Free-radical variant for the synthesis of functionalized 1,5-diketones

Article abstract of DOI:10.1021/ol402213k

A free-radical approach for the synthesis of functionalized 1,5-diketones has been accomplished through an effective combination play between alkenylacylphosphonates and keto-xanthates as radical surrogates of enolates and enones, respectively.

Full text of DOI:10.1021/ol402213k

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Free-Radical Variant for the Synthesis
of Functionalized 1,5-Diketones
Kelvin Kau Kiat Goh,†,‡ Sunggak Kim,*,† and Samir Z. Zard*,‡
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore, and
ꢀ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique,
91128 Palaiseau Cedex, France
sgkim@ntu.edu.sg; zard@poly.polytechnique.fr
Received August 5, 2013
ABSTRACT
A free-radical approach for the synthesis of functionalized 1,5-diketones has been accomplished through an effective combination play between
alkenylacylphosphonates and keto-xanthates as radical surrogates of enolates and enones, respectively.
1,5-Dicarbonyl compounds are invaluable building
blocks in the synthesis of fused-ring systems that are
commonly found in alkaloids, steroids, and terpenes.1 In
particular, 1,5-diketones are known to provide an easy
access to functionalized pyridines.2
Classical methods to synthesize 1,5-dicarbonyl com-
pounds generally invoke the use of enolates and methyl
vinyl ketones via conjugate addition as in the Robinson
annulation.3 Even so, limitations have plagued this ap-
proach owing to the nature of the requisite precursors, in
particular, the easily polymerized methyl vinyl ketone, and
the difficulty in controlling the reactivity of the anionic
enolate.1a
by the use of silyl enol ethers in Lewis acid catalyzed
Mukaiyama aldol reactions or enamine-mediated react-
ions4 and Mannich-type bases or R-silylated ketones.5
Nonetheless, since the synthesis remains revolved
around these two starting materials as 1,5-dicarbonyl pre-
cursors and their corresponding modifications,4,5 acidic or
basic reaction conditions are unavoidable. Thus, general
conditions to handle acid- or base-ensitive functionalities
remain elusive. In fact, most of the 1,5-diketones described
previously4,5 contain mainly alkyl or aryl substituents.
In contrast, radical-based approaches to the synthesis of
such 1,5-dicarbonyl compounds have not been as exten-
sively explored as their ionic counterparts. Radical reac-
tions are able to proceed in the absence of strong basic or
acidic conditions and should therefore be better suited for
To address these issues, modifications centered on these
starting precursors have been devised, as exemplified
† Nanyang Technological University.
‡ Ecole Polytechnique.
(4) Selected examples of modification of the enolate: (a) Stork, G.;
Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am.
Chem. Soc. 1963, 85, 207. (b) Narasaka, K.; Soai, K.; Aikawa, Y.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1976, 49, 779. (c) Takahashi, A.;
Yanai, H.; Taguchi, K. Chem. Commun. 2008, 2385.
(5) Selected examples of modifications of the enone: (a) Stork, G.;
Ganem, B. J. Am. Chem. Soc. 1973, 95, 6152. (b) Brewster, J. H. and
Eliel, E. L. In Organic Reactions; Adams, R., Eds; John Wiley and Sons:
New York, 1953; Vol. 7, pp 99À197.
(1) For reviews on annulation from 1,5-diketones, see: (a) Jung,
M. E. Tetrahedron 1976, 32, 3. (b) Gawley, R. E. Synthesis 1976, 777.
(2) (a) Pchelintseva, N. V.; Chalaya, S. N.; Kharchenko, V. G. Zh.
Org. Khim. 1990, 26, 1904. Chem. Abstr. 1991, 115, 71334. (b) Owton,
W. M.; Gallagher, P. T.; Brunavs, M. Synth. Commun. 1992, 22, 351.
(3) (a) Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285. (b)
Duhamel, P.; Hennequin, L.; Poirier, J. M.; Tavel, G.; Vottero, C.
Tetrahedron 1986, 42, 4777.
r
10.1021/ol402213k
XXXX American Chemical Society

acid- or base-sensitive functionalities. To date, only a
handful of radical-mediated 1,5-diketone syntheses have
been reported.6,7 Some of these earlier studies6 involved
ketonyl radical addition to specific surrogates of enones
and are often accompanied by oxidation and reduction or
protection and deprotection steps, which can be tedious
and troublesome. Hence, it is still of synthetic significance
to develop a facile and direct means to access highly
functionalized 1,5-diketones from simple precursors.
We have previously reported tin-mediated intramolecu-
lar radical acylation using alkenylacylphosphonate as a
carbonyl group acceptor with various radicals to afford
functionalized cyclic ketones.8 Building on these studies,
we reasoned that using ketonyl radicals to accomplish first
an intermolecular addition to an alkenylacylphosphonate,
followed by intramolecular cyclization with β-elimination
of a phosphonate radical from the intermediate alkoxy
radical should lead to the target 1,5-diketones.
allowing the synthesis of 5- or 6-membered carbocyclic
1,5-diketones from primary keto-xanthates bearing alkyl
(6a, 7a), chloro (6b, 7b), and aryl (6c, 7c) substituents in
good yields (72À80%). Secondary xanthates bearing alkyl
substituents (6d, 7d) reacted reasonably well to give mod-
erate yields of 63 and 61%, respectively (Figure 1).
Scheme 1. Tin-Mediated Reaction of R-Bromo Acetophenone
with an ω-Alkenyl Acylphosphonate
Figure 1. Synthesis of 5- and 6-carbocyclic 1,5-diketones. Con-
ditions: (a) To 1 and 2 or 3 (1.5 equiv) in anhydrous 1,2-
dichloroethane (DCE, 0.5 M in the xanthate) heated to reflux
under argon was added 0.2 equiv of dilauroyl peroxide (DLP)
every hour until 1 was mostly consumed as indicated by TLC;
isolated yields were based on 1. (b) DLP was added at a rate of
0.3 equiv every hour; diastereomers (1:1) were not separated.
Unfortunately, preliminary investigations toward this
end proved disappointing. Despite our earlier success with
various radical precursors, the ketonyl type radicals could
not be made to react efficiently by application of classical
methods.8 For example, the use of hexamethylditin with
R-halo ketones resulted in mostly reduction to the ketone
and only a trace amount of the desired product was
observed (Scheme 1).
Nevertheless, we decided to seek alternate systems to
add a ketonyl radical onto alkenylacylphosphonates. Since
keto-xanthates derived from the same R-halo ketones have
been shown to act as efficient ketonyl radical precursors
for the intermolecular addition to olefins,9 we therefore
decided to investigate their reactivity with ω-alkenylacyl-
phosphonates in the hope that we might overcome the
problems encountered with R-halo ketones.10
It should be noted that keto-xanthates 1aÀh are readily
synthesized11a from commercially available materials as
opposed to the corresponding enones used in the ionic
synthetic pathway to 1,5-diketones (Scheme 2).
Scheme 2. Comparison of Keto-xanthate 1b as a Radical
Surrogate for Its Corresponding Enone Equivalent
Gratifyingly, the keto-xanthates proved to be effective
reaction partners with the ω-alkenylacylphosphonates.
The phosphonate radical was found to effectively mediate
the xanthate transfer in this radical cascade reaction,
(6) (a) Briggs, M. E.; Qacemi, M. E.; Kalai, C.; Zard, S. Z. Tetra-
hedron Lett. 2004, 45, 6017. (b) Boivin, J.; Carpentier, F.; Jrad, R.
Synthesis 2006, 1664.
(7) For a radical-mediated 1,5-diketone synthesis, see: Debien, L.;
Zard, S. Z. J. Am. Chem. Soc. 2013, 135, 3808.
(8) (a) Kim, S.; Cho, C. H.; Lim, C. J. J. Am. Chem. Soc. 2003, 125,
9574. (b) Cho, C. H.; Kim, S. Can. J. Chem. 2005, 83, 917.
(9) (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 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) Quiclet-Sire, B.; Zard,
S. Z. Pure Appl. Chem. 2011, 83, 519.
Moreover, the presence of particularly acidic hydrogens
R to the ketone in some of these structures or a reactive
R-chlorine, as in 6b or 7b, would also pose problems in an
acidic or basic medium, leading to uncontrolled mixtures
(11) Keto-xanthates 1b, 1e, and 1f can be readily synthesized in one
step from 1,3-dichloroacetone, ethyl 4-chloroacetoacetate, and ethyl
2-chloroacetoacetate: (a) Greef, M. D.; Zard, S. Z. Org. Lett. 2007, 9,
1773. (b) Tate, E. Z.; Zard, S. Z. Tetrahedron Lett. 2002, 43, 4683.
(10) Our attempts to explore an alternative method under tin-free
conditions using R-halo ketones were unsuccessful.
B
Org. Lett., Vol. XX, No. XX, XXXX

of side products arising from further cyclization or other
transformations.
proving the ability to construct nitrogen-containing
heterocycles as well. Tetrahydroquinoline 1,5-diketones
9aÀe,g,h were thus obtained in good yields (Figure 3,
61À83%) with the exception of 9f. The excessive stability
of the intermediate carbon radical, as discussed above, had
a deleterious effect on the yield (9f, 40%). The ready
formation of compounds 9g and 9h further demonstrates
the broad functional group tolerance of this radical
process.
With these results in hand, we extended the sequence to
heteroatom substituted ω-alkenylacylphosphonates to test
the applicability of this method to form heterocyclic 1,5-
diketones. O-Allyl acylphosphonate 4 reacted with various
functionalizedketo-xanthates1aÀf togivethe correspond-
ing benzopyran 1,5-diketones or 3-substituted chroman-
4-ones in moderate to good yields (49À75%, Figure 2).
Chroman-4-ones are known to self-polymerize under basic
conditions during alkylation reactions,12a the present ra-
dical approach therefore offers a comparatively milder
synthetic alternative. Yields of benzopyran 1,5-diketones
8aÀd were slightly lower but comparable to those of the
carbocyclic 1,5-diketones 6 and 7. Keto-xanthates 1e and
1f showed that the ethyl ester functionality is well-tolerated
as well. For secondary keto-xanthate 1f, the intermediate
carbon radical is strongly stabilized by two carbonyl
groups and its addition to the olefin becomes therefore
less effective, leading to lower yield (49%). It is worth empha-
sizing again that vinyl ketones containing an R-chlorine or
R- ester group corresponding to keto-xanthates 1b, 1e, and
Figure 3. Synthesis of tetrahydroquinoline 1,5-diketones. Con-
ditions: (a) To 1 and 5 (1.5 equiv) in anhydrous 1,2-dichloro-
ethane (DCE) (0.5 M in the xanthate) heated to reflux under
argon was added 0.2 equiv of DLP every hour until 1 was mostly
consumed as indicated by TLC; isolated yields were based on 1.
(b) DLP was added at 0.3 equiv every hour; diastereomers (1:1)
were not separated.
As mentioned previously, 1,5-diketones pave an easy
route to functionalized pyridines. Selected examples of
pyridine synthesis are shown in Figure 4. Treatment of
the functionalized 1,5-diketones with excess ammonium
acetate in refluxing acetic acid led to either functionalized
carbocyclic (10 and 11) or heterocyclic (12À15) fused-ring
pyridines, including a tetrasubstituted pyridine 14 in good
yields (76À85%, Figure 4). Pyridine 15 can be further
transformed by the HornerÀWadsworthÀEmmons reac-
tion to give vinylpyridine derivatives.15 Fused-ring pyri-
dines such as 10À15 are an important class of aromatic
nitrogen heterocycles; they exhibit high bioactivity and
are valuable for medicinal purposes.16,18 The present
method offers yet another alternative to access novel
Figure 2. Synthesis of benzopyran 1,5-diketones. Conditions:
(a) To 1 and 4 (1.5 equiv) in anhydrous 1,2-dichloroethane
(DCE, 0.5 M in the xanthate) under argon was added 0.2 equiv
of dilauroyl peroxide (DLP) every hour until 1 was mostly
consumed as indicated by TLC; isolated yields were based on
1. (b) DLP was added at 0.3 equiv every hour; diastereomers
(1:1) were not separated.
1f would pose severe difficulties in both preparation13,14
and utilization as enone counterparts in ionic conjugate
addition.
As expected, the N-hetero alkenylacylphosphonates 5
reacted cleanly with functionalized keto-xanthates 1aÀh,
(12) (a) Padfield, E. M.; Tomlinson, M. L. J. Chem. Soc. 1950, 2272.
A five-step synthesis to a similar benzopyran 1,5-diketone has been
reported: (b) Venkateswararao, E.; Sharma, V. K.; Lee, K-C.; Roh, E.;
Kim, Y.; Jung, S-H. Bioorg. Med. Chem. 2013, 21, 2544.
(13) Preparation of the vinyl ketone equivalent of keto-xanthate 1e
proceeds in only 43% yield over two steps: Ghosh, S.; Rivas, F.; Fischer,
D.; Gonzalez, M. A.; Theodorakis, E. A. Org. Lett. 2004, 6, 941.
(14) The preparation of the vinyl ketone equivalent of keto-xanthate
1f proceeds in a low yield of 22%: Cocker, W.; McMurry, T. B. H.
J. Chem. Soc. 1955, 4430.
(15) (a) Chackalamannil, S.; Wang, Y.; Greenlee, W. J.; Hu, Z.; Xia,
Y.; Ahn, H.-S.; Boykow, G.; Hsieh, Y.; Palamanda, J.; Agans-Fantuzzi,
J.; Kurowski, S.; Graziano, M.; Chinatala, M. J. Med. Chem. 2008, 51,
3061. (b) Bradshaw, B.; Luque-Corredera, C.; Bonjoch, J. Org. Lett.
2013, 15, 326.
(16) Rizk, T.; Bilodeau, E. J.-F.; Beauchemin, A. M. Angew. Chem.,
Int. Ed. 2009, 48, 8325.
(17) Stolle, W. A.W.; Frissen, A. E.; Marcelis, A. T. M.; Van der Plas,
H. C. J. Org. Chem. 1992, 57, 3000.
Org. Lett., Vol. XX, No. XX, XXXX
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variations of structurally similar multisubstituted fused-
ring pyridines16À18 and thus improves the diversity needed
for structureÀactivity relationship (SAR) studies.
Scheme 3. Proposed Radical Cycle for Phosphonate
Radical-Mediated Xanthate Transfer
In conclusion, we have demonstrated an effective
combination play of alkenylacylphosphonates and
keto-xanthates, leading to a direct and facile access to
functionalized 1,5-diketones without the need for further
transformation. This is an example showing the use of
keto-xanthates as successful alternatives in place of R- halo
ketones, where the radical halogen atom transfer process is
mostly ineffective. R-Iodo ketones are generally unstable
and the fast iodine transfer cannot be exploited in this
instance. The strategic use of alkenylacylphosphonate
grants flexibility to construct carbocycles or heterocycles
in the 1,5-diketones via the radical cascade reaction while
the keto-xanthate partner allows easy incorporation of a
great variety of functionalities. Moreover, some of the
keto-xanthates can be prepared from commercially avail-
able substrates easier and faster than the usual ionic
precursors required for the synthesis of 1,5-diketones. In
addition, these 1,5-diketones can be further elaborated
into novel fused-ring pyridines.
Figure 4. Synthesis of functionalized fused-ring pyridines.
In the proposed mechanistic pathway (Scheme 3), keto-
xanthate 1 is converted into ketonyl radical A through
initiation by dilauroyl peroxide (DLP) and undergoes
radical addition to the alkenylacylphosphonate 2, fol-
lowed by a xanthate transfer to give the xanthate adduct
2a. This xanthate 2a is further reversibly converted into
radical intermediate 2b by more DLP and subsequently
undergoes a 5-exo-trig cyclization to give alkoxy radical
2c. β-Fragmentation of 2c then leads to the 1,5-diketone 6
with the extrusion of phosphonate radical B, which could
then participate in another xanthate exchange with keto-
xanthate 1 and reintroduce the ketonyl radical A, thus
propagating the radical chain process. The key to success
lies in the degenerate nature of the xanthate exchange,
which provides the intermediate radicals with an extended
lifetime, even in a concentrated medium. With R-halo
ketones, it is possible that formation of a tin or boron
enolate in the case of (Me3Sn)2 or Et3B-initiation causes
premature reduction of ketonyl radical A.19 Currently, this
is only observed for the ketonyl radicals, while other type
of radicals8 have been reported to work efficiently with
alkenylacylphosphonates.
Acknowledgment. This paper is dedicated to Professor
Teruaki Mukaiyama in celebration of the 40th anniversary
of the Mukaiyama aldol reaction. We also gratefully
acknowledge the startup grants from Nanyang Technolo-
gical University.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Cailly, T.; Begtrup, M. Tetrahedron 2010, 66, 1299.
(19) Charrier, N.; Gravestock, D.; Zard, S. Z. Angew. Chem., Int. Ed.
2006, 45, 6520.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX