Synthesis of a [2.2]paracyclophane based planar chiral palladacycle by a highly selective kinetic resolution/C-H activation reaction

Article abstract of DOI:10.1039/c2cc16864b

Kinetic resolution of racemic 4-N,N-dimethylaminomethyl[2.2]paracyclophane with 50% sodium tetrachloropalladate and (R)-N-acetylphenylalanine under basic conditions resulted in the formation of a (S_p)-planar chiral palladacycle (35%, >99% ee). Similarly use of 100 mol% sodium tetrachloropalladate resulted in higher levels of conversion and recovery of (S_p)-4-N,N-dimethylaminomethyl[2.2]paracyclophane (41%, >97% ee).

Full text of DOI:10.1039/c2cc16864b

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COMMUNICATION
Synthesis of a [2.2]paracyclophane based planar chiral palladacycle by a
highly selective kinetic resolution/C–H activation reactionw
Nathalie Dendele,ab Fabrice Bisaro,a Annie-Claude Gaumont,b Stephane Perriob and
Christopher J. Richards*a
Received 5th November 2011, Accepted 25th November 2011
DOI: 10.1039/c2cc16864b
Kinetic resolution of racemic 4-N,N-dimethylaminomethyl[2.2]-
paracyclophane with 50% sodium tetrachloropalladate and
(R)-N-acetylphenylalanine under basic conditions resulted in the
formation of a (Sp)-planar chiral palladacycle (35%, >99% ee).
Similarly use of 100 mol% sodium tetrachloropalladate resulted in
higher levels of conversion and recovery of (Sp)-4-N,N-dimethyl-
aminomethyl[2.2]paracyclophane (41%, >97% ee).
Scheme 1 Enantioselective palladation.6,7
Significant progress has recently been achieved in the development
also known based upon the [2.2]paracyclophane framework.9
of transition metal catalysed C–H activation reactions for
application in organic synthesis.1 Particular attention has been
These metallacycles were obtained by classical resolution, in
common with most non-racemic [2.2]paracyclophanes.10 The
focused on palladium catalysed ligand-directed ortho-C–H
only exception is the enzyme mediated kinetic resolution of
4-acetoxy[2.2]paracyclophane from which both 4-hydroxy[2.2]-
paracyclophane and recovered starting material were obtained
in high enantiomeric excess.11 In light of the success of chiral
carboxylate mediated enantioselective C–H activation, and the
relevance of this chemistry to the development of catalytic
protocols, we sought to extend this methodology to a kinetic
resolution for the efficient synthesis of a non-metallocene
[2.2]paracyclophane based planar chiral palladacycle.
activation of arenes for the construction of carbon–carbon
and carbon–heteroatom bonds.2 Despite the success and
importance of this area, there are very few examples of analogous
palladium catalysed enantioselective aryl C(sp2)–H activation
reactions.3,4 Those that are known are proposed to proceed via
the intermediacy of a chiral palladacycle in the catalytic cycle.
Chiral palladacycles have also been synthesised as isolated
products by enantioselective C–H activation, either by trans-
cyclopalladation from another chiral palladacycle,5 or by the
reaction of sodium tetrachloropalladate mediated by an amino
acid derived chiral carboxylate ligand. The latter reaction was
first described by Sokolov et al.,6 and recently one of us
reported the optimisation and further application of this reaction,
as exemplified by the highly enantioselective transformation of
prochiral ferrocene derivative 1 into the planar chiral product 2
(Scheme 1).7
As high ees have previously been achieved with the N,N-
dimethylaminomethyl ligating group in 1, the corresponding
[2.2]paracyclophane compound (rac)-5 was selected as a suitable
substrate. It was readily synthesised from racemic 4-carboxy[2.2]-
paracyclophane 312 as outlined in Scheme 2. To test the suitability
of this amine as a palladation substrate, (rac)-5 was heated with
palladium acetate in toluene which resulted exclusively in the
formation of (rac)-6 (Scheme 3). No product was observed from
metallation of the benzylic position, as previously observed in
the palladation of a [2.2]paracyclophane derivative containing
a 4-(2-oxazolinyl) substituent.9a Following conversion into the
monomeric hexafluoroacetylacetonate derivative (rac)-7, the two
The majority of metallocene based planar chiral palladacycles
are obtained by the diastereoselective palladation of C–H
bonds, and several of these complexes have been applied as
catalysts in a number of highly enantioselective organic trans-
formations.8 Non-metallocene planar chiral palladacycles are
a School of Chemistry, University of East Anglia, Norwich, NR4 7TJ,
UK. E-mail: Chris.Richards@uea.ac.uk; Fax: +44 (0)1603 592003;
Tel: +44 (0)1603 593890
b Laboratoire de Chimie Mole´culaire et Thioorganique - UMR CNRS
´
6507 ENSICAEN, 6 bd du Marechal Juin, 14050 CAEN, France.
E-mail: annie-claude.gaumont@ensicaen.fr;
Fax: +33 (0)231 452877; Tel: +33 (0)231 452873
w Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for (rac)-4, (rac)-5, (rac)-7, (Sp)-5
and (Sp)-7. See DOI: 10.1039/c2cc16864b
Scheme 2 Reagents and conditions: (i) (COCl)2, DMF, CH2Cl2, RT;
(ii) NHMe2, RT (75% for 2 steps); (iii) LiAlH4, THF, RT (80%).
c
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Chem. Commun., 2012, 48, 1991–1993 1991

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starting material at the expense of the ee of the palladacycle.
With a 48 hour reaction time and use of one equivalent of
sodium tetrachloropalladate, the ee of recovered 4-N,N-
dimethylamino[2.2]paracyclophane was determined as >97%
(entry 4). On a larger scale (934 mg of starting material), use of
50 mol% of the palladium reagent with a 17.5 hour reaction
time resulted in an essentially enantiopure sample (>99% ee) of
palladacycle (Sp)-7 (entry 5).
The availability of accurate ee data for both (Sp)-5 and (Sp)-
7 permits calculation of the percentage conversion (c) and thus
the selectivity factor (s) for each reaction.13,14 Application to
the data in entry 1 gives c = 43% and s = 204, and the data in
entry 4 gives c = 52% and s = 85. Intermediate corresponding
values were determined from the data in entries 2 and 3.
Although uniformly high, and notwithstanding the sensitivity
of s to small differences in c and ee, the decrease in the values of
the selectivity factor with increased sodium tetrachloropalladate
quantity or longer reaction time points to the formation of a
small quantity of another product. Upon repetition of the
palladation using the conditions described in entry 4, analysis
of the crude product mixture by 1H NMR revealed this to
contain 4-carbaldehyde[2.2]paracyclophane (o5%).
Scheme 3 Reagents and conditions: (i) Pd(OAc)2, PhMe, 60 1C (74%);
(ii) Na(hfacac), H2O/acetone, RT (33%).
The absolute configuration of the recovered amine 5 (97.5% ee)
was determined as Sp following oxidation to 4-carbaldehyde-
[2.2]paracyclophane (52%) with N-bromosuccinimide in
benzene.15 The specific rotation determined ([a]2D4 + 179 (c 0.6,
CHCl3)) is in good agreement with the literature value for (Sp)-4-
carbaldehyde[2.2]paracyclophane ([a]2D5 + 184 (c 0.41, CHCl3,
98.7% ee)).16 Thus faster reacting (Rp)-5 undergoes palladation
to give (Sp)-7. A model has been proposed to account for the
selective formation of (Sp)-2 mediated by (R)-N-acetylphenyl-
alanine,17 the chiral carboxylate ligand participating in a con-
certed metallation–deprotonation reaction pathway.18 Of note
here is the correspondence between the prochiral ferrocene and
chiral [2.2]paracyclophane substrates, exo palladation occurring
with the same sense of selectivity as outlined in Scheme 5.
In conclusion, we have demonstrated that enantioselective
palladation mediated by an amino acid derived chiral
carboxylate is applicable to the kinetic resolution of 4-N,N-
dimethylaminomethyl[2.2]paracyclophane. The resulting pall-
adacycle may be generated in essentially enantiopure form
from a reaction displaying a very high selectivity factor. The
less reactive enantiomer of the starting material may also be
recovered in high ee. The application of [2.2]paracyclophane
based planar chiral palladacycles to asymmetric synthesis is
currently under investigation.
Scheme 4 Reagents and conditions: (i) 0.5–1.0 eq. Na2PdCl4, 1.0 eq.
(R)-N-acetylphenylalanine, MeOH/H2O/CH2Cl2, pH 8.2, RT;
(ii) Na(hfacac), H2O/acetone, RT.
palladacycle enantiomers were readily separated by analytical
chiral HPLC.
The kinetic resolution of (rac)-5 was attempted by adding a
MeOH/CH2Cl2 solution of the amine to an aqueous solution of
one equivalent of (R)-N-acetylphenylalanine and half an equivalent
of sodium tetrachloropalladate at pH 8.2 (Scheme 4).z After
stirring at room temperature for 18 hours the solvent was
removed in vacuo and the residue treated with sodium hexa-
fluoroacetylacetonate to convert the initially formed chloride
bridged palladacycle (Sp)-8 into monomer (Sp)-7. Following
separation of the unreacted amine, the ee of the palladacycle
was determined as 97.8% by chiral HPLC (Table 1, entry 1).
The ee of recovered (Sp)-5 was determined in the same way
following reaction with palladium acetate and conversion into
(Rp)-7, as previously described for the corresponding racemate
(Scheme 3). Increasing the quantity of sodium tetrachloro-
palladate used to 75 mol% and then 100 mol% (entries 2 and 3)
had the expected effect of increasing the ee of the recovered
Table 1 Kinetic resolution of (rac)-5 to give (Sp)-5 and (Sp)-7
Na2PdCl4 Time/ ee (%) ee (%) Yield (%) Yield (%)
(Sp)-5d (Sp)-7e (Sp)-5f,g
Entry (mol%)
h
(Sp)-7f,h
1a
2a
3a
4b
5c
50
75
100
100
50
18
18
18
48
75.2
86.3
96.8
97.5
23.7
97.8
96.2
91.9
90.2
99.7
56
42
25
41
33
49
50
34
35
17.5
N/D
a
b
With 0.19 mmol of (rac)-5. With 0.75 mmol of (rac)-5. With
c
d
3.52 mmol of (rac)-5. Determined following conversion to (Rp)-7
e
with Pd(OAc)2 followed by Na(hfacac). Determined by HPLC.
f
g
Isolated by column chromatography. Based on (rac)-5. Based
h
Scheme 5 Correspondence between ferrocene and [2.2]paracyclo-
phane substrates in (R)-N-acetylphenylalanine mediated palladation.
on Na2PdCl4.
c
1992 Chem. Commun., 2012, 48, 1991–1993
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The ERDF (ISCE-Chem & INTERREGIVa programme
4061) is gratefully thanked for financial support. This work
was also supported by the CNRS and the Crunch (interregional
organic chemistry network). We also thank the EPSRC National
Mass Spectrometry Centre (University of Wales, Swansea).
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0.3 M solution of NaOH in water (630 mL, 0.19 mmol). The resulting
solution was added to a solution of Na2PdCl4 (0.0277 g, 0.094 mmol)
in MeOH (2.4 mL), and the pH of the resulting solution was adjusted
to 8.2 with a 50% aqueous solution of NaOH. To this solution was
added a solution of (rac)-5 (0.050 g, 0.19 mmol) in a 4/1 mixture of
MeOH and CH2Cl2 (4.3 mL). The reaction mixture was subsequently
stirred for 18 hours at room temperature, the organic solvents were
removed in vacuo and the residue was dissolved in a 2/1 mixture of
acetone and water (9.4 mL). Sodium hexafluoroacetylacetonate (0.108 g,
0.47 mmol) was added, and after stirring at room temperature for 18 hours,
the organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (5 ꢀ 10 mL). The combined organic layers were dried
over MgSO4, filtrated and evaporated in vacuo to give a brown solid.
Purification by flash column chromatography (SiO2–1% Et3N, 19%
EtOAc/petroleum ether then 2% MeOH/CH2Cl2) gave (Sp)-5 (0.028 g,
56% yield) and palladacycle (Sp)-7 (0.018 g, 33% yield—based on
Na2PdCl4) as a yellow glass solid. HPLC: Eurocel 1–5 mm chiral
column, 5% IPA/hexane 1 mL minꢁ1, (Sp)-7 5.96 min (98.90%),
(Rp)-7 10.24 min (1.10%). The ee of (Sp)-5 (75.2%) was determined
in the same way following conversion to 7 with Pd(OAc)2 and ligand
exchange with sodium hexafluoroacetylacetonate.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1991–1993 1993