Modular approach to saturated and α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol202399c

2-Fluoro-6-pyridinyloxy derivatives of 2-ethoxyvinyl carbinols react with radicals derived from xanthates by an addition-fragmentation pathway to give highly functionalized ketones after acid hydrolysis. 1,4-Diketones are readily accessible by this approa

Full text of DOI:10.1021/ol202399c

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5676–5679
Modular Approach to Saturated and r,β-
Unsaturated Ketones
ꢀ
Laurent Debien, Beatrice Quiclet-Sire, and Samir Z. Zard*
ꢁ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128
Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received September 5, 2011
ABSTRACT
2-Fluoro-6-pyridinyloxy derivatives of 2-ethoxyvinyl carbinols react with radicals derived from xanthates by an additionÀfragmentation pathway
to give highly functionalized ketones after acid hydrolysis. 1,4-Diketones are readily accessible by this approach. R,β-Unsaturated ketones can be
obtained by starting with geminal acetoxy xanthates prepared by addition of a simpler xanthate to vinyl acetate.
Ketones play a central role in organic chemistry and are
key building blocks in modern synthesis. They are involved
in many fundamental transformations such as the aldol,1
the Wittig2 and the HornerÀWadsworthÀEmmons2 reac-
tions to cite a few and are the direct precursors of numer-
ous organic functionalities such as imines, amines, oximes
and alcohols.
Furthermore, 1,4-diketones and, more generally, 1,4-di-
carbonyls are substrates of paramount importance for the
synthesis of valuable five-membered carbo- and heterocycles
such as cyclopentenones,3 pyrroles,4 furans,5 or thiophenes.6
Indeed, cyclopentenones, furans, and pyrroles are found in
many biologically important natural products such as
prostaglandins,7 terpenes5 and porphyrins.8 Furans are also
versatile dienes and dienophiles for DielsÀAlder reactions.9
(1) For a review on the aldol and related addition reactions see:
Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem.
Rev. 2011, 111, 3076.
(5) (a) Dean, F. M. Naturally Occurring Oxygen Ring Compounds;
Butterworths: London, 1963; Chapter 1, p 1. (b) Keay, B. A.; Dibble, P. W.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds; Pergamon Press: Oxford, 1997; Vol. 2, pp 395À 436.
(c) Elliot, M. C. J. Chem. Soc., Perkin Trans. I 2002, 2301. (d) Harmange,
J. C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711.
(6) (a) Campaigne, E. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds; Pergamon Press: Oxford, 1984; Vol. 4,
pp 909À934. (b) Russell, R. K. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds; Pergamon Press:
Oxford, 1997; Vol. 2, pp 679À729.
(2) For reviews of the Wittig and the Horner-Wadsworth-Emmons
€
reactions, see: (a) Schobert, R.; Holzel, C.; Barnickel, B. In Science of
Synthesis; de Meijere, A., Ed.; Thieme: Stuttgart, 2010; Vol. 47a, pp 9À84.
(b) Vedejs, E. J. Org. Chem. 2004, 69, 5159. (c) Kelly, S. E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 1, pp 729À818.
(3) (a) Mussatto, M. C.; Savoia, D.; Trombini, C.; Umani-Ronchi, A.
J. Org. Chem. 1980, 45, 4002. (b) Takahashi, K.; Aihara, T.; Ogura, K.
Chem. Lett. 1987, 2359. (c) Pecuniso, A.; Menicagli, R. J. Org. Chem.
1988, 53, 2614. (d) Bergman, R.; Nilsson, B.; Wickberg, B. Tetrahedron
1990, 31, 2783.
(7) For a review on the synthesis of prostaglandins see: (a) Collins,
P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533. (b) Suzuki, M.; Kiho, T.;
Tomokiyo, K.; Furuta, K.; Fukushima, S.; Takeuchi, Y.; Nakanishi,
M.; Noyori, R. J. Med. Chem. 1998, 41, 3084.
(4) (a) Jones, A.; Bean, G. P. The Chemistry of Pyrroles; Academic
Press: London, 1977. (b) Jones, A. Pyrroles; Wiley: New York, 1990.
(c) Sobenina, L. N.; Mikhaleva, A. I.; Trofimov, B. A. Russ. Chem. Rev.
(Engl. Transl.) 1989, 58, 163. For some more recent examples, see:
(d) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org. Chem.
2005, 5277. (e) Minetto, G.; Raveglia, L. F.; Tadde, M. Org. Lett. 2004,
6, 389. (f) Veitch, G. E.; Bridgwood, K. L.; Rands-Trevor, K.; Ley, S. V.
Synlett 2008, 17, 2597.
(8) (a) The Porphyrins; Dolphin, D., Ed.; Academic Press: New York,
1978. (b) Battersby, A. R. Nat. Prod. Rep. 2000, 17, 507.
(9) (a) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org. Chem.
1984, 49, 3427. (b) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am.
Chem. Soc. 1988, 110, 7188.
r
10.1021/ol202399c
Published on Web 09/28/2011
2011 American Chemical Society

Scheme 1. Synthetic Approach to Functionalized Ketones, Enones
and 1,4-Dicarbonyls
Scheme 2. Preliminary Example
of R-keto-xanthates 2C would give rise to 1,4-dicarbo-
nyls, via intermediates 3C, while prior addition of the
xanthate to vinyl acetate12,13 would ultimately furnish
RÀβ-unsaturated ketones after hydrolysis of 3B and
base-induced elimination of the β-acetate moiety. The
implementation of this synthetic strategy is detailed
hereafter.
In a preliminary experiment, enol ether 1a, prepared by
addition ofthe vinyl anion derivedfrom ethyl vinyl ether to
isovaleraldehyde followed by treatment of the resulting
allylic alcohol with 2,6-difluoropyridine in the presence of
NaH, was reacted with xanthate 2a under the reaction
conditions previously reported.5 To our surprise and dis-
appointment, the reaction gave a complex mixture of
compounds with only small amounts of the desired ketone
being isolated. One possible problem is a sluggish scission
of the CÀO bond due to a too great stabilization of the
intermediate radical by the ethoxy group. This would leave
the intermediate radical with enough lifetime to participate
in untoward bimolecular processes. Another complication
could be due to the premature hydrolysis of the starting
and product enol ethers induced by the lauric acid pro-
duced during the reaction. After some experimentation, we
found that simple moderate dilution of the reaction med-
ium circumvented the difficulty, and the expected 1,4-
diketone 4a could be isolated in 64% yield following acid
hydrolysis (Scheme 2).
Having successfully accomplished the desired radical
addition, we explored the scope of the reaction. The results
are collected in Tables 1 and 2. The three examples in the
first Table demonstrate the possibility of isolating the
relatively fragile initial enol ethers as mixtures of geome-
trical isomers and underscore the mildness of the experi-
mental conditions.
If desired, the enol ethers may be further modified
regioselectively, for example by bromination or epoxida-
tion, or simply hydrolyzed. In the examples in Table 2, the
enol ethers were not isolated but converted directly into the
corresponding ketones 4 by treatment with aqueous HCl at
room temperature. Thus, masked and free ketones can be
rapidly assembled in moderate to good yield. In any case,
the process tolerates many useful functional groups and
diversity may be introduced both by modifying the
xanthate and the starting aldehyde or ketone. Structures
Finally, five-membered heterocycles are useful building
blocks for the synthesis of materials with interesting physical
and electronic properties.10
We report herein a unique, modular, and convergent
method for preparing functionalized ketones, including
1,4-dicarbonyls and enones, from other readily available
ketones and aldehydes. Recently, we discovered that when
a 6-fluoro-pyridin-2-ol moietyis located vicinal toa radical
center, it readily undergoes β-elimination, essentially con-
verting an alcohol into a leaving group in a radical sense.11
Homolysis of the usually strong carbonÀoxygen bond is
rare and has thus been poorly exploited in organic synth-
esis. The ability of the alkoxyfluoropyridines to undergo
homolytic cleavage of the carbonÀoxygen bond under
mild conditions offers tremendous synthetic possibilities.
Indeed, we demonstrated in a preliminary study the syn-
thetic utility of such an olefination process, which in some
cases corresponds to an overall synthetic equivalent of the
Wittig reaction.5
Our approach relies on the use of xanthates 2 and
enol ethers such as 1 as partners in the additionÀfrag-
mentation reaction, as outlined in Scheme 1. Tri- and
tetra-substituted enol ethers 3A would thus be obtained
and would furnish the corresponding functionalized
homologous ketones upon acidic hydrolysis. The use
(10) (a) Kumar, A.; Bokria, J. G.; Buyukmumcu, Z.; Dey, T.;
Sotzing, G. A. Macromolecules 2008, 41, 7098. (b) Baumgartner, T.;
ꢀ
Reau, R. Chem. Rev. 2006, 106, 4681. (c) Osaka, I.; McCullough, R. D.
Acc. Chem. Res. 2008, 41, 1202.
(11) (a) Charrier, N.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc.
2008, 130, 8898. (b) Braun, M.-G.; Quiclet-Sire, B.; Zard, S. Z. J. Am.
Chem. Soc. 201110.1021/ja207944c.
(12) For reviews on xanthate radical addition-transfer reaction, see:
(a) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672. (b) Quiclet-Sire, B.;
Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002. (c) Quiclet-Sire, B.; Zard, S. Z.
Top. Curr. Chem. 2006, 264, 201. (d) Zard, S. Z. Aust. J. Chem. 2006, 59,
663. (e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205. (f) Quiclet-Sire, B.;
Zard, S. Z. Pure Appl. Chem. 2011, 83, 519.
(13) Binot, G.; Quiclet-Sire, B.; Saleh, T.; Zard, S. Z. Synlett 2003, 3, 382.
Org. Lett., Vol. 13, No. 20, 2011
5677

Table 1. Formation of Enol Ethers
Scheme 3. Access to Complex 1,4-Diketones
Table 2. Formation of Ketones and 1,4-Dicarbonyls
containing 1,4-dicarbonyl groups are particularly easy to
obtain (Table 2), but numerous other combinations may
also be envisaged.
The potential of this approach for the construction or
modification of complex structures is further highlighted
by the transformations involving steroid derived xanthates
2j14 and 2k. The side chain in these substrates are readily
extended through the additionÀfragmentation/hydrolysis
procedure to give 1,4-diketones 4k and 4l. Construction of
various steroid side-chains remains an important under-
taking, especially in the context of vitamin D-related
studies (Scheme 3).15
As previously stated, 1,4-diketones are key intermedi-
ates for the synthesis of five-membered carbo- and
heterocycles.3À6 Following literature procedures, pyr-
roles 5a,b,16,17 furan 618 and cyclopentenone 7,11 not
readily accessible by other routes, were swiftly prepared
in good yield as pictured in Scheme 4.
Another important feature of this approach derives
from the possibility of a prior addition of the xanthate
to vinyl acetate,13 followed by the additionÀfragmenta-
tion to the activated enol ether radical trap 1, as pictured
in Scheme 5. Upon hydrolysis, a β-acetoxy ketone is
produced, which undergoes base-induced β-elimination
on exposure to DBU to give an unsaturated ketone.
This variant is illustrated by the synthesis of enones
8aÀc.
(14) (a) Leanza, W. J.; Conbere, J. P.; Rogers, E. F.; Pfister, K. J. Am.
Chem. Soc. 1954, 76, 1691. (b) Bergstrom, C. G.; Sollman, P. B.;
Nicfiolson, R. T.; Dodson, R. M. J. Am. Chem. Soc. 1960, 82, 2323.
(15) Review: (a) Piatak, D. M.; Wicha, J. Chem. Rev. 1978, 78, 199.
For some recent references, see:(b) Michalak, K.; Wicha, J. J. Org.
Chem. 2011, 76, 6906. (c) Xu, W. -M.; He, J.; Yu, M. -Q.; Shen, G. -X.
Org. Lett. 2010, 12, 4431. (d) Maehr, H.; Lee, H. J.; Perry, B.; Suh, N.;
Uskokovic, M. R. J. Med. Chem. 2009, 52, 5505.
(16) Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301.
(17) Brummond, K. M.; Curran, D. P.; Mitasev, B.; Fische, S. J. Org.
Chem. 2005, 70, 1745.
(18) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69, 908.
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Org. Lett., Vol. 13, No. 20, 2011

Scheme 4. Transformation of Various 1,4-Diketones into Five
Membered Ring Carbo- and Hetero-cycles
Scheme 5. Synthesis of Enones
Acknowledgment. Wededicate this paper withrespect and
affection to the memory of Prof. Costas H. Issidorides
(American University of Beirut), a wonderful teacher of
organic chemistry. L.D. thanks the ANR for a scholarship.
In summary, we have developed a simple, flexible and
modular approach to ketones, 1,4-diketones and R, β-
unsaturated ketones. These are indeed the cornerstones
of organic synthesis. The mildness of the experimental
conditions and broad tolerance for most of the common
functional groups open up numerous synthetic opportu-
nities not otherwise available through more traditional
routes. It is worth emphasizing the fact that the intermedi-
ate enol ethers 3 may be isolated and eventually used for
further regioselective functionalization.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 20, 2011
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