Catalytic decarboxylative alkenylation of enolates

Article abstract of DOI:10.1021/ol401729m

A palladium-catalyzed decarboxylative alkenylation of stabilized enolates has been developed, which gives rise to alkenylated dicarbonyl products from enol carbonates regioselectively with concomitant installation of a quaternary all-carbon center. The broad scope of the reaction has been demonstrated by successfully utilizing a range of enolates and external phenol nucleophiles.

Full text of DOI:10.1021/ol401729m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalytic Decarboxylative Alkenylation
of Enolates
†
Sybrin P. Schroder, Nicholas J. Taylor, Paula Jackson, and Vilius Franckevicius*
†
†
,‡
€
ꢀ
Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K., and
Department of Chemistry, Lancaster University, Lancaster LA1 4YB, U.K.
v.franckevicius@lancaster.ac.uk
Received June 20, 2013
ABSTRACT
A palladium-catalyzed decarboxylative alkenylation of stabilized enolates has been developed, which gives rise to alkenylated dicarbonyl
products from enol carbonates regioselectively with concomitant installation of a quaternary all-carbon center. The broad scope of the reaction
has been demonstrated by successfully utilizing a range of enolates and external phenol nucleophiles.
Over the past decade, the transition-metal-catalyzed decar-
boxylative coupling of organic molecules has grown into a
versatile synthetic tool, offering atom-economical and waste-
minimized alternatives to conventional cross-coupling.1
One practical approach to generating sterically congested
sp3 centers is the palladium-catalyzed intramolecular dec-
arboxylative allylation of enolates (Scheme 1),2 which
proceeds via π-allylpalladium(II) enolate2 under very mild
and neutral conditions without the need for external base.3
This pioneering work has resulted in the development of a
number of elegant enantioselective approaches for the
decarboxylative allylation of enolates,4 generating an
all-carbon quaternary stereogenic center. In contrast, the
structurally similar propargylic counterparts 4 are known
to provide η3-π-allenylpalladium(II) intermediates 5 with
palladium catalysis.5 In particular, if the η3-π-allenyl-
palladium(II) unit is unsymmetrical, enolate addition at
either C-1 or C-3 in 5 can in principle take place, resulting
in the formation of either propargylated or allenylated
products 6 or 7, respectively.6
† University of York.
‡ Lancaster University.
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r
10.1021/ol401729m
XXXX American Chemical Society

We postulated that, by utilizing diketone-derived enol
carbonate 8a and, therefore, making the enolate following
decarboxylation softer (9), addition at the central C-2
position of the π-allenylpalladium(II) intermediate 9 by
the enolate could take place7,8 and furnish palladacyclo-
butene 10 in the first instance (pathway A). In the absence
of acidic hydrogen atoms, reaction with an external nu-
cleophile would then afford alkenylated diketone 11. The
proposed reaction was likely to pose selectivity challenges,
whereby the order of addition of the enolate and the
external nucleophile had been reversed, affording regioi-
somer 14 via palladacyclobutene 13 (pathway B). Herein,
we report the first regioselective palladium-catalyzed dec-
arboxylative alkenylation of stabilized enolates, which
enables the concomitant installation of a quaternary all-
carbon center in a single pot without the need for pre-
functionalized coupling partners and/or a strong base for
enolate generation.
Table 1. Optimization of Reaction Conditionsa
entry
ligand
solvent
ratio (15a:16a)b yieldc (%)
d
1
Pd(PPh3)4 THF
1:1.5
41
e
2
P(C6F5)3
dppe
THF
no reaction
3
THF
2.5:1
1.1:1
1.3:1
1.6:1
1.7:1
2.1:1
3.1:1
3.6:1
51
79
79
72
87
62
49
77
4
dppf
THF
5
DPEphos
Xantphos
Xantphos
Xantphos
Xantphos
THF
6
THF
7
CH2Cl2
CH3CN
DMF
8
9
10
Xantphos 1,4-dioxane
a Substrate concentration of all reactions was 0.16 M wrt 8a. b Ratio
determined by 1H NMR analysis of the crude product mixture. c Isolated
and combined yield of 15a and 16a following column chromatography.
d Used instead of Pd2(dba)3. e Reaction time was 16 h.
Scheme 1. Decarboxylative Coupling Processes
The scope of dicarbonyl-derived stabilized enolates in
regioselective alkenylation was studied next (Scheme 2).
It was found that six-membered diketones 15aÀd, bearing
alkyl groups in the R3 position, as well as ring substitution,
were all formed in generally good yields and selectivity.
It was then surprising to discover that the five-membered
indandione 15e was formed as a single isomer in excellent
yield despite comparableacidity (pKa ∼5) tosix-membered
diketone examples 15aÀd. Remarkably, complete control
of regioselectivity was also observed in the alkenylation of
the more basic exocyclic diketone 15f. This result is indeed
worthy of attention given its close similarity in pKa to
phenol (both ∼9À10 in water). Concerning exocyclic six-
membered diketones, cyclohexanone 15g was formed as a
single regioisomer, even in the presence of excess phenol.
Similarly excellent yields and selectivity were obtainedwith
cyclohexanones 15hÀj. Alongside the successful alkenyla-
tion of linear diketones 15kÀn, the reaction scope was also
extended to heterocyclic systems, including lactam and
lactone examples 15o and 15p, respectively, affording
products in good yields and selectivity.
From the outset ofthiswork, enol carbonate8awas used
as the test substrate in combination with phenol as the
external nucleophile (1.1 equiv) in our optimization studies
(Table 1). It was found that the reaction with Pd(PPh3)4 as
the catalyst in THF at 80 °C for 2 h did indeed result in
decarboxylation and formation of a new CÀC bond
(entry 1), although the ratio of isomers 15a and 16a was
in favor of the undesired isomer and the overall yield was
moderate (no propargylated or allenylated products re-
sulting from attack at either C-1 or C-3 were observed).
With the exception of electron-poor phosphine ligands for
palladium (entry 2), which halted the reaction altogether,
the use of other standard phosphines, such as dppe, dppf,
and DPEphos (entries 3À5), led to improved results
(see the Supporting Information for full details). Finally,
Xantphos as the ligand offered the best balance between
ratio and yield (entry 6), and following a solvent screen
(entries 7À10), 1,4-dioxane was settled upon as optimal,
providing easily separable 15a and 16a in 77% yield and
3.6:1 ratio in favor of the desired alkenylated diketone 15a.
The generality of this method with a variety of phenols
as the external nucleophile was probed next (Scheme 3).
In this context, 2,5-dimethyl-substituted phenol, sterically
demanding 2,6-diphenylphenol, as well as naphthol all
affordedthe desired products17aÀc with>19:1 selectivity
and high efficiency.9 Electron-rich methoxyphenols were
(9) X-ray data for 17a has been deposited with the Cambridge
Crystallographic Data Centre (CCDC 932185), which can be obtained
free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Enolate Scopea
Scheme 3. Phenol Scopea
1
a Ratio of 15:16 was determined by H NMR analysis of the crude
product mixture. b Major isomer 15 shown. c Isolated and combined
yield of 15 and 16 following column chromatography. d 1:1 dr.
also shown to afford the desired products 17d and 17e with
equally good results. We had found that, unlike phenol,
several other N- and O-based nucleophiles led to complex
product mixtures or decomposition under the reaction
conditions. We were thus intrigued to test whether other
unprotected nucleophilic functionalities, appended to the
phenol structure, would interfere with the desired mode of
reactivity. In this context, anilines, amides, amines, and
alcohols did not appear to impact the reaction, and the
expected products 17fÀk were formed both chemo- and
regioselectively without detriment to yield. Presumably,
the low pKa of phenol compared to the above functional
groups is essential in facilitating the protonation of the
palladacyclobutene intermediate of type 10. Indeed, a
second phenol hydroxy group in resorcinol was found to
be reactive, resulting in the formation of dimer 17l when
two equivalents of the starting carbonate 8g were used. We
were also pleased to discover that 4-halophenols afforded
products 17m and 17n as single isomers; however, use of
the significantly more acidic 4-nitrophenol substrate re-
sulted in product 17o being formed with diminished
selectivity.
a Ratio of 17:18 was determined by 1H NMR analysis of the crude
product mixture. b Isolated yield. c 1:1 dr. d 2 equiv of carbonate 8g was
used. e Single diastereoisomer. f Alkenylated isomer 17o shown. g Isolated
and combined yield of 17o and 18o.
deuterated diketone [D3]-19 afforded nondeuterated pro-
duct 15g. The lack of crossover indicates that the inter-
mediate enolate is likely to be tightly associated with the
palladium complex. This result was further corroborated
by mixing carbonate [D]-8g and the nondeuterated
isopropyl equivalent 8h (C): only [D]-15g and nondeuter-
ated 15h were formed. This observation is in stark contrast
to full enolate crossover detected in the decarboxylative
allylation of simple ketone enolates.4a Finally, substrates
[D]-8g and 8h in the presence of 4-nitrophenol as the
nucleophile (D), afforded the alkenylated methylketone
product [D]-17o and nondeuterated isopropyl-containing
product 17p. In contrast, crossover had taken place in the
formation of regioisomeric products 18o and 18p, which
was each isolated as mixtures of labeled and nonlabeled
material, suggesting dissociation of the enolate from the
palladium.
Mechanistically (Scheme 5), starting with carbonate 8g,
oxidative addition and decarboxylation provide η3-π-
allenylpalladium(II) enolate 21.10 In light of the absence
of enolate crossover in the formation of alkenylated
In order to gain deeper insight into the mechanism of
the reaction, deuterium-labeling studies were performed
(Scheme 4). Subjection of [D]-8g to the reaction conditions
resulted in deuterium incorporation at both the vinylic and
allylic positions in [D]-15g in nearly equal amounts (A),
lending support for the involvement of a symmetrical
π-allylpalladium(II) intermediate. In the next experiment
(B), reaction of equimolar amounts of carbonate 8g and
(10) (a) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa, H. J.
Am. Chem. Soc. 1998, 120, 1938–1939. (b) Baize, M. W.; Blosser, P. W.;
Plantevin, V.; Schimpff, D. G.; Gallucci, J. C.; Wojcicki, A. Organome-
tallics 1996, 15, 164–173.
Org. Lett., Vol. XX, No. XX, XXXX
C

and enol 27 and are no longer tightly associated. Finally,
isomer 18o is formed by protonation of 26 and subsequent
addition of the enolate to the π-allylpalladium(II) motif in 28.
Scheme 4. Deuterium Labeling Studies
Scheme 5. Mechanistic Rationale
In summary, a palladium-catalyzed decarboxylative
alkenylation of stabilized enolates is reported which gives
rise to alkenylated products from enol carbonates with
generally excellent regiocontrol and concomitant installa-
tion of a quaternary all-carbon center. A broad range of
enolates and external phenol nucleophiles can be readily
used in the reaction and appropriate deuterium labeling
studies have shed light on the mechanistic aspects of the
reaction. The development of enantioselective variants of
this process is underway.
products (pathway A), addition of the enolate to the
central carbon atom of the allenyl system in 21 is likely
to proceed intramolecularly via inner-sphere attack. This
observation issupportedby DFT studies inthe asymmetric
allylation of ketone enolates11 but contradicts the accepted
external outer-sphere mode of addition of soft stabilized
nucleophiles to η3-π-allylpalladium(II) intermediates.12
Following nucleophilic addition, transient palladacyclo-
butene complex 22 ensues,13 and rapid protonation by
4-nitrophenol (24) affords the symmetrical π-allylpalla-
dium(II) complex 25. Finally, addition of the phenolate
anion provides the alkenylated diketone 17o. Although the
examples we have studied favor pathway A, the reaction
with 4-nitrophenol (24) also affords regioisomer 18o
(pathway B). It is plausible that the initial nucleophilic
attack of η3-π-allenylpalladium(II) intermediate 21 by
phenol 24 furnishes palladacyclobutene 26 and enol 27.
However, in contrast to pathway A, significant crossover
at this stage takes place, suggesting that palladacycle 26
Acknowledgment. We gratefully acknowledge the Uni-
versity of York (N.J.T. and V.F.), the EU (Erasmus
Exchange Programme to S.P.S.), as well as the Nuffield
Foundation and the Royal Society of Chemistry
(Undergraduate Research Bursary to P.J.) for financial
support. We are very grateful to Prof. R. J. K. Taylor
(University of York) for the generous donation of chemi-
cals and consumables as well as useful discussions. We also
thank Dr. A. Whitwood (University of York) for X-ray
crystallographic analysis and Mr. K. Heaton (University
of York) for mass spectrometry analysis.
Supporting Information Available. Full experimental
procedures, characterization data, HRMS, as well as 1H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu,
S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A., III. J. Am. Chem. Soc.
2007, 129, 11876–11877.
(12) Trost, B. M.; Weber, L.; Strege, P. E.; Fullerton, T. J.; Dietsche,
T. J. J. Am. Chem. Soc. 1978, 100, 3416–3426.
(13) Nemoto, T.; Zhao, Z. D.; Yokosaka, T.; Suzuki, Y.; Wu, R.;
Hamada, Y. Angew. Chem., Int. Ed. 2013, 52, 2217–2220.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX