Palladium-catalyzed allylic alkylation of tert-butyl(diphylmethylene)-glycinate with simple allyl esters under chiral phase transfer conditions

Article abstract of DOI:10.1016/S0957-4166(01)00276-2

The first example of palladium-catalyzed allylic alkylation of an imino ester with simple allyl esters in the presence of a chiral quaternary ammonium salt is reported. The presence of molecular sieves was found to have a beneficial effect on the enantioselectivity of the reaction by scavenging water from the system. Alkylated products with e.e.s of up to 61% were obtained.

Full text of DOI:10.1016/S0957-4166(01)00276-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1567–1571
Palladium-catalyzed allylic alkylation of
tert-butyl(diphylmethylene)-glycinate with simple allyl esters
under chiral phase transfer conditions
a
a
a,
a,
a
a
Guoshu Chen, Yijian Deng, Liuzhu Gong, * Aiqiao Mi, * Xin Cui, Yaozhong Jiang,
b
b
Michael C. K. Choi and Albert S. C. Chan
a
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
b
Open Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, China
Received 2 April 2001; accepted 12 June 2001
Abstract—The first example of palladium-catalyzed allylic alkylation of an imino ester with simple allyl esters in the presence of
a chiral quaternary ammonium salt is reported. The presence of molecular sieves was found to have a beneficial effect on the
enantioselectivity of the reaction by scavenging water from the system. Alkylated products with e.e.s of up to 61% were obtained.
©
2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
however the enantioselectivity was not high with simple
allyl acetates as substrates. Although the highly enan-
3
The synthesis of non-proteinogenic amino acids has
been an area of great interest, since they have been
employed as building blocks for the preparation of
tioselective alkylation of imino esters under chiral PTC
conditions has been reported, this transformation suf-
4
fers from the limitation of the allyl halide sources and
thus it is difficult to extend this procedure to synthesize
enantiomerically pure amino acids containing allyl
groups. A potentially promising procedure for the
preparation of allyl amino acids involves combining a
palladium catalyst with a chiral PTC as co-catalyst to
promote the allylic alkylation of an imino ester, which
would avoid the disadvantages of both Pd-catalyzed
1
products with biological activities. Among them, com-
pounds containing an allyl moiety are of particular
interest, because they can be easily transformed into a
wide range of novel non-proteinogenic amino acids by
2
simple reactions. Recently, imino esters were used as
nucleophiles in palladium-catalyzed asymmetric allylic
alkylation reactions to afford alkylated amino acids,
R1
R2
R2
Ph
Palladium, Phosphine
PTC, CsOH.H2O, Solvent
R1
OR3
+
t
Ph
Ph
N
CO2 Bu
*
t
N
CO Bu
2
Ph
1
a-1e
2
3
a-3c
1
2
3
1
2
3
1
1
1
1
a. R = H, R = H, R = Ac;
1b. R = Ph, R = H, R = Ac;
1
2
3
3
3
a. R =H, R =H;
1
2
3
1
2
3
c. R =H, R =H,R =Boc;
1d. R =H, R =H, R =COOEt;
1
2
b. R =Ph, R =H;
1
2
3
1
2
3
e. R = Ph, R = H, R = Boc; 1f. R =Ph, R =H,R =COOEt;
1
2
c. R =H, R =Me;
1
2
3
g. R =H, R =Me, R =Ac
Scheme 1.
*
Corresponding authors.
0
957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00276-2

1
568
G. Chen et al. / Tetrahedron: Asymmetry 12 (2001) 1567–1571
asymmetric allylic alkylation and phase transfer cata-
lyzed alkylation methodologies. Herein, we report our
preliminary efforts directed towards this transformation
enantioselectivity, we observed that molecular sieves
(MS) could improve the e.e. of the products. This result
prompted us to study the function of the MS additive
in this reaction. The results are summarized in Table 2.
(
Scheme 1).
Br-
Cl-
Br-
Br-
OBn
OH
OBn
N
+
N
+
O
N
+
N
+
H H
H H
H
H
H H
N
N
N
N
4
5
6
7
2
. Results and discussion
Without molecular sieves in the reaction system, only
0% e.e. was induced by PTC 7 (entry 1). The e.e.s were
improved to 59 and 61%, respectively, by addition of
the 3 A and 4 A MS in the reaction mixture (entries 2
4
2
.1. The Pd complexes catalyzed allylic alkylation of
,
,
iminoester 2 with allyl estate 1a in the presence of
and 3). In other reactions, such as the Heck reaction,
Sharpless epoxidation, aziridation etc., the similar
beneficial effects of MS on the enantioselectivity were
also found. However, the function of MS was quite
chiral ammonium salts 4–7
In the presence of 1 mol% palladium complex, 2.5
mol% PPh , the allylic alkylation of imino ester 2 with
allyl acetate 1a in toluene was investigated using 10
mol% of each of the chiral PTCs 4–7. The results are
summarized in Table 1.
3
5
different in these reactions. Comparison of entries 2
and 4 in Table 2 indicates that the beneficial effect on
the enantioselectivity results from the water-scavenging
property of MS. With dry 3 A
additives, e.e.s of up to 61% were obtained. However,
when water-saturated 3 A MS was added to the reac-
and 4 A MS as the
, ,
The allyl ester reacted smoothly with the imino ester 2,
leading to the product 3a in high yield, but the enan-
tioselectivity was poor. Of the chiral PTCs 4–7, 7
developed by Corey induced the best enantioselectivity
for this transformation. By comparing entries 2 and 4,
it was found that the allylic group bonded to oxygen on
the chiral PTC played an important role for the
improvement of the enantioselectivity. [Pd(allyl)Cl]2
behaved a little more efficiently in both reactivity and
,
tion mixture, the product e.e. dropped to 35% (entry 4).
In a biphasic water/toluene system e.e. of only 10% was
obtained (entry 5). The detrimental effect of water on
Table 2. The effect of molecular sieves on the
a
enantioselectivity
Entry
Additive
Time (h)
Yield (%)b
E.e. (%)c
enantioselectivity than Pd(dba) (entries 6 and 7). Using
2
CH Cl in place of toluene as solvent resulted in lower
1
2
3
4
–
12
8
8
94
99
89
82
40
59
61
35
2
2
3 A
4 A
3 A
,
MS
MS
MS
reactivity and enantioselectivity (entries 5 and 6). Low-
ering the temperature to 0°C led to higher e.e. of 40%
,
,
12
(
entry 4). However, further lowering the reaction tem-
(
H O)
2
perature to −78°C resulted in a dramatic decrease in
both yield and enantioselectivity (entry 8).
5
H O
12
55
10
2
a
The reaction of 1a with 2 was carried out in the presence of 1 mol%
Pd(allyl)Cl]2 and 2.5 mol% PPh3 with toluene as solvent.
Isolated yield based on imino ester.
Determined by HPLC.
2.2. The effect of molecular sieves
[
b
c
During investigation of the effect of additives on the
Table 1. The Pd complexes catalyzed allylic alkylation of imino ester 2 with allyl acetate 1a under PTC conditions
Entry
Pd
PTC
Solvent
Temp. (°C)
Time (h)
Yield (%)a
E.e. (%)b
1
2
3
4
5
6
7
8
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(dba)2
4
5
6
7
7
7
7
7
Toluene
Toluene
Toluene
Toluene
CH Cl
Toluene
Toluene
Toluene
0
0
0
14
12
12
12
27
3
92
87
91
94
80
92
80
15
3
0
12
40
27
30
27
14
0
25
25
25
−78
2
2
24
30
[Pd(allyl)Cl]2
a
Isolated yield based on imino ester.
Determined by the HPLC.
b

G. Chen et al. / Tetrahedron: Asymmetry 12 (2001) 1567–1571
1569
was concluded that (S)-BINAP and PTC-7 were mis-
matched and resulted in decreased enantioselectivity.
Using (R)-BINAP as a chiral phosphine ligand in the
presence of PTC 7, the e.e. increased markedly to 60%
and the (S)- enantiomer predominated, a similar
product yield and e.e. was also obtained from the
the selectivity of the reaction probably results from the
destruction of the tight ion pair formed between the
chiral quaternary ammonium salt and the enolate by
water.
2.3. The effect of chiral phosphines
reaction with PTC 7 in the presence of PPh (entries 3
3
and 4).
In order to make further improvements in the selectiv-
ity, we replaced PPh with homochiral phosphine lig-
3
ands. We expected that double chiral induction would
occur in the palladium-catalyzed allylic alkylation in
the presence of two-component catalyst of chiral phos-
phine and chiral ammonium salt. As shown in Table 3,
2.4. Asymmetric allylic alkylation of imino ester with
different allyl esters
Under the optimal conditions, we extended the reaction
to other simple allyl substrates. These results are sum-
marized in Table 4. It seemed that the substituents on
the allylic compounds might affect the reaction, com-
pounds containing more steric hindrance groups led to
lower reactivity and enantioselectivity. For instance,
+
−
using (S)-BINAP as the ligand with n-Bu N Br as
4
phase transfer catalyst gave product with only 39% e.e.
with the (R)-enantiomer predominating (entry 1).
Employing the chiral ammonium bromide 7 in place of
+
−
n-Bu N Br , led to poor e.e. of 20% (entry 2). Thus, it
4
Table 3. The palladium-catalyzed allylic alkylation of imino ester with 1a in the presence of chiral BINAP and phase
a
transfer catalyst
Yield (%)b
E.e. (%) (config.)
c
d
Entry
Ligands
PTC
Time (h)
+
−
1
2
3
4
(S)-BINAP
(S)-BINAP
(R)-BINAP
PPh3
n-Bu N Br
24
24
24
8
69
75
98
95
39 (R)
20 (R)
60 (S)
59 (S)
4
7
7
7
a
The reaction was carried out at 0°C in the presence of 1 mol% of [Pd(allyl)Cl]2 and 2.5 mol% of phosphine with 3 A MS.
,
b
c
Isolated yield based on imino ester.
Determined by HPLC.
d
Determined by comparison of the optical rotation with the literature value.4a
Table 4. Palladium-catalyzed asymmetric allylic alkylation of imino ester with different allyl esters in the presence of chiral
ammonium bromide 7

1
570
G. Chen et al. / Tetrahedron: Asymmetry 12 (2001) 1567–1571
5
9% e.e. was obtained for substrate 1a (entry 1), but
eluting with petroleum ether–ether (7:1) to give the
there were small decreases in the enantioselectivities for
the products from substrates 1b and 1g of 55 and 47%
e.e., respectively (entries 2 and 7). The branched prod-
ucts for allyl esters 1b, 1e and 1f were not observed
from this transformation. Better leaving groups, on the
substrates (1c–1f), such as carbonate, resulted in dra-
matic decreases in selectivity for the transformation
products.
3a: 95% yield, 59% e.e. with (S)-isomer major was
determined by HPLC (Chiralcel OD column, heptane-
2-propanol, 99.5:0.5, u=254 nm); flow rate: 0.5 mL/
min; S-isomer, t
min. The NMR data are consistent with those reported
10.64 min and R-isomer t 11.72
R
R
4a
(
entries 3–6).
in the literature.
3
b: 64% yield, 55% e.e. was determined by HPLC
Chiralcel OD column, heptane-2-propanol, 99.5:0.5,
u=254nm); flow rate: 1.0 mL/min; t -major 9.45 min
(
3. Conclusion
R
1
and t -minor 12.83 min. H NMR (300 MHz,CDCl ) l
The first example of palladium-catalyzed allylic alkyl-
ation of imino ester with simple allylic substrates in the
presence of chiral quaternary ammonium salts was
presented. Molecular sieve additives improved the
enantioselectivity by scavenging water from the reac-
tion system. This catalyst system exhibited high reactiv-
ity and gave products with moderate e.e.s of up to 61%.
R
3
(
ppm) 1.48 (s, 9H, C(CH ) ), 2.80–2.87 (m, 2H), 4.11–
3 3
4
.15 (t, J=7.2 Hz, 1H, NCH), 6.13–6.22 (m, 1H,
PhCꢀCH), 6.45 ( d, J=15.0 Hz, 1H, PhCHꢀC), 7.18–
−
1
13
7
.68 (m, 15H, ArH); IR: w /cm 1729 (CꢀO);
C
max
NMR (75 MHz, CDCl ) l (ppm) 28.0, 37.3, 66.1, 81.0,
3
1
1
26.0, 126.4, 127.0, 127.9, 128.3, 128.4, 128.5, 128.8,
30.2, 132.4, 136.6, 137.4, 139.6, 170.2, 170.8; MS (ESI)
+
+
m/e 412.4 (M+H ), 434.3 (M+Na , 100).
4
. Experimental
3
c: 92% yield, 47% e.e. was determined by HPLC
(
Chiralcel OD column, heptane/propan-2-ol, 99.5:0.5,
4
.1. General data
u=254 nm); flow rate: 1.0 mL/min; (S)-isomer, t 5.45
R
min and (R)-isomer tR 7.59 min. The NMR data are
All allylic substrates were prepared from the corre-
sponding allyl alcohols. The chiral phase transfer cata-
4
a
6
consistent with those reported in the literature.
lysts 4–6 were prepared according to the literature
4
a
procedures and compound 7 was purchased from
Aldrich. Toluene was distilled from sodium benzophe-
none ketyl under nitrogen. Dichloromethane was dis-
Acknowledgements
tilled from CaH . The palladium complexes were gifts
from Professor Yoshinori Yamamoto at Tohoku Uni-
versity in Japan.
2
We are grateful for the financial support from the
National Science Foundation of China (29790124,
2
9972040) and the Hong Kong Polytechnic University
ASD6 Fund. We also thank Professor Yoshinori
Yamamoto at Tohoku University in Japan for his
generous gifts of palladium complexes.
Melting points were measured on a digital melting
point apparatus and were uncorrected. Mass spectra
were recorded on Finnigan LCQ DECA instrument. IR
spectra were obtained on a Nicolet 200SXV spectrome-
1
13
ter. H NMR and C NMR spectra were recorded on
a Bruker AC-E 300 instrument. Product e.e.s were
determined by HPLC on a Beckman-110A chromatog-
raphy with a Backman 165 variable wavelength detec-
tor. The Chiralcel OD column was purchased from
Daicel Chemical Industries, Ltd.
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