Construction of trifluoromethyl-bearing quaternary carbon centers by intramolecular decarboxylative allylation of α-trifluoromethyl β-keto esters

Article abstract of DOI:10.1002/adsc.201100359

A new palladium-catalyzed decarboxylative allylation of allyl α-trifluoromethyl-β-keto esters was developed in the presence of tris(dibenzylideneacetone)dipalladium [Pd₂(dba)₃] and 1,2-bis(diphenylphosphino)ethane (dppe) in tetrahydr

Full text of DOI:10.1002/adsc.201100359

FULL PAPERS
DOI: 10.1002/adsc.201100359
Construction of Trifluoromethyl-Bearing Quaternary Carbon
Centers by Intramolecular Decarboxylative Allylation of
a-Trifluoromethyl b-Keto Esters
Norio Shibata,a,* Satoru Suzuki,a Tatsuya Furukawa,a Hiroyuki Kawai,a
Etsuko Tokunaga,a Zhe Yuan,b and Dominique Cahardb,*
a
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology. Gokiso, Showa-ku,
Nagoya 466-8555, Japan
Fax : (+81)-52-735-7543; phone: (+81)-52-735-7543; e-mail: nozshiba@nitech.ac.jp
UMR 6014 COBRA, Universitꢀ et INSA de Rouen, 76130 Mont Saint Aignan, France
b
Fax : (+33)-02-3552-2466; phone: (+33)-02-3552-2466; e-mail: dominique.cahard@univ-rouen.fr
Received: May 7, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100359.
Abstract: A new palladium-catalyzed decarboxyla- dreaded a,b-unsaturated-b,b-difluoro ketones result-
tive allylation of allyl a-trifluoromethyl-b-keto esters ing from b-elimination of a fluoride ion was not ob-
was developed in the presence of tris(dibenzyli- served.
A
2ACHTNUGTREN(UNGN dba)3] and 1,2-bis(di-
ACHTUNGTRENNUNG
a-Trifluoromethyl ketones featuring a quaternary Keywords: allylation; decarboxylation; intramolecu-
carbon center were produced in good yields and the lar reactions; palladium; trifluoromethyl group
Introduction
ductive effects and negative hyperconjugation but
strongly destabilized due to a defluorination reaction,
The field of organofluorine chemistry has blossomed in particular under basic conditions. In addition, the
dramatically over the past decade to become an ex- carbanion possesses a low nucleophilicity due to the
tremely rich area of research.[1] The increasing electron-withdrawing effect of the trifluoromethyl
number of approved fluorinated pharmaceutical group. The defluorination could be encountered in
agents entering the market is fuelled by the rapid de- the manipulation of a-trifluoromethyl carbonyl com-
velopment of efficient synthetic methods that include pounds. This is particularly true for lithium enolates
direct fluorination and manipulation of fluorinated that produce a,b-unsaturated-b,b-difluoro ketones[5]
building blocks. In this context, the trifluoromethyl as represented in Scheme 1.
motif has stimulated high interest due to its specific
The undesired b-elimination reaction could be sup-
physical and biological properties, responsible of its pressed through the use of aluminum,[5] boron,[6] or ti-
increasing occurrence in a wide range of biologically tanium enolates[7] as examined in the aldol reaction of
active compounds but also in materials for optoelec- a-trifluoromethyl enolates with various aldehydes. In
tronic devices.[2] Among several effective methods
that have been investigated for the synthesis of tri-
fluoromethylated organic molecules,[3] we were inter-
ested in the approach based on the a-trifluoromethy-
lated carbanion synthons, which is one of the main
challenges.[4] The chemistry of a-trifluoromethylated
carbanions and related species has remained unex-
plored, despite their great mechanistic and synthetic
significance in organic chemistry.[4] It is well recog-
nized that carbanions in the a-position of a trifluoro-
methyl group are thermodynamically stabilized by in- manipulation of a-trifluoromethylated carbanion synthons.
Scheme 1. The defluorination could be encountered in the
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Norio Shibata et al.
FULL PAPERS
these cases, however, results were only partially satis- ly unknown, cyclic, quaternary a-trifluoromethyl car-
factory from the synthetic point of view. On the other bonyl compounds having indanone and tetralone
hand, in 1999 Kitazume and co-workers succeeded in frameworks was successfully obtained. These com-
the generation of stable a-trifluoromethyl carbanions pounds are attractive building blocks for medicinal
by palladium-catalyzed intermolecular allylation reac- chemistry and also interesting from a synthetic point
tions of 3,3,3-trifluoropropionates with allyl carbo- of view, because these cyclic compounds are difficult
nates.[8] Despite its potential usefulness in synthetic to obtain by intermolecular allylation reactions.[8–10]
chemistry, Kitazumeꢂs methodology has been given
scant attention and only a few reports of related pal-
ladium-catalyzed intermolecular allylation reactions Results and Discussion
have appeared, essentially due to the limitations in
substrate preparation.[9,10] We recently developed effi- Initial studies were performed with the allyl a-tri-
cient methods to prepare a broad range of a-trifluoro- fluoromethyl-b-keto ester derived from indanone as
methyl-b-keto esters containing diverse functionality substrate along with tris(dibenzylideneacetone) dipal-
by direct trifluoromethylation of b-keto esters using ladium [PdACTHNURGTNEUNG(dba)2] as a source of soluble Pd(0) and
either CF3I,[11] or electrophilic trifluoromethylation re- 1,2-bis(diphenylphosphino)ethane (dppe) as a com-
agents[12] in high yields. Taking advantage from a monly used bidentate ligand in THF at room temper-
practical preparation of the a-trifluoromethyl-b-keto ature.[14] Under these conditions, the reaction oc-
esters,[11–13] we thought the intramolecular version of curred within 2 h leading to the a-trifluoromethyl-a-
Kitazumeꢂs approach could provide a unique means allylindanone in 65% yield (Table 1, run 1). Palladi-
for constructing trifluoromethylated products. We
ACHTUNGTRENuNGNU m(II) sources could also be used albeit with negative
herein report our approach toward a-carbonyl tri- effects on the yield or the reaction time (Table 1, runs
fluoromethyl-bearing quaternary carbon centers 2 and 3). A change in the ligand-to-palladium ratio
based on a palladium-catalyzed intramolecular decar- resulted in an improved yield (80%; Table 1, run 4).
boxylative allylation of allyl a-trifluoromethyl-b-keto Different ligands were examined that include mono-
carboxylates (Scheme 2). To the best of our knowl- and bidentate phosphines; however, the yield was not
edge, this is the first example of an intramolecular improved (Table 1, runs 4–7). A solvent screening re-
variant of Kitazumeꢂs procedure. A series of previous- vealed that THF is the most appropriate for the reac-
tion. A longer reaction time is required in a chlorinat-
ed solvent (CH2Cl2), as it is the case in toluene, and
the yield was dramatically decreased whereas oxygen-
ated solvents (Et2O, 1,4-dioxane) gave reasonable
yields within a short reaction time (Table 1, runs 8–
11). Importantly, b-elimination of a fluoride ion that
would have produced a,b-unsaturated-b,b-difluoro ke-
Scheme 2. Palladium-catalyzed intramolecular decarboxyla-
tive allylation of allyl a-trifluoromethyl-b-keto carboxylates. tones was not observed in these crude reaction mix-
Table 1. Optimization of reaction conditions for the decarboxylative allylation.
Run
Pd (mol%)
Pd(dba)2 (5.0)
Ligand (mol%)
Solvent
Time [h]
Yield[a] [%]
1
2
3
4
5
6
7
8
G
dppe (6.25)
dppe (6.25)
dppe (6.25)
dppe (6.25)
PPh3 (12.5)
dppp (6.25)
PCy3 (12.5)
dppe (6.25)
dppe (6.25)
dppe (6.25)
dppe (6.25)
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
Et2O
2
12
3
1
2
5
1
12
12
1
65
28
65
80
69
38
0
14
71
69
75
A
U
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
G
E
E
E
U
U
CHTUNGTRENNUNG
CHTUNGTRENNUNG
E
9
10
11
1,4-dioxane
1
[a]
Isolated yield.
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Construction of Trifluoromethyl-Bearing Quaternary Carbon Centers
tures. This clearly demonstrates that the allylation
proceeds faster than the b-elimination reaction.
The mechanism of the decarboxylative allylation re-
action is thought to proceed via an oxidative addition
of the substrate to Pd(0)-phosphine complex to pro-
duce a carboxylate and a cationic p-allyl palladium
complex.[14] Decarboxylation of the b-keto carboxyl-
ate generates a palladium enolate, which undergoes a
reductive elimination leading to the product forma-
tion and concomitant regeneration of the Pd(0) cata-
lyst. An intimate relationship between p-allylpalladi-
um complex and a-trifluoromethyl carbanion prevents
the b-elimination reaction to unsaturated-b,b-difluoro
ketones (Scheme 3).
With adequate conditions in hand, the scope of the
decarboxylative allylation was further examined and
the results are presented in Scheme 4. A range of
allyl a-trifluoromethyl-b-keto esters as substrates for
the decarboxylative allylation reaction was easily syn-
thesized by the direct trifluoromethylation of allyl b-
keto esters with either our electrophilic trifluorome-
thylating reagents[12] or radical trifluoromethylation of
methyl b-keto esters by means of trifluoromethyl
iodide[11] followed by a Ti
ACTHNUTRGEN(NUG O-i-Pr)4-mediated transes-
terification.[15] Indanone derivatives with electron-
donor groups or halogen substitution at the aromatic
ring gave the desired products in yields ranging from
69 to 99%. In the case of the 5,6-dimethoxyindanone
derivative, a moderate yield could be obtained after a
Scheme 4. Variation of substrates for palladium-catalyzed
decarboxylative allylation.
longer reaction time. A substrate with a methallyl same reaction conditions. The reaction proceeded
ester was prepared to evaluate a different transferable smoothly to provide the corresponding allylic tri-
group. It appeared that methallyl transfer proceeds
equally well as far as the reaction mixture is heated at due to the high volatility of the product (Scheme 4).
608C for 1 h instead of room temperature. Good to The allyl group can be transformed later into a
ACHTUNGTRENfNGNU luoromethyl ketone 2m, although the yields are low
excellent yields were obtained with larger rings in tet- broad range of carbon appendages. One of the exam-
ralone and benzosuberone derivatives (59–99%). ples is shown in Scheme 5. Treatment of 2a, h with
Acyclic substrates 1k and 1l were also evaluated. methyl vinyl ketone in the presence of Grubbsꢂ 2nd
Both reactions proceeded quite well to provide 2k generation catalyst[16b] in CH2Cl2 under heating condi-
and 2l in 57% and 67%, respectively. The reaction of tions gave the enones 3a, h. Reduction of the enones
simple cyclopentanone-derived substrates 1m was also 3a, h with 10% Pd/C under an atmosphere of hydro-
performed in comparison with indanones under the gen gas for 12 h afforded 1,6-diketones 4a, h in good
yields. The tetralone derived 3h was also converted
into medicinally attractive carbocycle
5
using
[Ph3PCuH]6 in toluene at À408C (Scheme 5).[16d]
Towards Asymmetric Reactions
The successes of Stoltz[16] and Trost[17] on asymmetric
Tsuji decarboxylative allylations[18] prompted us to at-
tempt the asymmetric version of the intramolecular
decarboxylative allylation of a-trifluoromethyl b-keto
esters by the use of chiral bisphosphine ligands like
the Trost ligand, P,N ligands or the like. A racemic
allyl 2-trifluoromethyl-1-indanonecarboxylate (1a)
was tested to be converted into the corresponding op-
tically active 2-allyl-2-trifluoromethyl-1-indanone (2a)
Scheme 3. Catalytic cycle of palladium-catalyzed intramolec-
ular decarboxylative allylation of allyl a-trifluoromethylin-
danonecarboxylate.
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Norio Shibata et al.
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Scheme 7. Decarboxylative allylation of chiral, non-racemic
1a in the presence of achiral catalyst.
sulfonylacetic esters.[19] In our case, however, it was
disappointing to find that the decarboxylative allyla-
tion of enantioenriched 1a (prepared by enantioselec-
tive trifluoromethylation of 2-allyl 1-indanone 2-car-
Scheme 5. Reaction conditions: i) methyl vinyl ketone (2.5
equiv.), Grubbsꢂ 2nd catalyst (5.0 mol%), CH2Cl2, 408C,
18 h (3a: 40%; 3h: 47%); ii) 10% Pd-C/H2 (1 atm), EtOAc,
room temperature, 12 h (4a: 40% from 2a; 4h: 34% from
2h); iii) [Ph3PCuH]6 (0.5 equiv.), toluene, À408C, 4 h (5:
12%).
boxylate[20,21]
)
proceeded in
a
non-stereospecific
manner to provide 2a in 97% yield as a racemate
(Scheme 7).
Conclusions
by palladium-catalyzed extrusion of carbon dioxide
(Scheme 6). First, the treatment of 1a with [PdACHTUNTRGNEU(GN dba)2] In summary, we have demonstrated that palladium
(5 mol%) as a catalyst precursor and a chiral ligand, enolates generated by a catalyzed decarboxylation of
i-Pr-Phox (6.25 mol%) in THF at room temperature allyl a-trifluoromethyl-b-keto esters are suitable inter-
gave the desired 2a in 95% yield; however, no asym- mediates for subsequent intramolecular allylation
metric induction was detected. We further examined without b-elimination of fluoride ion. This work
the transformation of 1a to 2a using a variety of chiral offers a new entry to cyclic a-trifluoromethyl-a-qua-
ligands (6.25 mol%) and [Pd
ACHTUNGRTEN(NUNG dba)2] (5 mol%) or ternary ketones that are not easily accessible via eno-
Pd2A(dba)3 (2.5 mol%) at different temperatures, but late alkylation and provides valuable information for
CHTUNGTRENNUNG
the produced allyl trifluoromethyl indanone 2a was further breakthroughs in the chemistry of a-trifluoro-
racemic (See Table S1 in the Supporting Information methyl carbanions. The stereocontrol of the newly
for details).[21]
formed quaternary stereogenic carbon center is the
We next attempted the stereospecific, palladium- challenging object of current development and will be
catalyzed decarboxylative allylation of chiral, non-rac- reported in due course.
emic 1a under achiral catalyst conditions. Recently,
Tunge and co-workers reported that chiral allyl sulfo-
nylacetic esters undergo highly stereospecific, palladi- Experimental Section[21]
um-catalyzed decarboxylative allylation to furnish ter-
tiary homoallylic sulfones in high yields without General Conditions
major loss of the enantiopurity of the starting allyl
All reactions were performed in oven-dried glassware under
a positive pressure of nitrogen or argon. Solvents were
transferred via syringe and were introduced into the reac-
tion vessels though a rubber septum. All reactions were
monitored by thin-layer chromatography (TLC) carried out
on 0.25 mm Merck silica gel (60-F254). The TLC plates
were visualized with UV light and 7% phosphomolybdic
acid or KMnO4 in water/heat. Column chromatography was
carried out on a column packed with silica-gel 60N spherical
neutral size 63–210 mm.
Typical Procedures for Intramolecular Decarboxy-
lative Allylation of a-Trifluoromethyl-b-keto Esters
2-Allyl-2-trifluoromethyl-1-indanone (2a): To a solution of
Pd2ACTHNUTRGNE(NUG dba)3 (2.4 mg, 0.00264 mmol, 2.5 mol%) and dppe
(2.6 mg, 0.00663 mmol, 6.25 mol%) in THF (2.1 mL, 0.05M)
were added at room temperature under argon, and the mix-
ture was stirred for 30 min. b-keto ester 1a (30.0 mg,
Scheme 6. Decarboxylative allylation of 1a in the presence
of chiral ligands.
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Construction of Trifluoromethyl-Bearing Quaternary Carbon Centers
0.106 mmol, 1.0 equiv.) was added dropwise through a sy-
ringe to the room temperature. The resulting solution was
stirred at room temperature for 1 h (full conversion checked
by TLC), and the solvent was then evaporated under
vacuum. The residue was purified by column chromatogra-
phy on silica gel eluting with n-hexane/ethyl acetate=9/1 to
give 2a as a colorless oil; yield: 24.5 mg (0.102 mmol, 96%).
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A
solution of Pd2A(dba)3 (1.5 mg, 0.00167 mmol, 2.5 mol%) and
CHTUNGTRENNUNG
dppe (1.7 mg, 0.00418 mmol, 6.25 mol%) in THF (1.3 mL,
0.05M) was prepared at room temperature under argon,
and the mixture was stirred for 30 min. b-Keto ester 1c
(21.0 mg, 0.0668 mmol, 1.0 equiv.) was added dropwise
through a syringe at room temperature. The resulting solu-
tion was stirred at room temperature for 1 h (full conversion
checked by TLC), and the solvent was then evaporated
under vacuum. The residue was purified by column chroma-
tography on silica gel eluting with n-hexane/ethyl acetate=
9/1 to give 2c as a colorless oil; yield: 17.9 mg (0.0663 mmol,
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2-(2-Methylallyl)-2-trifluoromethyl-1-indanone (2g): A so-
lution of Pd2ACHTUNGTRENNUNG(dba)3 (2.3 mg, 0.00250 mmol, 2.5 mol%) and
dppe (2.5 mg, 0.00625 mmol, 6.25 mol%) in THF (2.0 mL,
0.05M) was prepared at room temperature under argon,
and the mixture was stirred for 30 min. b-Keto ester 1g
(29.8 mg, 0.100 mmol, 1.0 equiv.) was added dropwise
through a syringe at room temperature. The resulting solu-
tion was stirred at 608C for 1 h (full conversion checked by
TLC), and the solvent was then evaporated under vacuum.
The residue was purified by column chromatography on
silica gel eluting with n-hexane/ethyl acetate=9/1 to give 2g
as a colorless oil; yield: 21.9 mg (0.0861 mmol, 86%).
Acknowledgements
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The corresponding authors thank the JSPS in Japan and
CNRS in France for financial support of this work through a
Joint Research Project. This study was also financially sup-
ported in part by Grants-in-Aid for Scientific Research
(B21390030, 22106515) and the Asahi Glass Foundation.
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2041