Orthopalladated complexes as phase-transfer catalysts for asymmetric alkylation of achiral Schiff base esters

Article abstract of DOI:10.1007/s11243-010-9416-4

The asymmetric C-alkylation of benzophenone Schiff base glycine esters has been achieved using a palladium(II) chiral complex as a phase-transfer catalyst. The aromatic moiety around the metal center and various physicochemical parameters were investigated to study their effect on the asymmetric alkylation reaction under phase-transfer conditions. Moderate enantioselectivity(30-40%) was achieved under room temperature conditions, which is a significant improvement compared to no enantioselectivity with a chiral palladium-salen complex reported earlier. Computer simulation studies indicate that coordination of the metal center with Z-enolate forming a square planar complex provides a favorable steric environment where the α-carbon atom of the enolate is available for enantioselective alkylation.

Full text of DOI:10.1007/s11243-010-9416-4

Transition Met Chem (2010) 35:949–957
DOI 10.1007/s11243-010-9416-4
Orthopalladated complexes as phase-transfer catalysts
for asymmetric alkylation of achiral Schiff base esters
•
Dae Hyun Kim Jin Kyu Im Dae Won Kim
•
•
•
Hyunjoo Lee Honggan Kim Hoon Sik Kim
•
•
•
Minserk Cheong Deb Kumar Mukherjee
Received: 13 June 2010 / Accepted: 23 August 2010 / Published online: 11 September 2010
Ó Springer Science+Business Media B.V. 2010
Abstract The asymmetric C-alkylation of benzophenone
Schiff base glycine esters has been achieved using a pal-
ladium(II) chiral complex as a phase-transfer catalyst. The
aromatic moiety around the metal center and various
physicochemical parameters were investigated to study
their effect on the asymmetric alkylation reaction under phase-
transfer conditions. Moderate enantioselectivity(30–40%)
was achieved under room temperature conditions, which is
a significant improvement compared to no enantioselec-
tivity with a chiral palladium-salen complex reported ear-
lier. Computer simulation studies indicate that coordination
of the metal center with Z-enolate forming a square planar
complex provides a favorable steric environment where the
a-carbon atom of the enolate is available for enantiose-
lective alkylation.
Introduction
Asymmetric phase-transfer catalysis has been recognized
as a convenient tool for the synthesis of optically active
a-amino acid targets [1–6]. Several advantages like oper-
ational simplicity, mild reaction conditions in aqueous
media, environmental benefits and suitability of large scale
reactions have make phase-transfer reactions highly useful
in academia and industry. The first general synthesis of
racemic amino acids by phase-transfer catalysis (PTC)
based on the alkylation of glycine ester Schiff bases was
reported in 1978 [7]. Several chiral catalysts derived from
the cinchona alkaloids afforded optically active amino
acids in a room temperature enantioselective PTC process
[8–14]. In these reactions, a variety of alkyl halides were
used and either enantiomer of the product could be pre-
pared by selective use of the pseudoenantiomeric cincho-
nidine- or cinchonine-derived catalysts. Catalysts derived
from cinchonine and cinchonidine have been used exten-
sively in chiral PTC because the alkaloid precursors are
less expensive and can be easily tailored to give effective
phase-transfer catalysts. Polymer-supported quaternary
ammonium salts have also been successfully used in the
asymmetric alkylation reaction by various groups [15–20].
Although there are successful catalysts for phase-trans-
fer alkylation reaction, formation of C–C bonds through
direct alkylation using an orthopalladated complex was
unknown. In 1998, Belokon et al. reported [21, 22] the use
of sodium taddolate as a catalyst for the asymmetric
alkylation of alanine enolates. In subsequent years, this
group used chiral metal–salen complexes as phase-transfer
catalysts for asymmetric synthesis of a-methyl a-amino
acids. No model or mechanistic part has however been
discussed in their reported work [23]. The recent review
[24] on asymmetric alkylation reactions by Najera et al.
Electronic supplementary material The online version of this
article (doi:10.1007/s11243-010-9416-4) contains supplementary
material, which is available to authorized users.
D. H. Kim Á J. K. Im Á D. W. Kim Á H. S. Kim Á
M. Cheong (&) Á D. K. Mukherjee (&)
Department of Chemistry and Research Institute for Basic
Sciences, Kyung Hee University, 1 Hoegi-Dong,
Dongdaemun-Gu, Seoul 130-701, Republic of Korea
e-mail: mcheong@khu.ac.kr
D. K. Mukherjee
e-mail: debkumarmukherjee@rediffmail.com
H. Lee Á H. Kim
Energy Division, Korea Institute of Science and Technology,
Seoul 136 791, Republic of Korea
123

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Transition Met Chem (2010) 35:949–957
indicated that Cu(II) and Ni(II) salen complexes give
impressive enantioselectivity under PT conditions. No
enantioselectivity could be observed with the Pd-salen and
Pt-salen complexes under similar conditions. We have been
interested for some time in the application of phase-transfer
catalysis to the preparation of amino acid derivatives. The
optically active orthopalladated phenanthrylamine phase-
transfer catalyst has been produced and explored for
asymmetric glycine alkylation very recently by us [25].
The sterically hindered orthopalladated complex provided
asymmetric induction in benzophenone Schiff base sub-
strates under biphasic conditions. Prompted by the suc-
cessful results from the phenanthrylamine moiety in
PTC, we focused on different orthopalladated complexes,
hypothesizing that with the proper alignment of the
ammonium centers, optimum enantioselectivity would be
observed.
Mechanical stirring was performed at a constant agitation
rate by a magnetic stirrer. Initial products were dissolved in
CH2Cl2 and were added to the reactor. The start of the
reaction was measured after the addition of 50% aqueous
NaOH solution to the organic layer. Samples (0.1 mL)
were removed from the reactor after every 1 h, and the
concentrations of initial Schiff base were monitored by
HPLC assay.
Synthesis of di-l-acetatobis[(S,S)-9-(1-
(dimethylaminoethyl))-10-phenanthrenyl-C,N]
dipalladium(II)[26]; Complex-I
The orthopalladated complex (I), as reported in the litera-
ture [26], has been prepared by a slightly modified method.
The racemic form of 1-(9-phenanthryl)-ethylamine was
obtained in 60% yield upon the acid hydrolysis of the
reaction product between 9-acetyl phenanthrene and
ammonium formate at 180 °C. The racemic primary amine
was resolved using L(?)tartaric acid (Merck) as the
resolving agent. The enantiomer (-) variety was obtained
as a white solid in 30% yield. Methylation of the isolated
enantiomer with formic acid and formaldehyde gave the
corresponding N,N-dimethyl substituted amine as a color-
less oil in 60% isolated yield. Dipalladium acetato-bridged
complex (complex-I) was prepared by refluxing the
substituted amine with palladium(II) acetate in refluxing
acetic acid for 12 h [25]. This resulted in the formation of
the bridged complex as gray powder in 50% isolated yield.
The optically active l–chloro dimer (complex-II) could
be obtained efficiently by simply treating the palladium
acetato-bridged complex in CH2Cl2 with a solution of
ammonium chloride in water (yield * 70%). The corre-
sponding bromo complex (complex-III) was similarly
obtained in 60% isolated yield using a solution of ammo-
nium bromide.
We explored different reaction conditions such as tem-
perature variation from as low as -20 to 60 °C, different
alkylating agents from simple alkyl halides to robust
substituted aromatic halides and various solvents or solvent
mixtures in different ratios to promote effective displace-
ment reactions under phase-transfer conditions. Simulta-
neous computer simulation and model studies have been
made to focus on the nature of interactions involved and to
account for the role played by the many variables in
asymmetric induction mechanism. We believe that the area
of asymmetric induction by phase-transfer catalysis will
continue to grow as new catalysts, reagents and reaction
conditions are investigated as this methodology finds
application in the total synthesis of complex molecules.
Experimental
Analytical grade reagents and freshly distilled solvents
were used throughout our investigation. The palladium
complexes were prepared and characterized as per standard
literature methods with slight modifications done to suit
our experimental conditions. The Schiff base derivatives of
glycine were chromatographed on grade V basic alumina
with ethyl acetate in hexane as eluant. Vibrational, elec-
The purity of the complexes was checked by TLC,
IR and 1H NMR spectral data. 1H NMR (Complex-I)-
(DMSO-d6):d(ppm) = 2.1(s,6H), 2.41(d,3H), 2.47(d,3H),
2.66(s,3H), 2.75(s,3H), 2.88 (s,6H), 4.22(q,1H), 4.27
(q,1H), 7.4–8.7(m, 16H, aromatics); IR(KBr, pellets) 3100,
1734, 1610, 1535, 1398, 1166, 870, cm-1. Anal. Found: C,
57.9; H, 5.1; N, 3.3 Calcd for C36H36(CH3COO)2N2Pd2: C,
58.1; H, 5.1; N, 3.4.
1HNMR(Complex-II)(DMSO-d6):d(ppm) = 2.43(d,3H),
2.49(d,3H), 2.69(s,3H), 2.77(s,3H), 2.89 (s,6H), 4.25
(q,1H), 4.31(q,1H), 7.4–9.0(m,16H, aromatics); IR(KBr,
pellets)3096, 1614, 1530, 1160, 870, 650 cm-1. Anal.
Found: C, 55.2; H, 4.6; N, 3.5 Calcd for C36H36Cl2N2Pd2:
C, 55.4; H, 4.6; N, 3.6.
1
tronic and H NMR spectra were taken with Perkin Elmer
883, Shamadzu MPC-3700 and Bruker 400-MHz instru-
ments, respectively. The enantioselectivity was determined
by chiral HPLC analysis (chiracel OD, hexane:2-propanol
(99.5:0.5), flow rate 1 mL/min, 20 °C, k = 254 nm).
Optical rotation studies wherever necessary were deter-
mined on a Perkin Elmer 241 polarimeter using 1% solu-
tion in CH2Cl2.
For kinetic studies, the reaction was performed in a
50-mL three-necked round-bottomed flask submerged in a
water bath whose temperature was maintained at 20 °C.
1HNMR(Complex-III)(DMSO-d6):d(ppm) = 2.41(d,3H),
2.49(d,3H), 2.67(s,3H), 2.76(s,3H), 2.88 (s,6H), 4.22(q,1H),
4.3(q,1H), 7.4–8.7(m,16H, aromatics); IR(KBr, pellets)
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Transition Met Chem (2010) 35:949–957
951
3094, 1612, 1538, 1174, 872 cm-1. Anal. Found: C, 49.5;
H, 4.1; N, 3.2 Calcd for C36H36Br2N2Pd2: C, 49.7; H, 4.1; N, 3.2.
Anal. Found: C, 41.3; H, 4.6; N, 4.7 (Calcd for C20H28-
1
Cl2N2Pd2: C, 41.1; H, 4.8; N, 4.8). H NMR (DMSO-d6):
1.76, (d, 6H), 2.69 (s, 6H), 2.74 (s, 6H), 4.3 (q, 2H),
7.2–7.7 (m, 8H, aromatics). [a]D ?162.2 (c 1.0, CH2Cl2).
Synthesis of di-l-chloro-bis[(S,S)-(1-(dimethylamino-
ethyl))-2-Naphthylamine-C,N] dipalladium(II) [26, 27];
Complex-IV
Preparation of ethyl-N-diphenylmethylene
glycinate [29, 30]
l-dichloro-bis[(S,S)-(1-(dimethy1amino)ethyl]-2-naphtha-
lenyl-dipalladium(II)] was prepared from (S)-dimethy[1-
(1-naphthylethyl]amine and lithium tetrachloropalladate(II)
in the presence of triethylamine (1 eq.) in methanol (yield
88–90%) as described below.
The Schiff base ethyl-N-diphenylmethylene glycinate was
prepared in 77% isolated yield by refluxing benzophenone
(2.6 g, 14.3 mmol) with glycine ether ester (3.0 g,
21.5 mmol) in toluene (100 mL), containing a trace of
boron trifluoride etherate (BF3ÁEt2O). After refluxing for
24 h with a provision for removal of water (Dean Stark
apparatus), the crude product was obtained as an orange
liquid. This was distilled (195–200 °C/10-1 mbar) and
then recrystallized (ether/hexane) to give pure light yellow
solid (mp = 49–50 °C). 1H NMR and C13 NMR corre-
spond to the literature value [29], and the product is stable
in air at room temperature for extended periods of time.
1H NMR(DMSO-d6):d(ppm) = 1.2 (t, 3H), 4.2 (q, 2H),
4.2 (s, 2H), 7.1–7.7 (m, 10H); 13C NMR: 14.2, 55.7, 60.9,
127.6, 128, 128.7, 128.8, 130.4, 135.9, 139.2, 170.6, 171.8.
Palladium chloride (36.5 g) was dissolved in methanol
(400 mL) containing lithium chloride (18 g), and the
solution was filtered. To the filtrate was slowly added
(S)-dimethyl[1-(1-ethyl-2-naphthyl)]amine (82.2 g). After
6 h of stirring, the reaction mixture was filtered and the
yellow solid isolated. It was washed with cold methanol
and diethyl ether and then dried in vacuo (68.0 g, 88%
yield). Recrystallization of this material from dichloro-
methane-methanol mixture afforded the product as orange
crystals, mp 178 °C (62.5 g, 88–89%).
Anal. Found: C, 49.3; H, 4.6; N, 4.2 (Calcd for C28H32-
1
Cl2N2Pd2: C, 49.4; H, 4.7; N, 4.1) H NMR (DMSO-d6):
1.91, (m, 6H), 2.72 (s, 3H), 2.79 (s, 3H), 2.96 (s, 3H), 3.0
(s, 3H), 4.18 (br q, 1H) 4.22 (br q, 1H), 7.1–7.8 (m, 12H,
aromatics). [a]D ?170.2 (c 1.0, CH2Cl2).
Experimental procedure for the Pd-catalyzed
asymmetric alkylation
Palladium complex (0.05 mmol) was dissolved in methy-
lene chloride (1 mL). Aqueous KOH solution (50%,
0.5 mL) was added to a vigorously stirred solution of the
Schiff base (0.2 g, 0.70 mmol), metal complex and benzyl
bromide (1.2 eq, 0.1 mL, 0.85 mmol) in methylene chlo-
ride. The course of the reaction was followed by TLC
(eluent, n-hexane/ethylacetate, 90/10) until the starting
material was consumed. The suspension was diluted with
diethylether, and the organic layer was dried over Na2SO4,
filtered and concentrated in vacuum. Purification of the
residue by flash column chromatography on alumina 90
active basic (0.063–0.200 mm) afforded the alkylated
product as a colorless oil (yield generally [80%).
Synthesis of di-l-chloro-bis[(S,S)-(1-(dimethylamino-
ethyl))-benzylamine-C,N] dipalladium(II) [28]
Complex V
l-dichloro-bis[(S,S)-(1-(dimethy1amino)ethyl)-benzyl-
amine-
C,N]dipalladium(II) was prepared from (S)-dimethy[1-(1-
phenylethyl)]amine and lithium tetrachloropalladate(II) in
the presence of triethylamine (1 eq) in methanol (yield
78–80%) as described below.
Palladous chloride (18.2 g) was dissolved in methanol
(200 mL) containing lithium chloride (8.0 g), and the
solution was filtered. To the filtrate was slowly added
(S)-dimethyl[1-(1-ethyl-2-phenyl)]amine (41.2 g). After
4 h of stirring, the reaction mixture was filtered and the
white solid isolated. It was washed with cold methanol and
diethyl ether and then dried in vacuo (30.5 g, 80% yield).
Recrystallization of this material from dichloromethane-
methanol mixture afforded the product as white crystals,
mp 164 °C (26.2 g, 74%). The (R)–(–) form of the ben-
zylamine complex was obtained similarly (Complex VI)
by using the same procedure with (R)-dimethy[1-(1-phen-
ylethyl)]amine (97%, Aldrich chemicals) in approximately
60% yield.
Results and discussion
Catalytic alkylation of benzophenone imine glycinate
The orthopalladated dimeric complexes (Catalyst-I–V) and
the dimeric R-complex of the benzylamine variety (cata-
lyst-VI) were prepared by known literature methods
[26–28] (slight modifications undertaken as revealed in the
experimental section). These were then used as catalyst
precursors for phase-transfer alkylation reactions. With
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Transition Met Chem (2010) 35:949–957
ethyl-N-diphenylmethylene glycinate as substrate (sub-
strate-I) and methyl iodide as reactant (alkylating agent),
we achieved 35–40% enantiomeric excess (chiracel OD,
hexane:2-propanol (99.5:0.5); flow rate 1 mL/min, 20 °C,
k = 254 nm). tert-Butyl-N-diphenylmethylene glycinate
(substrate II) was used under similar phase-transfer con-
ditions to explore the steric effect. The temperature in all
the runs was maintained at 20 °C since lowering the tem-
perature up to -20 °C did not have much impact on the
percentage yield or the product composition (Table 1).
Chilling the reaction mixture, instead, lowered the rate of
conversion. A 50% aqueous sodium hydroxide solution and
1.2 equivalents of the alkylating agent have been used in
most of the runs under biphasic conditions. The effect of
various bases and different solvents on enantioselectivity is
discussed separately.
Scheme 1 Metal–salen complexes used in asymmetric alkylation
reactions [24]
to its closely related benzyl analog in alkylation reactions
(Table 2, comparison of catalytic runs 8, 9 and runs
12, 13).
Alkylation of the Schiff bases was explored using the six
set of catalysts (10 mol%) in dichloromethane with 50%
aqueous KOH at 20 °C. T he highest enantioselectivity was
achieved when methyl iodide was used as the electrophile
for the alkylation of tert-butyl glycinate benzophenone
Schiff base (40%, Table 2, entry 6). Under similar condi-
tions and using the same set of catalyst and the Schiff base,
lower enantioselectivity (15–20%) was noticed with benzyl
bromide as electrophile (Table 2, entry 14–16). Though we
expected better enantioselectivity with these alkylating
agents due to their extended planarity and steric bulkiness
compared to methyl iodide, we witnessed the opposite.
Lower enantioselectivity was however observed when the
ethyl ester was used as the substrate for alkylation com-
pared to the tert-butyl glycine esters as evident from the
catalytic runs 1, 3, and 5, 6 (Table 2). Though the differ-
ence in ee content is small, the trend of increased bulkiness
giving better selectivity is evident both from the viewpoint
of different glycine esters and different chiral palladium
complexes used in our studies. Acetato-, chloro- or bromo-
bridged ligands attached to palladium make no difference
as far as product yield, rate of alkylation or the enanti-
oselectivity is concerned.
Though the ee obtained was modest, it was the first
report of a chiral palladium complex to induce asymmetric
induction under phase-transfer conditions. Palladium and
Platinum salen complexes (Scheme 1) employed as phase-
transfer catalysts by different groups for such studies did
not yield any ee (Table 1).
Like the highly efficient cinchona alkaloid systems
previously employed for the above-mentioned reactions by
various groups, we believe that the enantioselectivity in our
case is attributed to the rigid orthometalated aromatic rings
(Scheme 2).
To verify, we prepared the three sets of catalysts based
on naphthylamine (catalyst-IV) and benzylamine moiety
(catalyst-V) as shown in Scheme 3, and the catalytic
studies were made under similar conditions. The naph-
thylamine complex has been found to be slightly superior
Table 1 Metal–salen complexes and the corresponding
obtained in asymmetric alkylation reactions [24]
% ee
Entry
Metal
Complex
Yield (%)
ee (%)
1
Ni?2
Cu?2
Mn?2
Fe?2
Co?2
Zn?2
Rh?2
Pd?2
Pt?2
1a
1b
1c
1d
1e
1f
54
91
15
34
82
39
92
56
55
46
66
21
30
81
01
03
80
01
14
01
00
07
00
00
The enantiomeric R-complex of palladium (complex-
VI) was also studied as the catalyst in the enantioselective
alkylation reaction of tert-butyl glycinate under similar
optimized conditions to find the match-mismatch effect.
The mismatch effect was evident as the R-variety of the
palladium complex gave the R-product and the S-variety
produced the S-product in major amounts (Table 2) under
similar phase-transfer conditions.
2
3
4
5
6
7
1g
1h
1i
8
9
10
11
12
Co?3
Co?3
Co?1
1j
Influence of bases and solvents
1k
1l
Different bases with varied concentrations were tried to
optimize the yield as well as the ee content of the alkylated
products. It was observed that 50% aqueous NaOH and
Methyl ester as substrate/50% aq NaOH/C6H5CH2Br(electrophile)/
toluene/RT/18 h
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Transition Met Chem (2010) 35:949–957
953
Scheme 2 Orthopalladated
phenanthryamine complex
employed in asymmetric
alkylation reaction
Me
Me
N
Me
Me
O
O
O
S
Pd
S
Pd
N
Me
O
Me
Me
Me
I
Scheme 3 Orthopalladated
complexes used as catalysts in
enantioselective alkylation
reaction
CH3
H3C
H3C
CH3
H3C
N
CH3
Pd
X
Me
N
Me
S
N
Me
S
Pd
X
2
X
Pd
2
2
X=OAc, catalyst- (S, enantiomer)
X=Cl, catalyst- (S, enantiomer)
X=Br, catalyst- (S, enantiomer)
X=C l, catalyst-
X=C l
catalyst- (S, enantiomer)
catalyst- (R, enantiomer)
Asymmetric alkylation of benzophenone imine
glycinate using different electrophiles
KOH solutions are more effective than solid–liquid phase-
transfer alkylation reactions employing solid bases like
KOH, K2CO3, NaOH, CsOH.H2O (Sigma) or Cs2CO3.
Using the much weaker base K2CO3 either in solid state or
in aqueous solution retards the rate of alkylation and nearly
20 h is needed to accomplish the same product yield
(80%). Organic solvents like toluene, chloroform, dichlo-
romethane and chlorobenzene were tried either individu-
ally or as mixed solvents in our investigation to improve
the ee of the alkylated products. We did not notice any
significant difference either in the rate or product compo-
sition. Effect of relative amount of aqueous NaOH and
dichloromethane as solvent on the rate of PTC alkylation
reveals that with decrease in ratio beyond 1:4, the rate drop
is significant (Fig. 1). We have therefore performed the
catalytic reactions using 0.5 mL 50% aqueous NaOH
solution and 1 mL of CH2Cl2 or toluene:chloroform (2:1)
under ambient temperature conditions.
Having optimized the reaction conditions, the alkylation of
tert-butyl benzophenone imine glycinate with a range of
other electrophiles was investigated and the results are
given in Table 3. For cinchona alkaloid catalyzed reac-
tions, it is known that the steric bulk of the glycine ester
and that of the alkylating agent are both important for
efficient asymmetric induction. However, this is not the
case for catalysis in our chiral palladium complexes.
Though the more bulky tert-butyl glycinate gave a slightly
better enantioselectivity compared to the ethyl esters, the
benzylic alkyl halides under the standard conditions gave a
low chemical yield and also low enantiomeric excess.
Simple alkyl halides like MeI and EtI exhibited the highest
activity and allylic bromides also gave good chemical
yields and moderate enantiomeric excesses.
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Transition Met Chem (2010) 35:949–957
Table 2 Alkylation of glycine derivatives under phase-transfer conditions using chiral orthopalladated complex
Entry No.
Catalyst used
Substrate
Electrophile
Solvent
Pdt/yield (%)a
ee (%)b
1
Complex-I
Complex-I
Complex-I
Complex-II
Complex-II
Complex-II
Complex-III
Complex-IV
Complex-V
Complex-VI
Complex-VI
Complex-VI
Complex-IV
Complex-III
Complex-II
Complex-I
Complex-I
Complex-I
I
CH3I
CH2Cl2
Ia/84
24
26
38
30
33
40
38
30
25
28
22
12
15
18
17
15
05
17
2
I
CH3I
PhMe:CHCl3
CH2Cl2
Ia/70
3
II
I
CH3I
IIa/86
Ia/88
4
CH3I
CH2Cl2
5
I
CH3I
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
PhMe:CHCl3
Ia/86
6
II
II
II
II
II
I
CH3I
IIa/90
IIa/85
IIa/88
IIa/85
IIa/86
Ia/84
7
CH3I
8
CH3I
9
CH3I
10
11
12
13
14
15
16
17c
18d
CH3I
CH3I
II
II
II
II
II
II
II
C6H5CH2Br
C6H5CH2Br
C6H5CH2Br
C6H5CH2Br
C6H5CH2Br
C6H5CH2Br
C6H5CH2Br
IIb/78
IIb/75
IIb/75
IIb/78
IIb/84
IIb/70
IIb/72
Alkylating agent: benzyl bromide(b)/methyl iodide(a), T = 20 °C, time = 12 h
* Absolute configuration of products was determined to be (S) from literature data for catalysts I–V and (R) for catalyst-VI
a
Isolated crude oil before column chromatography
1
Determined by H NMR, HPLC and optical rotation studies
b
c
d
A higher temperature of 50 °C was employed
A lower temperature of -20 °C was employed
Table 3 Alkylation of tert-butyl-N-(diphenylmethylene)glycinate
(substrate II) with different electrophiles under phase-transfer
conditions
1 4
1 2
1 0
8
Alkylating agent
Product
yield (%)
Enantiomeric
excess (%)
C6H5CH2Br
4-O2NC6H4CH2Br
CH2=CHCH2Br
PhCH=CHCH2Br
CH3I
78
70
84
80
90
88
15
10
30
22
40
35
6
4
2
0
10:10
5:10
2.5:10
1.5:10
1:10
CH3CH2I
Vol. 50% aq.NaOH/Vol. CH2 Cl2
Catalyst: orthopalladated l–chloro dimer (complex-II, 10 mol%);
solvent: PhMe:CHCl3(2:1); T = 20 °C; time = 12 h; Base = 50%
Aq. KOH
Fig. 1 Effect of relative amount of aqueous NaOH on rate of PTC
alkylation
diethyl ether, the catalyst appeared as a white solid
between the lower aqueous layer and the upper organic
layer. After stirring vigorously for 5 min, this white solid
adhered to the reaction vessel. The solid was easily sepa-
rated by simple decantation and reused without further
purification. The recovered catalyst under the same phase-
transfer alkylation condition showed the same catalytic
efficiency (86% yield, 26% ee) with methyl iodide.
Catalyst recovery and reuse
In contrast to commonly used cinchona alkaloid derived
catalysts, the chiral palladium complexes are stable and
suffer no decomposition under phase-transfer conditions.
As a result, we recovered the benzylamine chloro complex
(catalyst-V) from the reaction mixture by simple decanta-
tion. After quenching the reaction with deionized water and
123

Transition Met Chem (2010) 35:949–957
955
Computational studies with the chiral palladium
complex
the alkaloid species (Scheme 5). For the chiral palladium
complexes, the bridged dimer species spontaneously disso-
ciates into the monomer solvent adduct and immediately
combines with the Z-enolate to form a stable square planar
species. This mode of bonding actually prevents the enolate
component to be solvated or racemized in strongly basic
solution and explains why the different bridging ligands in
complexes I to III do not affect enantioselectivity. The
enolate with the catalyst is successfully transferred to the
organic layer where it is lined up in the sterically most
favorable geometry with the alkyl halide (alkylating agent).
Only the appropriate re face or the si face of the a-carbon of
the enolate is available for electrophilic attack leading to the
observed R and S products, respectively.
Computer simulations have been made to examine the
complexes formed and the nature of interactions between the
chiral phase-transfer catalyst and enolates that are known to
be alkylated enantioselectively. A similar molecular recog-
nition technique and computational tool has been employed
by Lipkowitz et al. [31] although their catalysts, used as
asymmetric templates, were derived from the cinchona
alkaloid family. It has already been reported [32] that the
benzophenone imine anions can exist as E- or Z-enolates and
that with a metal ion like lithium the Z-enolate has been
found to be more stable. The palladium metal in our studies
should therefore associate with the N and O- atoms simul-
taneously to stabilize the Z-enolate by orbital interactions or
by coulombic attractions (Scheme 4). The four-coordinated
square planar geometry of the palladium complex with the
enolate has therefore been considered as a computational
tool to initialize the energy minimization steps.
The interactions between the Z-enolate form of glycine
derivative and palladium chiral catalysts were theoretically
investigated using the Gaussian 03 program [35]. The
geometry optimizations and thermodynamic corrections
without including the bulk solvent effect were performed
with hybrid Becke 3-Lee–Yang–Parr (B3LYP) exchange–
correlation functional with the 6-31?G* basis sets for
C, H, N and O, and LanL2DZ(ECP) basis sets for S and Pd.
In order to obtain the most stable geometries, all kinds of
possible interaction patterns were optimized. No restric-
tions on symmetries were imposed on the initial structures.
All stationary points were verified as minima by full
A detailed molecular mechanism has been described for
the phase-transfer catalyzed enantioselective alkylation of
an enolate with the chiral quaternary cinchonidinium salt by
Corey et al. [33, 34]. In their mechanistic model, contact ion
pairing takes place between the anionic oxygen of the enolate
and just one of the tetrahedralfacesof the cationic nitrogenof
Scheme 4 Coordination of the
Pd-chiral complex to the
Z-enolate under PT conditions
Pd +2
Pd-chiral complex(S)
O
O
-
O
(10 mol%)
(S)
Ph
Ph
N
t-Bu
Ph
Ph
N
H
t-Bu
O
O
Ph
Ph
N
t-Bu
50% KOH(aq)
PhCH2Br(1.2 equiv.)
CH2Cl2, 20°C, 12h
O
CH2Ph
(Alkylated enantiomer)
Scheme 5 General phase-
transfer mechanism for
asymmetric alkylation of active
methylene compounds
OtBu
O
RX
Ph2C
N
Ph2C
MX
*
N
OtBu
OQ*
R
(Organic phase)
Q*X
Asymmetric induction
O
Ph2C
N
OtBu
OtBu
OM
RX
Racemic Product
Ph2C
N
interface
(Aqueous phase)
MOH
H2O
123

956
Transition Met Chem (2010) 35:949–957
Fig. 2 Chiral palladium benzyl
complex (S-enantiomer)
coordinated to Z-enolate
Acknowledgments This work was financially supported by
National Energy Resources Technology Development R&D Program
for Greenhouse Gas Mitigation under the Korea Ministry of Knowl-
edge Economy.
calculation of the Hessian and a harmonic frequency
analysis. tert-Butyl-N-diphenylmethyleneglycinate has been
taken as the reference substrate in all model computational
studies with chiral palladium complexes.
Analysis based on findings
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