Allylic alcohols as radical allylating agents. An overall olefination of aldehydes and ketones

Article abstract of DOI:10.1021/ja802899m

2-Fluoropyridyl derivatives of allylic alcohols react with xanthates in the presence of lauroyl peroxide to give alkenes, often with high stereoselectivity. If the allylic alcohols are themselves derived from aldehydes or ketones, the overall process becomes a synthetic equivalent of the classical Wittig and related olefination reactions. Copyright

Full text of DOI:10.1021/ja802899m

Published on Web 06/18/2008
Allylic Alcohols as Radical Allylating Agents. An Overall Olefination of
Aldehydes and Ketones
Nicolas Charrier, Be´atrice Quiclet-Sire, and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, Ecole Polytechnique, 91128 Palaiseau, France
Received April 27, 2008; E-mail: zard@poly.polytechnique.fr
Scheme 1. Radical-Based Approach for the Olefination of Ketones
Not least of the advantages of radical reactions is the little
tendency of many oxygen and nitrogen functions (alcohols, esters,
amides, etc.) to undergo ꢀ-elimination when located vicinal to the
radical center.1 Radical 1, for example, does not normally undergo
elimination to give alkene 2 and a carbonyloxyl radical (Scheme
1).2,3 Nonetheless, the possibility of converting an alcohol into a
leaving group, in the radical sense, opens up many synthetic
opportunities. As pictured in Scheme 1, this would correspond to
an overall equivalent of the Wittig reaction: alkene 7, formally
derived from ketone or aldehyde 3 by reaction with hypothetical
phosphonium ylid 9, would be obtained via intermediates 4 and 5
by a radical addition-fragmentation on the latter.
Scheme 2. Preliminary Experiments
The key issue is finding an appropriate Y appendage that
encourages rupture of the strong carbon-oxygen bond at a rate
that is competitive with alternative pathways open to radical 6. After
some experimentation, we identified the 6-halopyridine motif as a
suitable group; it is easy to introduce, and its elimination leads to
a stabilized 2-pyridoxyl radical 8 (Y ) 6-halopyridyl).4 Further-
more, the electron-withdrawing pyridine nucleus speeds up the
fragmentation by a favorable interplay of polar effects.1
In a preliminary experiment (Scheme 2), we found that butenyl
derivative 10 underwent lauroyl peroxide mediated addition of xanthate
11 in refluxing 1,2-dichloroethane (DCE) to give adduct 13 in 78%
yield but only traces of the desired olefin 14. However, when adduct
13 was heated in chlorobenzene with di-tert-butyl peroxide, a smooth
reaction took place to give olefin 14 in 63% yield as a 3:1 E:Z mixture.
The possibility of returning from the adduct back to the intermediate
radical (i.e., from 13 to 12) is a key property of xanthate transfers: it
provides the intermediate radical with enough accumulated lifetime
to undergo what remains a relatively slow elimination.5 The peroxide
is required in stoichiometric amounts, as the expelled pyridyloxyl 15
does not propagate the chain but is converted mainly into 2-chloro-
6-hydroxypyridine 16, which could indeed be isolated.6 Similarly,
fluoropyridine analogue 17 reacted with xanthate 18 to give olefin 20
via intermediate 19.
observed with derivatives of tertiary alcohols. Only the E isomer
was formed in most instances, due in part to the milder reaction
conditions. It is also worth underscoring the ease of formation of
tetrasubstituted olefins as illustrated by the reaction of vinyl carbinol
41 with xanthates 39 and 43 to give the corresponding alkenes 42
and 44.
Because of their better accessibility, the fluoropyridine derivatives
were selected for the remainder of the study. The starting allylic
alcohol derivatives are readily obtained by reacting the allylic
alcohol with 2,6-difluoropyridine in DMSO using sodium hydride
as base.7 The examples in Table 1 give an idea of the scope (FPy
) 6-fluoropyridin-2-yl). We found that it was not necessary to
isolate the xanthate adduct (e.g., 13 or 19) nor was high temperature
needed to promote the elimination step: treatment of the xanthate
and the derivatized allylic alcohol with stoichiometric amounts of
lauroyl peroxide in refluxing ethyl acetate was sufficient to bring
about the desired transformation.
Combining the xanthate addition to an ordinary olefin with the
allylation results in an expedient and modular approach to complex
frameworks (Scheme 3). Thus, addition of 27 and 22 to vinyl
pivalate and 3-methyl-3-butenyl acetate provides xanthates 45 and
47, and these in turn react with dimethylallyl derivative 24 to give
imide 46 and Weinreb amide 48, respectively. In the case of
xanthate 51, a ring closure was expected to precede allylation
leading to 54. In the event, the reaction with prenylating reagent
24 led mostly to the open chain derivative 52. The ring-closed
structure 54 could, however, be obtained by initial treatment of 51
with peroxide in the absence of olefin 24 to induce cyclization into
53, followed by the allyation. The freedom to access at will open
or cyclized structures such as 52 or 54 is noteworthy.
The reaction is successful with a broad range of allylic alcohol
derivatives, and a variety of useful functions could be readily
introduced.8 In contrast to secondary allylic alcohol derivatives such
as 10, 17, or 21, where the xanthate adduct could be isolated, the
final addition-elimination product was the only major compound
One final surprising observation deserves mention. We noticed
that fluoropyridine derivatives of tertiary allylic alcohols gradually
rearranged on heating; for example, 24 was quantitatively converted
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8898 J. AM. CHEM. SOC. 2008, 130, 8898–8899
10.1021/ja802899m CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Substituted Olefins by Radical Allylation
fortunate that it is slow enough to allow the desired radical process
to proceed unhindered.
In summary, we have identified a convenient way to convert
the hydroxy group of alcohols into a radical leaving group. As stated
in the opening paragraph, the overall result is a formal olefination
sequence. For instance, reagents 21, 26, 31, and 36 derive initially
from citronellal, menthone, camphor, and dihydro-ꢀ-ionone, re-
spectively, yet it would have been difficult to access the corre-
sponding olefinic products displayed in Table 1 by a direct classical
Wittig reaction. In view of the critical importance of olefins in
organic synthesis, the present strategy, which benefits from the
considerable advantages associated with radical processes, nicely
complements existing routes.
Acknowledgment. We thank Ecole Polytechnique for a fel-
lowship to N.C. This paper is dedicated with respect to the memory
of Dr. Ron Magolda.
Supporting Information Available: Experimental procedures as
well as a compilation of spectral and analytical data of all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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Scheme 3. Modular Construction of Substituted Olefins
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(6) The possibility, raised by one of the reviewers, that the fragmentation could
be heterolytic (see ref 2) leading to a radical cation and the anion of pyridone
16 appears unlikely for various reasons. The anion of pyridone 16 is not a
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(see Bordwell, F. G.; Singer, D. L.; Satish, A. V. J. Am. Chem. Soc. 1993,
115, 3543. ), and there are no groups in structure 12 to stabilize a radical
cation. Furthermore, it is difficult to see how a radical cation could evolve
cleanly into olefin 14 under our conditions. Note that the oxygen of the
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should such an electrophilic species form.
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into 3-prenyl hydroxypyridine 55 upon heating in refluxing ethyl
acetate for 8 h. The rarely studied sigmatropic rearrangement of
2-allyloxypyridines normally requires much higher temperatures
and results in migration of the allyl group on both the adjacent
carbon and nitrogen.9 This regioselective rearrangement under such
mild conditions could have synthetic utility; it is nevertheless
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