Alkenes from terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide and organolithiums or Grignard reagents

Article abstract of DOI:10.1021/ja045513a

E-Alkenes (including arylated alkenes, dienes, and allylsilanes) are efficiently prepared by α-deprotonation of terminal epoxides using lithium 2,2,6,6-tetramethylpiperidide, followed by in situ trapping with organolithiums or Grignard reagents. Copyright

Full text of DOI:10.1021/ja045513a

Published on Web 09/11/2004
Alkenes from Terminal Epoxides Using Lithium 2,2,6,6-Tetramethylpiperidide
and Organolithiums or Grignard Reagents
David M. Hodgson,*,† Matthew J. Fleming,† and Steven J. Stanway#
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road,
Oxford OX1 3TA, U.K., and GlaxoSmithKline, New Frontiers Science Park, Third AVenue,
Harlow, Essex CM19 5AW, U.K.
Received July 26, 2004; E-mail: david.hodgson@chem.ox.ac.uk
As originally reported by Crandall and Lin,1 and subsequently
studied in more detail by Mioskowski and co-workers,2 terminal
Table 1. Alkenes 6 from Epoxide 5 Using LTMP and Aryl- or
Alkenyllithiums
epoxides 1 can function as vinyl cation equivalents with organo-
lithiums. This is potentially a very powerful process for the synthesis
of alkenes 3, because of its convergent nature, the regiospecificity
in the double bond installation, and the ready availability of the
starting materials. However, the reaction currently suffers from three
significant limitations: (1) only simple alkyllithiums are effective
partners in the chemistry (for example, aryllithiums, vinyllithiums,
and R-silyl-substituted alkyllithiums all give secondary alcohols 4
by direct epoxide ring-opening);3 (2) high E-selectivity is observed
only with secondary and tertiary alkyllithiums (E:Z, 3:1 and 2:1
are obtained using 1,2-epoxydodecane in THF with BuLi and MeLi,
respectively);2 and (3) at least 2 equiv of the organolithium are
required (the first equivalent functions as a base to form an
R-lithiated epoxide 2, and the second as nucleophile on this transient
carbenoid).4
a Isolated yield. b Determined by GCMS. Ratios refer to E:Z (entries
1-3), E,E:Z,E (entries 5-7, 10), Z,E:E,E (entry 8), and Z,E:other isomers
(entry 9). c 1.5 equiv of RLi used.
We recently reported the reaction of terminal epoxides with
column chromatography) byproducts became more noticeable. The
chemistry was also applicable to p-MeOC6H4Li (entry 2), and to a
range of alkenyllithiums which gave the corresponding dienes
(entries 3-10). The reaction was highly E-selective for the newly
formed double bond. E-Alkenyllithiums gave E,E-dienes with
g98:2 selectivity (entries 5-7). Using Z-vinyllithiums (entries 8
and 9) gave the corresponding Z,E-dienes as the major isomers
(g90% selectivity). Using an unsymmetrical 2,2-disubstituted
1-alkenyllithium gave the diene 6j in 85% yield and 91% isomeric
purity (entry 10). In each case, addition of the alkenyllithium (3
equiv) to the terminal epoxide under the same reaction conditions,
but without LTMP present, gave the corresponding homoallylic
secondary alcohol from direct ring-opening of the epoxide as the
major product (72-99%).3,8
Regio- and stereo-defined allylsilanes are valuable intermediates
in synthesis.9 E-Allylsilanes 7 were found be conveniently accessed
(Table 2) by addition of a variety of terminal epoxides to a mixture
of LTMP and commercially available Me3SiCH2Li, or 1-(trimeth-
ylsilyl)hexyllithium (generated by the addition of BuLi to vinylt-
rimethylsilane).10 For Me3SiCH2Li, E-selectivity is higher in ethereal
solvents compared to that obtained in reactions carried out in
hexane. Entries 4-7 illustrate a straightforward way to access
R-alkylated E-allysilanes in a completely regioselective manner.
lithium 2,2,6,6-tetramethylpiperidide (LTMP), which proceeds
through trapping of a trans-R-lithiated epoxide 25 with LTMP to
give an enamine 3 (R2 ) tetramethylpiperidin-1-yl).6 During this
study we considered whether the presence of an organolithium
might divert the chemistry to alkene synthesis. This could provide
a solution to the limitations mentioned above, provided (i) R-lithia-
tion of the epoxide by LTMP is faster than direct ring-opening (and/
or R-lithiation) of the epoxide by the organolithium, (ii) the resulting
trans-R-lithiated epoxide 2 is preferentially trapped by the organo-
lithium rather than by LTMP, and (iii) the organolithium is not
consumed in deprotonating tetramethylpiperidine7 generated by the
desired epoxide lithiation pathway. Although these are demanding
criteria, in the present Communication we report that the combina-
tion of LTMP and organolithiums (or Grignard reagents) provides
promising new and straightforward methodology for alkene syn-
thesis from terminal epoxides.
Initial studies on the addition of 1,2-epoxydodecane to a mixture
of LTMP (2 equiv) and PhLi (1.3 equiv) indicated that the desired
alkene 6a was isolated in excellent yield (93%) when the reaction
was carried out in hexane (Table 1, entry 1). In ethereal solvents,
secondary alcohol and enamine (isolated as the aldehyde after
† University of Oxford.
# GlaxoSmithKline.
9
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J. AM. CHEM. SOC. 2004, 126, 12250-12251
10.1021/ja045513a CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Allylsilanes 7 from Terminal Epoxidesa
Table 3. Alkenes 6 from Epoxide 5 Using LTMP and Grignard
Reagentsa
a Et2O as solvent unless otherwise indicated. b Isolated yield. c Deter-
mined by 1H NMR, 500 MHz (entry 1) or GCMS (entries 1-3). Ratios
refer to E:Z (entries 1, 2), Z,E:other isomers (entry 3), and E,E:Z,E (entry
4). d Hexane as solvent, 1.8 equiv of ClMgMe, and 1.5 equiv of LTMP
used.
of such alkenes from epoxides, we have found that Grignard
reagents offer an attractive solution (Table 3, entries 1 and 2).13
Dienes are also accessible using alkenyl Grignard reagents (entries
3 and 4). To our knowledge, these are the first examples of Grignard
reagents inserting into R-metalated epoxides to produce alkenes.
In summary, we report chemistry that significantly broadens the
use of epoxides as regio- and stereo-defined vinyl cation equivalents.
The ability of lithium amides and organolithiums (or Grignard
reagents), present in the same flask, to operate apparently inde-
pendently of each other14 but in defined sequence on a terminal
epoxide substrate, resulting in transformations that neither can
achieve by themselves, may have broader utility.
a Hexane as solvent unless otherwise indicated. b Isolated yield. c De-
termined by GCMS. d Et2O as solvent (in hexane, 84% yield, E:Z, 65:35).
e THF as solvent (in hexane (entry 2), 88% yield, E:Z, 80:20; (entry 3)
83% yield, E:Z, 83:17).
It was considered important to probe whether the stereochemistry
of the R-lithiated epoxide influences product alkene geometry. This
was studied using an R-deuterated epoxide 8 and LTMP with PhLi,
vinyllithium, and Me3SiCH2Li. Reaction of cis-8 gave the corre-
sponding E-alkenes with high deuterium retention (g94%). With
trans-8 the major product in each case is still the E-alkene, but
with low deuterium content (e8%). These results suggest that, for
these organolithiums, a trans-lithiated epoxide leads mainly to
E-alkene formation. With trans-8 a kinetic isotope effect leads to
increased levels of Z-alkene; the high deuterium content (g92%)
in the Z-alkene indicates that it is mainly formed from cis-lithiated
epoxide.
Acknowledgment. We thank the EPSRC and GlaxoSmithKline
for a CASE award, the EPSRC for a research grant (GR/S46789/
01), and the EPSRC National Mass Spectrometry Service Centre
for mass spectra.
Supporting Information Available: Experimental procedures and
NMR spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Crandall, J. K.; Lin, L.-H. C. J. Am. Chem. Soc. 1967, 89, 4527-4528.
(2) Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett. 1994, 35, 7943-
7946.
(3) See Supporting Information.
(4) For a recent review, see: Hodgson, D. M.; Gras, E. Synthesis 2002, 1625-
1642.
(5) Yanagisawa, A.; Yasue, K.; Yamamoto, H. J. Chem. Soc., Chem. Commun.
1994, 2103-2104.
(6) Hodgson, D. M.; Bray, C. D.; Kindon, N. D. J. Am. Chem. Soc. 2004,
126, 6870-6871. See also: Hodgson, D. M.; Chung, Y. K.; Paris, J.-M.
J. Am. Chem. Soc. 2004, 126, 8664-8665.
(7) Podraza, K. F.; Bassfield, R. L. J. Org. Chem. 1988, 53, 2643-2644.
(8) The geometry of the homoallylic alcohols confirmed the geometrical
integrity of the alkenyllithiums used.
(9) Sarkar, T. K. In Science of Synthesis; Fleming, I., Ed.; Thieme: Stuttgart,
2001; Vol. 4, pp 837-925.
Use of the LTMP-modified alkene synthesis with 1,2-epoxy-
dodecane and a representative primary alkyllithium (BuLi, 1.4
equiv) in Et2O11 gave alkene 6k (73%) with only a modest
improvement in stereoselectivity (E:Z, 90:10) compared to the
LTMP-free reaction (3 equiv of BuLi, 76%, E:Z, 81:19). The likely
origin of the Z-alkene in these reactions is removal of the
cis-terminal hydrogen by BuLi, since reaction of cis-8 with BuLi
in Et2O gave the corresponding alkene exclusively as the E-isomer
(100%D). MeLi (1.5 equiv), LTMP (2 equiv), and 1,2-epoxydode-
cane in Et2O11 also gave modest stereoselectivity (alkene 6l, 61%,
E:Z, 72:28).12 In seeking to improve stereocontrol in the synthesis
(10) Ager, D. J. Org. React. 1990, 38, 1-227.
(11) Use of hexane led to lower stereoselectivities.
(12) In the absence of LTMP, MeLi in Et2O gave only the corresponding
secondary alcohol from direct ring-opening.
(13) In the absence of LTMP, only secondary alcohols and chlorohydrins are
observed.
(14) (a) Pratt, L. M.; Newman, A.; St. Cyr, J.; Johnson, H.; Miles, B.; Lattier,
A.; Austin, E.; Henderson, S.; Hershey, B.; Lin, M.; Balamraju, Y.;
Sammonds, L.; Cheramie, J.; Karnes, J.; Hymel, E.; Woodford, B.; Carter,
C. J. Org. Chem. 2003, 68, 6387-6391. (b) Pratt, L. M. Mini-ReV. Org.
Chem. 2004, 1, 209-217. (c) Shimizu, M.; Fujimoto, T.; Liu, X.; Hiyama,
T. Chem. Lett. 2004, 33, 438-439.
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