
Vol. 3, No. 14
229-2231
Imidazolinium Salts as Catalysts for the
Ring-Opening Alkylation of meso
2
Epoxides by Alkylaluminum Complexes
Hongying Zhou, E. Joseph Campbell, and SonBinh T. Nguyen*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
stn@chem.northwestern.edu
Received May 12, 2001
ABSTRACT
Imidazolinium salts and their N-heterocyclic carbene (NHC) derivatives catalyze the alkylation of a variety of meso epoxides in the presence
of triethylaluminum (yield ) 70−90%), under mild conditions. Imidazolinium salts are better catalysts than their NHC derivatives but can lead
to dimerization side reactions under extended reaction time. Preformed NHC‚AlEt complexes and Wanzlick-type olefins, which are dimers of
3
free NHCs, are also catalysts for this reaction.
Due to the prevalence of optically active alcohols as products
and intermediates in fine chemical synthesis, substantial
research efforts have been devoted to the catalytic synthesis
agents have been known to give excellent yields of nucleo-
philic addition products when other carbon nucleophiles
fail. Thus, any catalyst promoting the utilization of
alkylaluminum reagents for epoxide alkylation reactions
would greatly expand the current scope of alcohol-forming
methodology.
2
,6
1
of these versatile synthons. Of the many pathways that have
been explored, the desymmetrization of meso-epoxides via
nucleophilic addition of a carbon nucleophile is particularly
attractive due to the simultaneous formation of a carbon-
carbon bond. To date, the most common nucleophilic
alkylating reagents used in this catalytic addition reaction
have been organometallic complexes such as alkyllithium,
Grignard reagents, organocopper, and/or alkylaluminum
Recently, Schneider et al. reported the high-yield synthesis
of alcohols from the ring-opening reaction of epoxides with
triethylaluminum using catalytic amounts of Lewis bases
4
such as phosphines. For decades, the use of phosphines as
ligands has been ubiquitous in organometallic chemistry.7
More recently N-heterocyclic carbenes (NHC), so-called
“phosphine-mimics”, have attracted attention as an alternative
-9
2-4
compounds. However, the use of alkylithium and Grignard
reagents is only of moderate synthetic utility due to facile
2
10
rearrangements of epoxides. Although organocopper re-
to phosphine ligands in homogeneous catalysis. More
agents are the best to date for epoxide desymmetrization,
their complicated synthesis often limits their laboratory
utility. Since trialkylaluminum compounds are readily
importantly, NHC are less toxic and can be synthesized in a
2
(
5) Cotton, F. A.; Wilkinson, G. AdVanced Inorganic Chemistry, 4th ed.;
Wiley: New York, 1980.
6) Boireau, G.; Abenhaim, D.; Henry-Basch, E. Tetrahedron 1980, 36,
available commercially and are prepared inexpensively on
an industrial scale, they are ideal reagents for the nucleophilic
(
3
061-3070.
5
alkylation of epoxides. Furthermore, organoaluminum re-
(7) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University Science
Books: Mill Valley, CA, 1987.
(
1) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52,
(8) Huang, J.; Stevens, E. D.; Nolan, S. P. Organometallics 2000, 19,
1194-1197.
1
9
4361-14384.
(
2) Smith, J. G. Synthesis 1984, 629-656.
(9) Pignolet, L. H. Homogeneous Catalysis with Metal Phosphine
Complexes; Plenum: New York, 1983.
(3) Oguni, N.; Miyagi, Y.; Itoh, K. Tetrahedron Lett. 1998, 39, 9023-
026.
(10) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 2162-2187.
(4) Schneider, C.; Brauner, J. Tetrahedron Lett. 2000, 41, 3043-3046.
1
0.1021/ol0161110 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/16/2001

more facile manner compared to phosphine compounds.
Recent developments have also shown that NHC closely
mimic tertiary phosphines electronically and that these
Ring Opening of Cyclohexene Oxidea
3
Table 1. AlEt
8
ligands may be interchangeable in homogeneous catalysis.
In fact, researchers have utilized members of the NHC ligand
family in place of tertiary phosphines in a variety of reactions,
such as the palladium-mediated Heck11 and amination
12
entry
catalyst
time (h)
yield (%)b
13
reactions, the rhodium-catalyzed hydrosilylation and hydro-
14
1
2
3
4
none
24
24
24
24
0
28
76
40
formylation of olefins, and the ruthenium-catalyzed olefin
metathesis reaction.15 On the basis of these reports, we
5
6
7
hypothesized that NHC may also be useful as catalysts for
the addition of triethylaluminum to epoxides (reaction 1).
a
Reaction conditions: AlEt3 (2 equiv), toluene, room temperature.
Determined by GC vs internal standard.
b
1
%
). However, with the addition of the free carbene 5 (5 mol
), the epoxide can be alkylated at room temperature to form
We were pleasantly surprised to find that not only do NHC
catalyze this reaction but the precursors to NHC, imidazo-
linium salts, also exhibit very high activity. Herein, we wish
to report the catalytic ring-opening desymmetrization of meso
epoxides using triethylaluminum and catalytic amounts of
either an imidazolinium salt or an NHC.
trans-2-ethylcyclohexanol in 28% yield after 24 h (Table 1,
entry 2). To improve this conversion, we investigated the
activity of other nucleophilic carbene catalysts, such as a
18
preformed aluminum carbene complex 6 and the “Wanzlick-
1
9
type” olefin 7 (Figure 1).
Compounds 1, 3, and 4 were synthesized according to
literature procedures.1
6,17
The imidazolinium salt 2 was
synthesized by adapting literature reports of similar com-
1
6
pounds. The free carbene 5 can be generated by deproto-
17
nation of imidazolinium salt 3 with potassium hydride. This
free carbene coordinates to AlEt to give 6, which can be
3
isolated in quantitative yield (Scheme 1, Supporting Informa-
tion).18
Scheme 1. Formation of a Stable Aluminum Carbene
Complex
Figure 1. Effect of catalyst generation conditions on the ring
opening of cyclohexene oxide.
The aluminum carbene complex 6 demonstrated improved
catalytic activity over the free carbene for the ring-opening
of cyclohexene oxide (Table 1, entry 3). This is quite
surprising when we consider that 6 should form in the free
3
carbene-catalyzed reaction where AlEt is used in excess.
1
The H NMR spectrum of 6 and 1 equiv of AlEt
temperature in C shows a broadening of the CH
2
of AlEt ; however, no broadening of the CH protons of 6
3
at room
protons
D
6 6
2
3
(
14) Chen, A. C.; Ren, L.; Decken, A.; Crudden, C. M. Organometallics
000, 19, 3459-3461.
15) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
53-956.
16) Saba, S.; Brescia, A. M.; Kaloustian, M. K. Tetrahedron Lett. 1991,
32, 5031-5034.
17) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.;
Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999, 55,
2
(
9
(
As a substrate for the ring-opening addition of triethyl-
aluminum, cyclohexene oxide is unreactive (Table 1, entry
(
1
4523-14534.
(
11) Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J. Organomet.
(18) Li, X.-W.; Su, J.; Robinson, G. H. Chem. Commun. 1996, 2683-
Chem. 1998, 557, 93-96.
2684.
(
(
12) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309.
(19) Goldwhite, H.; Kaminski, J.; Millhauser, G.; Ortiz, J.; Vargas, M.;
13) Herrmann, W. A.; Goossen, L. J.; Koecher, C.; Artus, G. R. J.
Vertal, L.; Lappert, M. F.; Smith, S. J. J. Organomet. Chem. 1986, 310,
21-25.
Angew. Chem., Int. Ed. Engl. 1997, 35, 22805-2807.
2230
Org. Lett., Vol. 3, No. 14, 2001

is observed. Interestingly, the Wanzlick-type olefin 7, which
When using the imidazolinium salts 1-4 as catalysts,
prolonging the overall reaction time beyond 18 h leads to
formation of trans-2-[(trans-2-ethylcyclohexyl)oxy]cyclo-
hexanol as the side product and thus a decrease in the overall
yield of the desired trans-2-ethylcyclohexanol product.
The saturated imidazolinium salts 1-3 were found to give
higher yields than their unsaturated analogue 4 (Table 2,
entries 1-4). Further, complex 1 possessing a noncoordi-
has been reported and debated to exist in equilibrium with
free NHC species (Scheme 1),2
0-22
also catalyzes reaction 1
(Table 1, entry 4). Presumably, 7 dissociates into the
corresponding NHC under our reaction conditions to give
an active NHC-type catalyst.
1
Given the high acidity of the C proton of the imidazo-
linium salts 1-4, we theorized that the alkyl groups of AlEt
3
could be used as Br o¨ nsted bases to directly generate the
carbene catalyst in situ for reaction 1. Complete deprotana-
tion, if achieved, would be observable by dissolution of the
toluene-insoluble imidazolinium salt. Indeed, heterogeneous
slurries of 1-4 in toluene become homogeneous in the
4
nating BF counterion results in better catalytic activity than
3 which has a Cl counterion (Table 2, entries 1 and 3).
Although the uncatalyzed reaction between terminal ep-
4
oxides and AlEt
3
proceeds at room temperature, cyclic
epoxides such as cyclopentene and norbornene oxides are
only slightly reactive with triethylaluminum (Table 3, entries
3
presence of only 1 equiv of AlEt .
Building upon this result, we employed catalytic amounts
of 1-4 directly in reaction 1. We noted an increase in
catalytic activity during the first 8 h of the reaction. During
this initial time, the activity is more than three times that
observed for either the free carbene 5 or the preformed
aluminum carbene complex 6 (Figure 1). This rate accelera-
Table 3. AlEt
3
Addition to meso Epoxides Catalyzed by 2a
yield (%)b
entry
substrate
catalyst
time (h)
1
1
2
2
3a
3b
a
b
a
b
none
2
none
2
none
2
none
2
12
12
12
12
4
4
12
12
0
77
0
53
25c
90c
0
cyclopentene oxide
2,3-butene oxide
norbornene oxide
tion cannot be attributed to either the BF
4
anion or acidic
C protons which result from an incomplete deprotonation
of the imidazolinium salt as both NH BF and 2,6-lutidinium
chloride do not catalyze reaction 1 (Table 2, entries 5 and
).
1
4
4
4
4
a
b
2,3-epoxy-2,3-
dimethylbutane
6
15
a
Reaction conditions: 2 (5 mol %); AlEt3 (2 equiv), toluene, room
temperature. b Determined by GC vs internal standard. c 1 equiv of AlEt3.
Table 2. AlEt
3
Ring Opening of Cyclohexene Oxide by
Imidazolinium Saltsa
1
a and 3a). Using precatalyst 2, the ring-opening nucleophilic
addition of AlEt to these substrates was greatly accelerated
Table 3, entries 1b and 3b). In addition to cyclic epoxides,
entry
catalyst
time(h)
yield (%)b
3
1
2
3
4
5
6
1
2
3
4
12
12
12
12
24
24
71
93
62
20
6
(
2,3-butene oxide, an acyclic epoxide that exhibits no reactiv-
ity toward triethylaluminum, produced over 50% yield of
-methylpentan-2-ol under our reaction conditions (Table 3,
3
NH4BF4
lutidine‚HCl
entries 2a and 2b).
3
In summary, the alkylation of meso epoxides with AlEt
3
a
Reaction conditions: AlEt3 (2 equiv), toluene, room temperature.
Determined by GC vs internal standard
b
can be successfully accomplished using catalytic amounts
of imidazolinium salts, their NHC derivatives, and Wanzlick-
type olefins to produce functionalized alcohols. Further
mechanistic study of this catalyst system will be reported in
due course.
The rate acceleration observed for the in situ generated
catalysts that result from the reaction of 1-4 and AlEt
specific to the initial generation conditions. The direct
reaction between the imidazolinium salt 1 with AlEt (10
equiv) in toluene (reaction time ) 12 h) yielded a white solid
after the removal of all volatile reactants. The H NMR
spectrum of this solid is quite complicated and is different
from that of the Al(carbene) complex 6. This solid is not as
active as 1. However, its activity is very similar to that of
complex 6 during the first 12 h of the reaction (Figure 1).
3
is
Acknowledgment. Support from the Dupont and Union
Carbide companies and the Beckman, Dreyfus, and Packard
Foundations are gratefully acknowledged. S.T.N. is an Alfred
P. Sloan research fellow. E.J.C. acknowledges the GEM and
IMGIP fellowship programs for financial support.
3
1
Supporting Information Available: Synthetic procedures
and characterization data for 2 and 6 and experimental and
analytical procedures (including a typical GC trace). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Liu, Y.; Lindner, P. E.; Lemal, D. M. J. Am. Chem. Soc. 1999,
1
21, 10626-10627.
(
(
21) Liu, Y.; Lemal, D. M. Tetrahedron Lett. 2000, 41, 599-602.
22) Hahn, F. E.; Wittenbecher, L.; Le Van, D.; Frohlich, R. Angew.
Chem., Int. Ed. 2000, 39, 541-544.
OL0161110
Org. Lett., Vol. 3, No. 14, 2001
2231