Alkenes from β-lithiooxyphosphonium ylides generated by trapping α-lithiated terminal epoxides with triphenylphosphine

Article abstract of DOI:10.3762/bjoc.8.219

Terminal epoxides undergo lithium 2,2,6,6-tetramethylpiperidide-induced a-lithiation and subsequent interception with Ph3P to provide a new and direct entry to β-lithiooxyphosphonium ylides. The intermediacy of such an ylide is demonstrated by representative alkene-forming reactions with chloromethyl pivalate, benzaldehyde and CD₃OD, giving a Z-allylic pivalate, a conjugated E-allylic alcohol and a partially deuterated terminal alkene, respectively, in modest yields

Full text of DOI:10.3762/bjoc.8.219

Alkenes from β-lithiooxyphosphonium ylides
generated by trapping α-lithiated terminal epoxides
with triphenylphosphine
David. M. Hodgson* and Rosanne S. D. Persaud
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1896–1900.
Department of Chemistry, Chemistry Research Laboratory, University
of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
doi:10.3762/bjoc.8.219
Received: 06 September 2012
Accepted: 15 October 2012
Published: 07 November 2012
Email:
David. M. Hodgson* - david.hodgson@chem.ox.ac.uk
* Corresponding author
Associate Editor: I. Marek
Keywords:
© 2012 Hodgson and Persaud; licensee Beilstein-Institut.
License and terms: see end of document.
alkenes; epoxides; lithiation; synthetic methods; ylide
Abstract
Terminal epoxides undergo lithium 2,2,6,6-tetramethylpiperidide-induced α-lithiation and subsequent interception with Ph3P to
provide a new and direct entry to β-lithiooxyphosphonium ylides. The intermediacy of such an ylide is demonstrated by represen-
tative alkene-forming reactions with chloromethyl pivalate, benzaldehyde and CD3OD, giving a Z-allylic pivalate, a conjugated
E-allylic alcohol and a partially deuterated terminal alkene, respectively, in modest yields.
Introduction
β-Lithiooxyphosphonium ylides 4 are useful intermediates in ry phosphonium salts [10-19], where the latter are obtained
synthesis as they react with a variety of electrophiles to provide from Ph3P and 1,2-halohydrins [10-16,19] or (in the presence of
a convergent entry to alkenes, often with high regio- and stereo- acid) from terminal epoxides [17,18]. In seeking a more concise
control (Scheme 1) [1-9]. These ylide intermediates can be way than the above approaches to β-lithiooxyphosphonium
generated by initiating a Wittig reaction between an aldehyde 1 ylides 4 (R2 = H), we were attracted to the possibility of phos-
and a phosphorane 2 at low temperature in the presence of phines intercepting α-lithiated terminal epoxides 10 (Scheme 2)
lithium salts, which promote ring opening of the initially and report here the results of that study. Such carbenoids 10 are
formed oxaphosphetane 3, followed by deprotonation typically unstable, but they can be easily formed from terminal epoxides
using PhLi [5].
8 by using hindered lithium amides, such as lithium tetra-
methylpiperidide (9, LTMP) [20], and have shown synthetic-
We recently reported the use of methylenetriphenylphos- ally useful carbene reactivity (e.g., cyclopropanation [21,22],
phorane (2) (R2 = H) in this chemistry for the synthesis of dimerization [23-25]). The reaction of carbenes and carbenoids
Z-allylic esters such as 6 [8] and conjugated E-allylic alcohols with heteroatom lone pairs is a popular strategy to access ylides
such as 7 [9]. β-Lithiooxyphosphonium ylides 4 (R2 = H) can [26], although phosphonium ylides for carbonyl-olefination
also be generated by double deprotonation of β-hydroxy prima- chemistry are usually prepared by deprotonation of phos-
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Beilstein J. Org. Chem. 2012, 8, 1896–1900.
chloromethyl pivalate (5) was added, resulting in the isolation
of allylic ester 6 (23%). Only the Z-isomer of 6 was observed,
indicating that stereoselectivity is not altered by this method of
β-lithiooxyphosphonium ylide formation. The presence of LiBr
(1 equiv) from the start of an otherwise identical reaction made
no significant difference to the yield of Z-allylic ester 6 (26%),
although the presence of such a salt is considered essential for
efficient generation of 4 from carbonyl compounds (Scheme 1)
[5]; this observation lends support to the notion that the prin-
cipal role of LiBr is to facilitate oxaphosphetane ring opening to
enable subsequent lithiation, and its presence does not signifi-
cantly influence subsequent reaction steps, at least with this
electrophile. While simple phosphoranes (Ph3PCH2 and
Ph3PCHMe) are known to react with epoxides (32–68% yields)
in the presence of soluble lithium halides [33,34], the
homoallylic alcohol, which would arise [35] from any reaction
of β-lithiooxyphosphonium ylide and terminal epoxide, was not
observed in the present studies; this suggests that the latter
ylides are not capable of reacting with terminal epoxides [35],
or the presence of LTMP and/or PPh3 prevents this reaction
from occurring.
Scheme 1: Typical generation of ylide 4 and reaction examples.
phonium salts [1-4]. In fact, phosphine trapping of lithium
carbenoids followed by carbonyl olefination has been little
studied since Seyferth and Wittig independently reported the
synthesis of chloro alkenes in modest yields (20–30%) by this
route (using CH2Cl2 and BuLi in the presence of Ph3P) over
half a century ago [27-31].
Scheme 3: Z-Allylic ester 6 from epoxide 11.
The original study on the reaction between LTMP and terminal
epoxides in THF showed this to be an efficient way to prepare
the corresponding isomerized aldehydes [20] (later established
as proceeding through an intermediate TMP enamine) [36,37].
In the present work, neither decanal nor its corresponding TMP
enamine were not detected as side-products, and we also estab-
lished that the presence of LiBr (1 equiv) did not interfere in
Scheme 2: Proposed ylide 4 formation from α-lithiated epoxide 10.
Results and Discussion
The feasibility of generating and reacting β-lithiooxyphos- this isomerization process, giving decanal from epoxide 11 in
phonium ylides 4 (R2 = H) derived directly from epoxides 65% yield (67% without LiBr) and with no unreacted epoxide
began with studies to produce allylic ester 6 under LTMP-based observed. The use of shorter reaction times (2–4 h) for the
conditions for α-lithiation of terminal epoxides [20-22] but with generation of the epoxide-derived ylide 4 (R2 = H), including
Ph3P also present (Scheme 3). Encouragingly, a red-orange increasing the quantities of LTMP and Ph3P (to 3 equiv), or the
colour, which is characteristic of a β-lithiooxyphosphonium use of t-BuOMe as solvent [21,22], did not lead to improved
ylide [8,9], gradually developed (mixing only LTMP and PPh3 yields of ester 6.
in THF at 0 °C for 24 h, gave no colour change from an initial
yellow solution), becoming very intense after 3 h, although As terminal epoxides are readily available as single enan-
some epoxide 11 was still present after 24 h (TLC monitoring); tiomers [38,39], it was considered important to study the possi-
the reduced activity of LTMP may be due to phosphine coordin- bility of using an aldehyde electrophile with the epoxide-
ation [32]. At this point, following cooling to −78 °C [8], derived ylide. This would provide an entry into allylic alcohols
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Beilstein J. Org. Chem. 2012, 8, 1896–1900.
[40], where the epoxide stereocentre is preserved in the product of allylic alcohol 7 (18%) was obtained by using s-BuLi in Et2O
[17,18]. In the event, benzaldehyde was successfully trapped to at −78 °C with a 24 h lithiation time (Scheme 5); lithiation by
give E-allylic alcohol 7 in up to 33% yield (Scheme 4) by using using other organolithiums (t-BuLi, PhLi, BuLi, MeLi), or at
LTMP (1 equiv), Ph3P (5 equiv) and LiBr (2 equiv; 24% yield higher or lower temperatures (−90 °C or −40 °C), for a longer
in the absence of LiBr). Essentially the same yields (31% and period (48 h) or in the presence of increased Ph3P (2 equiv), or
30%) were obtained under otherwise identical conditions but TMEDA (1 equiv) or LiBr (2 equiv) as additives were all less
with 2 equiv of Ph3P, or with excess LTMP (3 equiv) and Ph3P effective.
(9 equiv). Other experimental variations (use of sub-
stoichiometric TMP (0.25 equiv) [22] or substitution of LiBr by The use of a proton (deuterium) source as the electrophile to
LiCl) did not improve the yield of alcohol 7 (20% and 10%, res- trap an epoxide-derived ylide prepared by using LTMP was
pectively), whereas substitution of Ph3P by Bu3P or Cy3P did next examined. This was anticipated to provide a base-induced
not lead to the orange–red colouration suggestive of ylide for- method to deoxygenate epoxides [43], which in the case of
mation, and only starting epoxide 11 was observed.
deuteration would provide a regiospecific and potentially
stereoselective entry to 1-deuterated terminal alkenes [44,45].
Use of a slightly higher molecular weight epoxide, 1,2-epoxy-
dodecane (13) to facilitate product isolation, gave dodecene
(14) (41%, 50% D [46]) after reaction with CD3OD (Scheme 6),
where the deuterium incorporation was nonstereoselective [44].
Modest deuterium incorporation suggests partial collapse of the
intermediate β-lithiooxy ylide occurs under the conditions of its
generation, by elimination of Ph3PO after or before protonation
(e.g., from solvent) and before electrophile addition. Dodecene
was also observed as a byproduct in the corresponding reaction
Scheme 4: E-allylic alcohol 7 from epoxide 11.
We also studied the possibility of generating alcohol 7 from of epoxide 13 with benzaldehyde, supporting this hypothesis.
terminal epoxide 11 using an organolithium instead of a
hindered lithium amide as the base (Scheme 5). Organolithiums,
in particular secondary and tertiary organolithiums, are known
to react with terminal epoxides by α-lithiation, although this is
typically followed by trapping of the α-lithiated epoxide with a
second equivalent of the organolithium and elimination of Li2O
to give an E-alkene (e.g., 12): a process referred to as reductive
alkylation [41]. Also, while PPh3 is itself capable of being lithi-
Scheme 6: Terminal alkene 14 from epoxide 13.
ated–carboxylated (at a meta-position, 6% yield) by using BuLi
in Et2O [42], this requires significantly higher temperatures
(reflux, 46 h) than those applied here. In the event, the use of Conclusion
either s-BuLi or t-BuLi with epoxide 11 in the presence of Ph3P Among phosphoranes, β-lithiooxyphosphonium ylides occupy a
in a variety of solvents (THF, Et2O, t-BuOMe, toluene) fol- special place, because of their utility in Wittig–Schlosser and
lowed by the addition of benzaldehyde was found to give allylic SCOOPY-type stereoselective olefination reactions [1-19]. Here
alcohol 7, albeit in low yields with reductive alkylation always we have shown a new and concise method to such valuable
being the dominant reaction pathway, and typically ~30% of intermediates, directly from readily available terminal epoxides.
epoxide 11 and ~60% Ph3P being recovered. The highest yield Significantly, the work validates the compatibility of lithium
amide and phosphine to generate such ylides, whose interme-
diacy is demonstrated by representative alkene-forming reac-
tions with chloromethyl pivalate, benzaldehyde and CD3OD,
giving a Z-allylic pivalate, a conjugated E-allylic alcohol and a
partially deuterated terminal alkene, respectively. High stereo-
chemical control is retained in the Z-allylic pivalate and
E-allylic alcohol syntheses. While the overall yields for the
transformations are modest, they stand up to comparison with
Scheme 5: E-allylic alcohol 7 and alkene 12 from epoxide 11 by using
s-BuLi.
the earlier methods, given the experimental simplicity and
brevity of the current approach.
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Beilstein J. Org. Chem. 2012, 8, 1896–1900.
22.Hodgson, D. M.; Chung, Y. K.; Nuzzo, I.; Freixas, G.; Kulikiewicz, K. K.;
Cleator, E.; Paris, J.-M. J. Am. Chem. Soc. 2007, 129, 4456–4462.
doi:10.1021/ja0672932
Supporting Information
Supporting Information File 1
Preparative details of 6, 7, 12 and 14 are reported, together
with their spectroscopic data.
23.Hodgson, D. M.; Bray, C. D.; Kindon, N. D. Org. Lett. 2005, 7,
2305–2308. doi:10.1021/ol050402h
24.Hodgson, D. M.; Bray, C. D.; Humphreys, P. G. Synlett 2006, 1–22.
doi:10.1055/s-2005-921925
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-219-S1.pdf]
25.Hodgson, D. M.; Humphreys, P. G.; Hughes, S. P. Pure Appl. Chem.
2007, 79, 269–279. doi:10.1351/pac200779020269
26.Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263–309.
doi:10.1021/cr00003a001
References
27.Seyferth, D.; Grim, S. O.; Read, T. O. J. Am. Chem. Soc. 1960, 82,
1510–1511. doi:10.1021/ja01491a066
1. Gosney, I.; Rowley, A. G. Transformations via phosphorus-stabilized
anions. 1. Stereoselective synthesis of alkenes. In Organophosphorus
Reagents in Organic Synthesis; Cadogan, J. I., Ed.; Academic Press:
New York, 1979; pp 17–153.
28.Seyferth, D.; Grim, S. O.; Read, T. O. J. Am. Chem. Soc. 1961, 83,
1617–1620. doi:10.1021/ja01468a017
29.Wittig, G.; Schlosser, M. Angew. Chem. 1960, 72, 324.
doi:10.1002/ange.19600720913
2. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
doi:10.1021/cr00094a007
30.Wittig, G.; Schlosser, M. Chem. Ber. 1961, 94, 1373–1383.
doi:10.1002/cber.19610940532
3. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157.
doi:10.1002/9780470147306.ch1
31.Khaskin, B. A.; Molodova, O. D.; Torgasheva, N. A. Russ. Chem. Rev.
1992, 61, 306–334. doi:10.1070/RC1992v061n03ABEH000947
32.Rönnholm, P.; Hilmersson, G. ARKIVOC 2011, No. v, 200–210.
http://www.arkat-usa.org/get-file/38691
4. Schobert, R.; Hözel, C.; Barnickel, B. Wittig and related
phosphorus-based alkenations. In Science of Synthesis; de Meijere, A.,
Ed.; Thieme: Stuttgart, Germany, 2010; Vol. 47a, pp 9–84.
5. Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Chem.–Eur. J. 2003,
9, 570–574. doi:10.1002/chem.200390061
33.Schlosser, M.; Tuong, H. B.; Respondek, J.; Schaub, B. Chimia 1983,
37, 10–11.
6. Hodgson, D. M.; Arif, T. J. Am. Chem. Soc. 2008, 130, 16500–16501.
doi:10.1021/ja8076999
34.Materal-Saadi, M. S. Phosphorus, Sulfur Silicon Relat. Elem. 2000,
164, 269–275. doi:10.1080/10426500008045252
35.Heath, R. R.; Doolittle, R. E.; Sonnet, P. E.; Tumlinson, J. H.
J. Org. Chem. 1980, 45, 2910–2912. doi:10.1021/jo01302a032
36.Hodgson, D. M.; Bray, C. D.; Kindon, N. D. J. Am. Chem. Soc. 2004,
126, 6870–6871. doi:10.1021/ja031770o
7. Hodgson, D. M.; Arif, T. Org. Lett. 2010, 12, 4204–4207.
doi:10.1021/ol101843q
8. Hodgson, D. M.; Arif, T. Chem. Commun. 2011, 47, 2685–2687.
doi:10.1039/c0cc04429f
9. Hodgson, D. M.; Persaud, R. S. D. Org. Biomol. Chem. 2012, 10,
7949–7951. doi:10.1039/c2ob26346g
37.Hodgson, D. M.; Bray, C. D.; Kindon, N. D.; Reynolds, N. J.;
Coote, S. J.; Um, J. M.; Houk, K. N. J. Org. Chem. 2009, 74,
1019–1028. doi:10.1021/jo802016t
10.Corey, E. J.; Shirahama, H.; Yamamoto, H.; Terashima, S.;
Venkateswarlu, A.; Schaaf, T. K. J. Am. Chem. Soc. 1971, 93,
1490–1491. doi:10.1021/ja00735a032
38.Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N.
J. Am. Chem. Soc. 2002, 124, 1307–1315. doi:10.1021/ja016737l
39.Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001,
343, 5–26.
11.Corey, E. J.; Niwa, H.; Knolle, J. J. Am. Chem. Soc. 1978, 100,
1942–1943. doi:10.1021/ja00474a058
12.Corey, E. J.; Marfat, A.; Hoover, D. J. Tetrahedron Lett. 1981, 22,
1587–1590. doi:10.1016/S0040-4039(01)90384-3
doi:10.1002/1615-4169(20010129)343:1<5::AID-ADSC5>3.0.CO;2-I
40.Hodgson, D. M.; Humphreys, P. G. Allylic alcohols. In Science of
Synthesis; Clayden, J., Ed.; Thieme: Stuttgart, Germany, 2007; Vol. 32,
pp 583–665.
13.Schwarz, S.; Weber, G.; Depner, J.; Schaumann, J. Tetrahedron 1982,
38, 1261–1268. doi:10.1016/0040-4020(82)85112-0
14.Russell, S. W.; Pabon, H. J. J. J. Chem. Soc., Perkin Trans. 1 1982,
545–552. doi:10.1039/P19820000545
41.Doris, E.; Dechoux, L.; Mioskowski, C. Tetrahedron Lett. 1994, 35,
7943–7946. doi:10.1016/0040-4039(94)80017-0
15.Johnson, F.; Paul, K. G.; Favara, D.; Ciabatti, R.; Guzzi, U.
J. Am. Chem. Soc. 1982, 104, 2190–2198. doi:10.1021/ja00372a015
16.Yadagiri, P.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett. 1988, 29,
5497–5500. doi:10.1016/S0040-4039(00)80796-0
42.Gilman, H.; Brown, G. E. J. Am. Chem. Soc. 1945, 67, 824–826.
doi:10.1021/ja01221a039
43.Murai, S.; Murai, T.; Kato, S. Reduction of epoxides. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
U.K., 1991; Vol. 8, pp 871–893.
17.Kubota, T.; Yamamoto, M. Tetrahedron Lett. 1992, 33, 2603–2606.
doi:10.1016/S0040-4039(00)92255-X
18.Okuma, K.; Tanaka, Y.; Ohta, H.; Matsuyama, H. Bull. Chem. Soc. Jpn.
1993, 66, 2623–2632. doi:10.1246/bcsj.66.2623
doi:10.1016/B978-0-08-052349-1.00249-3
44.Schlosser, M.; Christmann, K.-F. Synthesis 1969, 38–39.
45.Schlosser, M.; Christmann, K.-F.; Piskala, A. Chem. Ber. 1970, 103,
2814–2820. doi:10.1002/cber.19701030915
19.El Fangour, S.; Guy, A.; Vidal, J.-P.; Rossi, J.-C.; Durand, T.
J. Org. Chem. 2005, 70, 989–997. doi:10.1021/jo048179+
20.Yanagisawa, A.; Yasue, K.; Yamamoto, H.
46.Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 2877–2880.
J. Chem. Soc., Chem. Commun. 1994, 2103–2104.
doi:10.1039/C39940002103
doi:10.1016/S0040-4039(00)88048-X
21.Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem. Soc. 2004,
126, 8664–8665. doi:10.1021/ja047346k
1899

Beilstein J. Org. Chem. 2012, 8, 1896–1900.
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