Palladium(II)-catalyzed one-pot enantioselective synthesis of arylglycine derivatives from ethyl glyoxylate, p-toluenesulfonyl isocyanate and arylboronic acids

Article abstract of DOI:10.1002/adsc.200700362

A palladium(II)-catalyzed, one-pot enantioselective synthesis of arylglycine derivatives from ethyl glyoxylate, p-toluenesulfonyl isocyanate and arylboronic acids giving moderate to good yields and enantioselectivity has been developed. This reaction prov

Full text of DOI:10.1002/adsc.200700362

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DOI: 10.1002/adsc.200700362
Palladium(II)-Catalyzed One-Pot Enantioselective Synthesis of
Arylglycine Derivatives from Ethyl Glyoxylate, p-Toluenesulfonyl
Isocyanate and Arylboronic Acids
Huixiong Dai,a Miao Yang,a and Xiyan Lua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: xylu@mail.sioc.ac.cn
Received: July 24, 2007; Revised: November 20, 2007; Published online: January 4, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A palladium(II)-catalyzed, one-pot enan-
tioselective synthesis of arylglycine derivatives from
ethyl glyoxylate, p-toluenesulfonyl isocyanate and
arylboronic acids giving moderate to good yields
and enantioselectivity has been developed. This re-
action provides a convenient and efficient method
for the synthesis of arylglycines.
amino acid derivatives and b-lactams.[7] Holmes re-
ported the preparation of imino esters by the thermal
[2+2]cycloaddition of p-toluenesulfonyl isocyanate
and methyl glyoxylate (Scheme 1).[8] The reaction
took place in refluxing toluene to give a solution of
the imino ester which was at least 80% pure as
1
judged by H NMR, and could be used in situ in sub-
sequent reactions. It occurred to us that it should be
possible to combine the synthesis of the imino esters
and Pd(II)-catalyzed enantioselective synthesis of
arylglycines in one-pot to enhance the synthetic effi-
ciency.
Keywords: arylboronic acids; arylglycines; enantio-
selectivity; one-pot reaction; palladium
Our group has recently reported the Pd(II)-cata-
lyzed conjugate addition of arylboronic acids to a,b-
As a non-proteinogenic class of amino acids, arylgly- unsaturated carbonyl compounds[9] and the addition
cines are applied extensively in drugs, many b-lactam of arylboronic acids to nitriles.[10] It was found that
antibiotics, and cardiovascular agents.[1] The synthesis the ligand 2,2’-bipyridine (bpy) is crucial in these re-
of optically active arylglycines has received much at- actions. The presence of the bpy ligand in these reac-
tention[1,2] and the application of asymmetric catalysis tions might influence the arylpalladium species from
towards the formation of these compounds is a funda- being electrophilic to being more nucleophilic,
mental challenge.[3,4]
making the above addition reactions possible. It oc-
Ellman reported a diastereoselective synthesis of curred to us that bpy may also be useful in the addi-
arylglycine derivatives by the rhodium-catalyzed addi- tion reaction of arylboronic acids to imines catalyzed
tion of arylboronic acids to N-tert-butanesulfinylimino by Pd(II) species.
esters,[5] which proceeds in high yields with very high
Initially, we investigated the reaction of p-toluene-
diastereoselectivity for both electron-rich and elec- sulfonyl isocyanate (1) (0.355 mmol) with ethyl glyox-
tron-poor arylboronic acids. Recently, we reported a ylate (2) (0.355 mmol) in refluxing toluene (2 mL) for
similar work using cationic palladium catalysis.[6] two days, after which Pd
(OAc)2 (5 mol%), 2,2’-bipyri-
N
However, to the best of our knowledge, there is no dine (bpy, 6 mol%) and phenylboronic acid (3a)
report about a catalytic enantioselective synthesis of (0.71 mmol) were added. To our delight, the reaction
arylglycines based on the transition metal-catalyzed
addition of arylboronic acids to imino acids or esters.
Herein, we report a palladium(II)-catalyzed, one-pot
enantioselective synthesis of arylglycine derivatives
from ethyl glyoxylate, p-toluenesulfonyl isocyanate
and arylboronic acids that gives moderate to good
yields and enantioselectivity.
Imino esters are excellent electrophilic substrates
for the synthesis of the optically enriched a- and b- isocyanate and methyl glyoxylate.
Scheme 1. Formation of imino esters from p-toluenesulfonyl
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Huixiong Dai et al.
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Table 1. Screening of the ligands.[a]
proceeded to yield the addition product 4a in 53%
yield after refluxing for additional 24 h (Table 1,
entry 1).
To achieve the asymmetric addition, we screened
some homochiral nitrogen-containing and diphos-
phine ligands instead of the bpy as shown in Table 1.
We initially employed the easily available monooxa-
zoline (pymox) and bisoxazoline as ligands. When
bisoxazoline was used, no addition products were ob-
tained (Table 1, entries 2 and 3). When using the
pymox instead of the bpy ligand, the reaction did pro-
ceed smoothly. It was found that the different sub-
stituents on the oxazoline ring significantly affected
the enantioselectivity of the reaction (Table 1, en-
tries 4–6). The employment of (S)-pymox-Bn (9) as
the ligand led to the highest enantioselectivity (up to
80% ee). Upon use of diphosphines as the ligand, no
addition product was formed (Table 1, entries 7–9).
With these results in hand, further efforts to im-
prove the yield were made. In our reaction, the time
of first step (step a) could be shortened by the addi-
tion of a catalytic amount of AlCl3.[11] First, we inves-
tigated the reaction of 1 (0.355 mmol), 2 (0.355 mmol)
and AlCl3 (10 mol%) in refluxing toluene (2 mL) for
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
bpy
5
6
7
8
53
-
-
-
37
48
80
-
-
-
3 h, after which the Pd(OAc)2 (5 mol%), ligand 9 (6
A
trace
trace
42
45
51
NR
NR
trace
mol%) and 3a (0.71 mmol) were added. Unfortunate-
ly no addition product was formed (Table 2, entry 2).
In view of the strong Lewis acidity of cationic Pd(II)
complexes,[12] Pd
AlCl3 and Pd
tained (Table 2, entry 3). When the combination of
Pd(CF3CO2)2 and ligand 9 was used, a satisfactory
ACHTREUNG
9
10
11
12
AHCTREUNG
AHCTREUNG
[a]
result (65% yield and 76% ee) was obtained (Table 2,
entry 4). Limited improvement was made by utilizing
Reaction conditions: 1 (0.355 mmol) and 2 (0.355 mmol)
in refluxing toluene (2 mL) for two days, then Pd(OAc)2
AHCTREUNG
Pd
N
N
(5 mol%), ligand (6 mol%) and 3a (0.71 mmol) were
added with refluxing for additional 24 h.
Isolated yields.
value but a lower yield (35%) (Table 2, entry 5). Slow
addition of phenylboronic acid (3a) to maintain the
low concentrations of 3a might favor the imine addi-
[b]
[c]
Determined by HPLC analysis using a Chiralcel column.
Table 2. Optimization of the reaction conditions.[a]
Entry
Step a
Step b
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
reflux 48 h
AlCl3 (10 mol%), reflux 3 h
Pd
Pd
C
51
80
-
-
76
84
38
NR
NR
65
35
77
Pd
Pd(CF3CO2)2 + L-9, reflux 3 h
Pd(OAc)2 + L-9, reflux 3 h
Pd(CF3CO2)2 + L-9, reflux 3 h
A
L-9 + 3a, reflux 24 h
3a, reflux 24 h
3a, reflux 24 h
E
E
C
3a (slow addition 24 h), reflux 24 h
[a]
Reaction conditions: p-toluenesulfonyl isocyanate (1, 0.355 mmol) with ethyl glyoxylate (2, 0.355 mmol), Pd
ACHTREUNG
Pd(CF3CO2)2 (5 mol%), phenylboronic acid (3a, 2 equivs.), L-9 (6 mol%) in refluxing toluene (2 mL), detailed conditions
ACHTREUNG
see Table 1.
Isolated yields.
Determined by HPLC analysis using a Chiralcel column.
[b]
[c]
250
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Palladium(II)-Catalyzed One-Pot Enantioselective Synthesis of Arylglycine Derivatives
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Table 3. Palladium(II)-catalyzed, one-pot enantioselective
synthesis of arylglycine derivatives from ethyl glyoxylate, p-
toluenesulfonyl isocyanate and arylboronic acids.[a]
light, with arylboronic acids bearing electron-with-
drawing groups, which are not efficient for the Petasis
reaction[3] and the Jorgensen reaction,[4] this reaction
can proceed successfully (Table 3, entries 4–7). The
yield from b-naphthylboronic acid was higher than
that with a-naphthylboronic acid (Table 3, entries 10
and 11). Sterically hindered ortho-substituted arylbor-
onic acids are problematic for our reaction (Table 3,
entries 11 and 12).
Entry
Ar
Product
Yield [%][b]
ee [%][c]
75 (+)[d]
70 (+)
75 (+)
81 (+)
64 (+)
68 (+)
71 (+)
70 (+)
72 (+)
-
In the case of using b-naphthylboronic acid as the
substrate, a by-product 4i’ (yield: <5%) was observed
(Scheme 2), which might be formed from the reaction
of ethyl glyoxylate (2) and b-naphthylboronic acid.
However, the amount of 4i’ apparently did not in-
crease when only ethyl glyoxylate (2) and b-naphthyl-
boronic acid were reacted under the optimized reac-
tion conditions, implying that the reactivity of ethyl
glyoxylate (2) is less than that of the the imino ester
and our reaction will not be affected.
The absolute configuration of product 4a was deter-
mined as (S) by comparison with the optical rotation
of the sample synthesized from (S)-phenylglycine.
The removal of the tosyl group from similar amino
acids has been reported with no detectable racemiza-
tion.[3d,f]
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
65
71
57
73
64
63
61
73
60
35
23
-
4-CH3C6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
3-NO2C6H4
4-CF3C6H4
3-CH3C6H4
b-naphthyl
a-naphthyl
2-CH3C6H4
2-ClC6H4
9
10
11
12
4j
4k
4l
-
-
[a]
Reaction conditions: p-toluenesulfonyl isocyanate (1,
0.355 mmol), ethyl glyoxylate (2, 0.355 mmol),
Pd(CF3CO2)2 (5 mol%), L-9 (6 mol%) in refluxing tolu-
ene (2 mL) for 3 h, then phenylboronic acid (3a,
0.71 mmol) was added and reflux comtinued for addition-
ACHTREUNG
The possible mechanism for the addition reaction
of arylboronic acids to the imino esters is shown in
al 24 h.
Isolated yields.
[b]
[c]
Determined by HPLC analysis using a Chiralcel column. Scheme 3. First, the combination of Pd
(CF3CO2)2 and
G
The sign of optical rotation is indicated in parentheses.
The absolute configuration of compound 4a was deter-
mined as (S) (see Supporting Information).
ligand 9 generated the palladium species B, which can
act as a Lewis acid to catalyze the formation of imino
esters. Meanwhile, transmetalation of arylboronic acid
with palladium species B forms the arylpalladium spe-
[d]
tion to provide higher yields.[13] As expected, the yield cies C, which can be coordinated with imino esters
was enhanced to 77% but the ee value decreased to giving intermediate D or D’.[7,14] The palladium spe-
38% (Table 2, entry 6).
cies can activate the imino group due to its Lewis
On the basis of the optimization of the reaction acidity. In addition, both the 1,4-binding mode D and
conditions, the scope of this reaction with various the 1,3-binding mode D’ of the imino esters to palla-
aryl-substituted boronic acids was explored. This reac- dium make the addition of the aryl group to the
tion is tolerant of many functional groups. Arylboron- imines go in a highly selective manner to produce the
ic acids with either electron-neutral groups or elec- addition product E, which upon hydrolysis forms
tron-donating groups could smoothly add to the product 4 and regenerates the catalytically active spe-
imino ester (Table 3, entries 1–3 and 8). To our de- cies B to complete the catalytic cycle.
Scheme 2. Formation of a by-product from b-naphthylboronic acid.
Adv. Synth. Catal. 2008, 350, 249 – 253
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Huixiong Dai et al.
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Scheme 3. Proposed mechanism for the palladium(II)-catalyzed one-pot enantioselective synthesis of arylglycines from ethyl
glyoxylate, p-toluenesulfonyl isocyanate and arylboronic acids.
filtered, and concentrated under reduced pressure. The resi-
In conclusion, a palladium(II)-catalyzed one-pot
due was purified by flash column chromatography (eluent:
EtOAc/petroleum ether) to afford the 4a; yield: 77 mg
enantioselective synthesis of arylglycine derivatives
from ethyl glyoxylate, p-toluenesulfonyl isocyanate
(65%).
and arylboronic acids giving moderate to good yields
and enantioselectivity has been developed. In this re-
action, the formation of imino esters and the addition
of arylboronic acids can be accomplished in one pot,
providing a convenient and efficient method for the
Acknowledgements
synthesis of arylglycines.
This work was supported by the Major State Basic Research
Program (2006CB806105). We also thank the National Natu-
ral Science Foundation of China (20472099, 20423001,
20332060, 20420130645) and Chinese Academy of Sciences
for financial support.
Experimental Section
Typical Procedure
To a Schlenk tube were added p-toluenesulfonyl isocyanate References
(1) (0.355 mmol), ethyl glyoxylate (2) (0.355 mmol),
Pd
A
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