Palladium-catalyzed allylic alkylation of doubly deprotonated carboxylic acids

Article abstract of DOI:10.1002/adsc.201100372

Doubly deprotonated carboxylic acids undergo smooth palladium-catalyzed carbon alkylations with the allylic substrates methyl allyl carbonate and (E)-methyl (pent-3-en-2-yl) carbonate to give γ,δ-unsaturated carboxylic acids. A diastereoselective and enantioselective protocol leads to (2S,3R)-hexenoic acid in 87% ee. Copyright

Full text of DOI:10.1002/adsc.201100372

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DOI: 10.1002/adsc.201100372
Palladium-Catalyzed Allylic Alkylation of Doubly Deprotonated
Carboxylic Acids
Manfred Braun,a,* Panos Meletis,a and Robin Vissea
a
Institut fꢀr Organische Chemie und Makromolekulare Chemie, Universitꢁt Dꢀsseldorf, Universitꢁtsstr. 1, 40225
Dꢀsseldorf, Germany
Fax : (+49)-211-811-5079; e-mail: braunm@uni-duesseldorf.de
Received: May 11, 2011; Revised: July 27, 2011; Published online: December 8, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100372.
Abstract: Doubly deprotonated carboxylic acids un-
dergo smooth palladium-catalyzed carbon alkyla-
tions with the allylic substrates methyl allyl carbon-
ate and (E)-methyl (pent-3-en-2-yl) carbonate to
give g,d-unsaturated carboxylic acids. A diastereo-
selective and enantioselective protocol leads to
(2S,3R)-hexenoic acid in 87% ee.
A class of carbonyl compounds known to form re-
active, non-stablilized enolates are carboxylic acids
when doubly deprotonated. They can be considered
as particularly “hard” nucleophiles. This is illustrated
by the pKa value of their parent carbon acid, the ace-
tate, which was determined to amount to 33.5.[14] Re-
markably, it was never tried before to use the dilithi-
um salts 1 of carboxylic acids, developed by Creger,[15]
in palladium-catalyzed allylic alkylations and to com-
bine this type of nucleophile with electrophilic allyl-
palladium complexes 2 generated in situ (Scheme 1).
Keywords: allylation; lithium; stereoselectivity; syn-
thetic methods
The palladium-catalyzed allylic alkylation, the “Tsuji–
Trost reaction”, has developed into an exceptionally
useful method for carbon-carbon and carbon-hetero-
ACHTUNGTRENNUNG
atom bond formation,[1] particularly since efficient
Scheme 1. Doubly deprotonated carboxylic acids as nucleo-
philes in palladium-catalyzed allylic alkylations.
enantioselective variants have been elaborated.[2] For
a long period, however, the major drawback of the
Tsuji–Trost allylation was its limitation in the type of
carbon nucleophiles: “soft”, stabilized carbanions In this communication, we show that Tsuji–Trost ally-
have been used almost exclusively. Obviously, the lations are indeed feasible with doubly lithiated car-
scope of the method can be extended considerably, if boxylic acids 1 and open a possibility for a diastereo-
“hard”, non-stabilized, preformed enolates[3] will func- selective and enantioselective variant.
tion as nucleophiles. After early approaches,[4] asym-
The two-fold deprotonation of carboxylic acids 3
metric allylic alkylations of ketones through lithium was performed with lithium diisopropylamide[15d] to
and magnesium enolates[5,6] as well as enol stan- give the dilithiated intermediates 1. They were treated
nanes[7] and silanes,[8] enamines[9] and allyl enol carbo- with the allylic substrates 5a or 5b in the presence of
nates[10] have been developed during the last decade
only. Recently, several carboxylic acid derivatives
a
G
palladium catalyst that was generated from
CHTUNGTRENNUNG
have been submitted successfully to palladium-cata- BINAP (4). A smooth reaction occurred with the di-
lyzed allylic alkylations, amongst them a-amino car- lithium reagents 1 at 08C to give the carboxylic acids
boxylic esters, which carry electron-with drawing N- 6 in fair yields. In all the reactions shown in Table 1,
protecting groups[11] as well as lactams[12] and lithium chloride was used as an additive, thus follow-
amides[13]. In addition, suitable ketones, after having ing the protocol that has been elaborated for ketone
been submitted to an allylation, were converted into enolates.[5c,d] Although detailed information about the
carboxylic esters.[5g,10l]
structure of doubly deprotonated carboxylic acids is
rare,[16] the lithium salt is expected to enhance the re-
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Palladium-Catalyzed Allylic Alkylation of Doubly Deprotonated Carboxylic Acids
Table 1. Palladium-catalyzed allylic alkylation of carboxylic acids.
Entry
1
Carboxylic acid 3
Allylic substrate 5
Product 6
Yield [%]
52
5a
2
3
5a
5a
79
48
4
5
6
5a
5a
5b
50
58
51[a]
7
8
5a
5b
92
70[b,c]
9
5b
51[b,d]
[a]
(S)-(À)-5,5’-Dichloro-6,6’-dimethoxy-2,2’-bis(diphenylphosphino)-1,1’-biphenyl was used as ligand; product 6f was ob-
tained in 72% ee.
(S)-4 was used as ligand.
Mixture of diastereomers (67:33), main diastereomer: 82% ee.
Mixture of diastereomers (79:21), main diastereomer: 91% ee.
[b]
[c]
[d]
activity of the carboxylic acid-derived enolates to- pattern of the carboxylic acids submitted to the allylic
wards the allylpalladium complexes by desaggrega- alkylation could be varied in a wide range. Aside
tion.[17] On the other hand, the presence of lithium from alkyl or aryl substituents R1/R2 in the a-position
chloride is known to influence the structure and reac- of the enolates 1 (entries 1, 2, and 9), branched resi-
tivity of allylpalladium complexes.[18] The substitution dues including the sterically demanding tert-butyl
Adv. Synth. Catal. 2011, 353, 3380 – 3384
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Manfred Braun et al.
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Table 2. Diastereoselective and enantioselective allylation of phenylacetic acid 3b mediated with rac- or (S)-4
Entry
Ligand
Temperature/Time
Yield
dr (anti:syn)
ee [%]
1
2
3
rac-4
rac-4
(S)-4
08C/20 h
65%
78%
66%
71:29
83:17
84:16
–
–
87
À788C/40 h
À788C/40 h
group were tolerated as well (entries 3 and 4). As il-
The relative configuration of 6j was proven by ozo-
lustrated by cyclopentyl- (entries 5 and 6) and indane- nolysis of a diastereomerically pure sample and im-
carboxylic acids (entries 7 and 8), the protocol is suit- mediate oxidation of the aldehyde thus obtained (that
able for the formation of quaternary carbon centers. mainly exists as pseudo acid in an equilibrium with
Not only methyl allyl carbonate 5a (entries 1–5 and 7) the carboxylic acid) (Scheme 2). The assignment of
but also methyl (pent-3-en-2-yl) carbonate 5b (en- the anti-configuration to the main diastereomer of 2-
tries 6, 8, and 9) gave satisfactory results and led to methyl-3-phenylsuccinic acid 7 was possible by com-
the carboxylic acids 6f, 6h, and 6i with branched side parison of its NMR data with those described in the
chains. The latter products, 6h and 6i were obtained literature.[20] On the other hand, the absolute configu-
as diastereomeric mixtures (entries 8 and 9). It was ration of the allylation product 6j was assigned after
proven, in the case of doubly deprotonated phenyl- hydrogenation to the acid 8. Comparison of its optical
acetic acid, that no conversion with the carbonates 5 rotation with those of a series of 2-phenylalkanoic
occurred in the absence of the palladium catalyst.
acids[21] permitted us to assign the configuration at the
The possibility for diastereoselectivity and enantio- a-carbonyl center to be (S) so that the configuration
selectivity was studied in the reaction of phenylacetic of the acid 6j could be determined as (2S,3R).
acid (3b) with carbonate 5b to deliver the branched
In summary, doubly deprotonated carboxylic acids
carboxylic acid 6j (Table 2). When the allylation of are shown for the first time to be suitable nucleo-
the corresponding dilithium reagent 1 (R1 =Ph, R2 = philes in palladium-catalyzed allylic alkylations. As a
H) was mediated with rac-4, a diastereomeric ratio of consequence, the breadth and versatility of the Tsuji–
71:29 in favour of anti-6j was obtained (entry 1). Low- Trost reaction is enhanced substantially. From a syn-
ering the reaction temperature led to an increase of thetic point of view, the protocol described offers a
diastereoselectivity to 83:17 (entry 2). The latter con- direct, one-step alternative to the Ireland–Claisen re-
ditions were used to bring about an enantioselective arrangement of allylic esters[22] including the advant-
version by switching from rac- to (S)-BINAP (4).
Thus, the enantiomeric excess of anti-6j was found to
amount to 87% ee (entry 3).
The enantiomeric excess was determined, after re-
moval of the minor diastereomer, by chiral GC of the
methyl ester generated by treatment of the isolated
acid 6j with trimethylsilyldiazomethane. In addition,
the acid was reduced to the alcohol by treatment with
lithium aluminium hydride and subsequent conversion
1
into Mosherꢃs ester[19] that was investigated by H and
19F NMR spectroscopy. As shown in entries 6, 8, and
9 of Table 1, enantioselectivity is also reached in the
formation of carboxylic acids 6f, 6h, and 6i, the
former two featuring a quaternary carbon center.
Scheme 2. Derivatives 7 and 8 of carboxylic acid 6j for de-
termination of the configuration.
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Adv. Synth. Catal. 2011, 353, 3380 – 3384

Palladium-Catalyzed Allylic Alkylation of Doubly Deprotonated Carboxylic Acids
(125 MHz, CDCl3): d=17.9, 18.2, 40.0, 58.7, 125.9, 127.3,
age of enantioselective catalysis. Further stereoselec-
tive variants of this protocol might develop into a
suitable method that will no longer rely on the detour
through malonate allylation, saponification, and de-
carboxylation, in particular as the direct route dis-
closed here permits one to obtain products with qua-
ternary carbon centers.
128.5, 128.7, 133.2, 137.0, 179.8; anal. calcd. for C13H16O2: C
76.44, H 7.90; found: C 76.46, H 7.88; Chiral GC (methyl
ester of 6j: DN-GAMMA 25 mꢄ0.25 mmꢄ0.25 m, column
temperature 958C, flow 1.5 mLminÀ1): methyl ester of
(2R,3S)-6j tR =59.5 min, methyl ester of (2S,3R)-6j tR =
61.1 min.
Experimental Section
Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (Br 604/16-1,2).
Procedure for the Diastereoselective and Enantio-
selective Palladium-Catalyzed Allylation of Phenyl-
acetic Acid (3b)
A 100-mL two-necked flask was equipped with a magnetic
stirrer and charged with [Pd
N
25 mmol), (S)-BINAP [(S)-4] (62.3 mg, 101 mmol) and LiCl
(0.51 g, 12 mmol). The flask was closed with a septum, con-
nected to a combined nitrogen/vacuum line, evacuated for
4 h at 258C in order to remove traces of water from the lith-
ium salt, and filled with nitrogen. To this flask was added a
solution of methyl (pent-3-en-2-yl) carbonate (5b) (0.72 g,
5 mmol) in dry THF (30 mL). The resulting solution was
stirred at room temperature for 1 h and thereafter cooled
down to À788C. A 100-mL two-necked flask was equipped
with a magnetic stirrer, a connection to the combined nitro-
gen/vacuum line and a resistance low-temperature thermom-
eter that was introduced through the septum. The flask was
evacuated and refilled with nitrogen three times. Into this
flask diisopropylamine (1.41 mL; 10.0 mmol) and 30 mL of
dry THF were injected. After cooling to À788C, a 1.6 M so-
lution of butyllithium in hexane (6.25 mL; 10.0 mmol) was
added dropwise by syringe, while keeping the temperature
below À708C. After stirring at 08C for 30 min, a solution of
vacuum-dried phenylacetic acid (3b) (0.68 g; 5.0 mmol) in
5 mL of dry THF was injected by syringe. In the course of
the addition, the internal temperature of the solution was
not allowed to exceed +38C. This solution was stirred for
1 h at room temperature and then transferred, after cooling
again to À788C, through a cannula into the first flask, which
was cooled also to À788C. After stirring at À788C for 40 h,
the mixture was poured into a saturated solution of ammo-
nium chloride (100 mL) and acidified with 2N sulphuric
acid. The aqueous layer was extracted three times with
50 mL portions of diethyl ether. Then the combined organic
layers were extracted with 75 mL of a 20% aqueous solution
of potassium carbonate. Thereafter, the aqueous layer was
acidified with 6N sulphuric acid to pH 1–2 and re-extracted
with diethyl ether (3ꢄ50 mL). The resulting combined or-
ganic layer was dried with magnesium sulphate, filtered, and
concentrated under reduced pressure. The resulting yellow
crude product, which contained the acid 6j in 66% yield ac-
cording to GC analysis, was purified by chromatography on
silica gel to afford an analytically pure sample of (2S,3R)-3-
methyl-2-phenylhex-4-enoic acid (6j) as a white solid. Rf =
0.58 (hexane/ethyl acetate, 1:4 and a few drops acetic acid);
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